RESUMEN
Mimicking the transition state of tryptophan (Trp) and O2 in the enzymatic reaction is an effective approach to design indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC50 of 82-91 nM, and exhibited selectivity between IDO1 and tryptophan 2,3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.
Asunto(s)
Benzoxazoles , Diseño de Fármacos , Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Lipopolisacáridos , Animales , Ratones , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Células RAW 264.7 , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Benzoxazoles/farmacología , Benzoxazoles/química , Benzoxazoles/síntesis química , Estructura Molecular , Edema/tratamiento farmacológico , Edema/inducido químicamente , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/síntesis química , Relación Dosis-Respuesta a Droga , Inflamación/tratamiento farmacológico , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , MasculinoRESUMEN
Tryptophan dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO) belong to a unique class of heme-based enzymes that insert dioxygen into the essential amino acid, L-tryptophan (Trp), to generate N-formylkynurenine (NFK), a critical metabolite in the kynurenine pathway. Recently, the two dioxygenases were recognized as pivotal cancer immunotherapeutic drug targets, which triggered a great deal of drug discovery targeting them. The advancement of the field is however hampered by the poor understanding of the structural properties of the two enzymes and the mechanisms by which the structures dictate their functions. In this review, we summarize recent findings centered on the structure, function, and dynamics of the human isoforms of the two enzymes.
Asunto(s)
Hemo , Indolamina-Pirrol 2,3,-Dioxigenasa , Triptófano Oxigenasa , Humanos , Triptófano Oxigenasa/metabolismo , Triptófano Oxigenasa/química , Hemo/química , Hemo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Quinurenina/metabolismo , Quinurenina/química , Triptófano/química , Triptófano/metabolismo , AnimalesRESUMEN
Tryptophan (Trp) metabolism plays a vital role in cancer immunity. Indoleamine 2.3-dioxygenase 1 (IDO1), is a crucial enzyme in the metabolic pathway by which Trp is degraded to kynurenine (Kyn). IDO1-mediated Trp metabolites can inhibit tumor immunity and facilitate immune evasion by cancer cells; thus, targeting IDO1 is a potential tumor immunotherapy strategy. Recently, numerous IDO1 inhibitors have been introduced into clinical trials as immunotherapeutic agents for cancer treatment. However, drawbacks such as low oral bioavailability, slow onset of action, and high toxicity are associated with these drugs. With the continuous development of nanotechnology, medicine is gradually entering an era of precision healthcare. Nanodrugs carried by inorganic, lipid, and polymer nanoparticles (NPs) have shown great potential for tumor therapy, providing new ways to overcome tumor diversity and improve therapeutic efficacy. Compared to traditional drugs, nanomedicines offer numerous significant advantages, including a prolonged half-life, low toxicity, targeted delivery, and responsive release. Moreover, based on the physicochemical properties of these nanomaterials (eg, photothermal, ultrasonic response, and chemocatalytic properties), various combination therapeutic strategies have been developed to synergize the effects of IDO1 inhibitors and enhance their anticancer efficacy. This review is an overview of the mechanism by which the Trp-IDO1-Kyn pathway acts in tumor immune escape. The classification of IDO1 inhibitors, their clinical applications, and barriers for translational development are discussed, the use of IDO1 inhibitor-based nanodrug delivery systems as combination therapy strategies is summarized, and the issues faced in their clinical application are elucidated. We expect that this review will provide guidance for the development of IDO1 inhibitor-based nanoparticle nanomedicines that can overcome the limitations of current treatments, improve the efficacy of cancer immunotherapy, and lead to new breakthroughs in the field of cancer immunotherapy.
Asunto(s)
Inmunoterapia , Indolamina-Pirrol 2,3,-Dioxigenasa , Nanopartículas , Neoplasias , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Nanopartículas/química , Animales , Nanomedicina , Triptófano/química , Triptófano/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , QuinureninaRESUMEN
Indoleamine 2,3-dioxygenase-1 (IDO-1) is an enzyme that catalyzes the metabolism of tryptophan (Trp). It is expressed in limited amounts in normal tissues but significantly upregulated during inflammation and infection. Various inflammatory factors, especially IFN-γ, can induce the expression of IDO-1. While extensive research has been conducted on the role of IDO-1 in tumors, its specific role in complex central nervous system tumors such as glioblastoma (GBM) remains unclear. This study aims to explore the role of IDO-1 in the development of GBM and analyze its association with tryptophan levels and CD8+T cell exhaustion in the tumor region. To achieve this, we constructed an orthotopic mouse glioblastoma tumor model to investigate the specific mechanisms between IDO-1, GBM, and CD8+T cell exhaustion. Our results showed that IDO-1 can promote CD8+T cell exhaustion by reducing tryptophan levels. When IDO-1 was knocked down in glioblastoma cells, other cells within the tumor microenvironment upregulated IDO-1 expression to compensate for the loss and enhance immunosuppressive effects. Therefore, the data suggest that the GBM microenvironment controls tryptophan levels by regulating IDO-1 expression, which plays a critical role in immune suppression. These findings support the use of immune therapy in combination with IDO-1 inhibitors or tryptophan supplementation as a potential treatment strategy.
RESUMEN
Obesity activates both innate and adaptive immune responses in adipose tissue. Adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-γ)-producing cluster of differentiation (CD)4+ T cells in adipose tissue of obese subjects. The increased formation of neopterin and degradation of tryptophan may result in decreased T-cell responsiveness and lead to immunodeficiency. The activity of inducible indoleamine 2,3-dioxygenase-1 (IDO1) plays a major role in pro-inflammatory, IFN-γ-dominated settings. The expression of several kynurenine pathway enzyme genes is significantly increased in obesity. IDO1 in obesity shifts tryptophan metabolism from serotonin and melatonin synthesis to the formation of kynurenines and increases the ratio of kynurenine to tryptophan as well as with neopterin production. Reduction in serotonin (5-hydroxytryptamine; 5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. According to the monoamine-deficiency hypothesis, a deficiency of cerebral serotonin is involved in neuropsychiatric symptomatology of depression, mania, and psychosis. Indeed, bipolar disorder (BD) and related cognitive deficits are accompanied by a higher prevalence of overweight and obesity. Furthermore, the accumulation of amyloid-ß in Alzheimer's disease brains has several toxic effects as well as IDO induction. Hence, abdominal obesity is associated with vascular endothelial dysfunction. kynurenines and their ratios are prognostic parameters in coronary artery disease. Increased kynurenine/tryptophan ratio correlates with increased intima-media thickness and represents advanced atherosclerosis. However, after bariatric surgery, weight reduction does not lead to the normalization of IDO1 activity and atherosclerosis. IDO1 is involved in the mechanisms of immune tolerance and in the concept of tumor immuno-editing process in cancer development. Serum IDO1 activity is still used as a parameter in cancer development and growth. IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment. There is an inverse correlation between serum folate concentration and body mass index, thus folate deficiency leads to hyperhomocysteinemia-induced oxidative stress. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated protein-4 synergizes with imatinib, which is an inhibitor of mitochondrial folate-mediated one-carbon (1C) metabolism. Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment.
Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa , Obesidad , Triptófano , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Obesidad/metabolismo , Obesidad/enzimología , Triptófano/metabolismo , Animales , Serotonina/metabolismo , Tejido Adiposo/metabolismo , Quinurenina/metabolismoRESUMEN
Epigenetic changes have long-lasting impacts, which influence the epigenome and are maintained during cell division. Thus, human genome changes have required a very long timescale to become a major contributor to the current obesity pandemic. Whereas bidirectional effects of coronavirus disease 2019 (COVID-19) and obesity pandemics have given the opportunity to explore, how the viral microribonucleic acids (miRNAs) use the human's transcriptional machinery that regulate gene expression at a posttranscriptional level. Obesity and its related comorbidity, type 2 diabetes (T2D), and new-onset diabetes due to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are additional risk factors, which increase the severity of COVID-19 and its related mortality. The higher mortality rate of these patients is dependent on severe cytokine storm, which is the sum of the additional cytokine production by concomitant comorbidities and own cytokine synthesis of COVID-19. Patients with obesity facilitate the SARS-CoV-2 entry to host cell via increasing the host's cell receptor expression and modifying the host cell proteases. After entering the host cells, the SARS-CoV-2 genome directly functions as a messenger ribonucleic acid (mRNA) and encodes a set of nonstructural proteins via processing by the own proteases, main protease (Mpro), and papain-like protease (PLpro) to initiate viral genome replication and transcription. Following viral invasion, SARS-CoV-2 infection reduces insulin secretion via either inducing ß-cell apoptosis or reducing intensity of angiotensin-converting enzyme 2 (ACE2) receptors and leads to new-onset diabetes. Since both T2D and severity of COVID-19 are associated with the increased serum levels of pro-inflammatory cytokines, high glucose levels in T2D aggravate SARS-CoV-2 infection. Elevated neopterin (NPT) value due to persistent interferon gamma (IFN-γ)-mediated monocyte-macrophage activation is an indicator of hyperactivated pro-inflammatory phenotype M1 macrophages. Thus, NPT could be a reliable biomarker for the simultaneously occurring COVID-19-, obesity- and T2D-induced cytokine storm. While host miRNAs attack viral RNAs, viral miRNAs target host transcripts. Eventually, the expression rate and type of miRNAs also are different in COVID-19 patients with different viral loads. It is concluded that specific miRNA signatures in macrophage activation phase may provide an opportunity to become aware of the severity of COVID-19 in patients with obesity and obesity-related T2D.
Asunto(s)
COVID-19 , Síndrome de Activación Macrofágica , Obesidad , SARS-CoV-2 , Humanos , COVID-19/virología , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/complicaciones , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/epidemiología , Obesidad/virología , SARS-CoV-2/fisiología , SARS-CoV-2/patogenicidad , Síndrome de Activación Macrofágica/virología , Síndrome de Activación Macrofágica/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/virología , Diabetes Mellitus Tipo 2/metabolismo , Pandemias , MicroARNs/genética , MicroARNs/metabolismo , Citocinas/metabolismo , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virologíaRESUMEN
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) play a pivotal role in regulating kynurenine catabolism pathway and immunosuppressive environment, which are promising drug targets for cancer immunotherapy. In this work, a variety of isoquinoline derivatives were designed, synthesized and evaluated for the inhibitory activity against IDO1 and TDO. The enzymatic assay and structure-activity relationship studies led to the most potent compound 43b with IC50 values of 0.31 µM for IDO1 and 0.08 µM for TDO, respectively. Surface plasmon resonance (SPR) revealed direct binding affinity of compound 43b to IDO1 and TDO and molecular docking studies were performed to predict the possible binding mode. Further pharmacokinetic study and biological evaluation in vivo showed that 43b displayed acceptable pharmacokinetic profiles and potent antitumor efficacy with low toxicity in B16-F10 tumor model, which might provide some insights into the discovery of novel IDO1/TDO inhibitors for cancer immunotherapy.
RESUMEN
Rationale: Immunosuppressive tumor microenvironment (iTME) plays an important role in carcinogenesis, and some macrophage subsets are associated with iTME generation. However, the sub-population characterization of macrophages in oral carcinogenesis remains largely unclear. Here, we investigated the immunosuppressive status with focus on function of a macrophage subset that expressed indoleamine 2,3 dioxygenase 1 (Macro-IDO1) in oral carcinogenesis. Methods: We built a single cell transcriptome atlas from 3 patients simultaneously containing oral squamous cell carcinoma (OSCC), precancerous oral leukoplakia (preca-OLK) and paracancerous tissue (PCA). Through single-cell RNA sequencing and further validation using multicolor immunofluorescence staining and the in vitro/in vivo experiments, the immunosuppressive cell profiles were built and the role of a macrophage subset that expressed indoleamine 2,3 dioxygenase 1 (Macro-IDO1) in the malignant transformation of oral leukoplakia was evaluated. Results: The iTME formed at preca-OLK stage, as evidenced by increased exhausted T cells, Tregs and some special subsets of macrophages and fibroblasts. Macro-IDO1 was predominantly enriched in preca-OLK and OSCC, distributed near exhausted T cells and possessed tumor associated macrophage transformation potentials. Functional analysis revealed the established immunosuppressive role of Macro-IDO1 in preca-OLK and OSCC: enriching the immunosuppression related genes; having an established level of immune checkpoint score; exerting strong immunosuppressive interaction with T cells; positively correlating with the CD8-exhausted. The immunosuppression related gene expression of macrophages also increased in preca-OLK/OSCC compared to PCA. The use of the IDO1 inhibitor reduced 4NQO induced oral carcinogenesis in mice. Mechanistically, IFN-γ-JAK-STAT pathway was associated with IDO1 upregulation in OLK and OSCC. Conclusions: These results highlight that Macro-IDO1-enriched in preca-OLK possesses a strong immunosuppressive role and contributes to oral carcinogenesis, providing a potential target for preventing precancerous legions from transformation into OSCC.
Asunto(s)
Transformación Celular Neoplásica , Indolamina-Pirrol 2,3,-Dioxigenasa , Leucoplasia Bucal , Macrófagos , Neoplasias de la Boca , Análisis de la Célula Individual , Microambiente Tumoral , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Leucoplasia Bucal/inmunología , Leucoplasia Bucal/genética , Leucoplasia Bucal/patología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Ratones , Microambiente Tumoral/inmunología , Transformación Celular Neoplásica/genética , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Análisis de la Célula Individual/métodos , Análisis de Secuencia de ARN , Masculino , Tolerancia Inmunológica , Femenino , Carcinogénesis/inmunología , Carcinogénesis/genéticaRESUMEN
Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment.
Asunto(s)
Neoplasias del Colon , Inmunoterapia , Micelas , Fototerapia , Polímeros , Receptor de Muerte Celular Programada 1 , Animales , Neoplasias del Colon/terapia , Neoplasias del Colon/inmunología , Neoplasias del Colon/tratamiento farmacológico , Ratones , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Polímeros/química , Línea Celular Tumoral , Fototerapia/métodos , Verde de Indocianina/química , Verde de Indocianina/uso terapéutico , Verde de Indocianina/farmacología , Ratones Endogámicos BALB C , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fotoquimioterapia/métodos , Femenino , Humanos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Lípido A/análogos & derivadosRESUMEN
BACKGROUND: Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. METHODS: Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis. RESULTS: We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. CONCLUSIONS: Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.
RESUMEN
Although therapies based on mesenchymal stromal cells (MSCs) are being implemented in clinical settings, many aspects regarding these procedures require further optimization. Domestic dogs suffer from numerous immune-mediated diseases similar to those found in humans. This study aimed to assess the immunomodulatory activity of canine (c) Wharton jelly (WJ)-derived MSCs and refer them to human (h) MSCs isolated from the same tissue. Canine MSC(WJ)s appeared to be more prone to in vitro aging than their human counterparts. Both canine and human MSC(WJ)s significantly inhibited the activation as well as proliferation of CD4+ and CD8+ T cells. The treatment with IFNγ significantly upregulated indoleamine-2,3-dioxygenase 1 (IDO1) synthesis in human and canine MSC(WJ)s, and the addition of poly(I:C), TLR3 ligand, synergized this effect in cells from both species. Unstimulated human and canine MSC(WJ)s released TGFß at the same level (p > 0.05). IFNγ significantly increased the secretion of TGFß in cells from both species (p < 0.05); however, this response was significantly stronger in human cells than in canine cells. Although the properties of canine and human MSC(WJ)s differ in detail, cells from both species inhibit the proliferation of activated T cells to a very similar degree and respond to pro-inflammatory stimulation by enhancing their anti-inflammatory activity. These results suggest that testing MSC transplantation in naturally occurring immune-mediated diseases in dogs may have high translational value for human clinical trials.
Asunto(s)
Proliferación Celular , Células Madre Mesenquimatosas , Gelatina de Wharton , Perros , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/citología , Animales , Humanos , Gelatina de Wharton/citología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Inmunomodulación , Interferón gamma/metabolismo , Células Cultivadas , Factor de Crecimiento Transformador beta/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Activación de Linfocitos/inmunología , Poli I-C/farmacología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismoRESUMEN
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.
Asunto(s)
Inflamación , Quinurenina , Humanos , Quinurenina/metabolismo , Inflamación/tratamiento farmacológico , Animales , Terapia Molecular Dirigida , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidoresRESUMEN
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are attractive drug targets for cancer immunotherapy. After disappointing results of the epacadostat as a selective IDO inhibitor in phase III clinical trials, there is much interest in the development of the TDO selective inhibitors. In the current study, several data analysis methods and machine learning approaches including logistic regression, Random Forest, XGBoost and Support Vector Machines were used to model a data set of compounds retrieved from ChEMBL. Models based on the Morgan fingerprints revealed notable fragments for the selective inhibition of the IDO, TDO or both. Multiple fragment docking was performed to find the best set of bound fragments and their orientation in the space for efficient linking. Linking the fragments and optimization of the final molecules were accomplished by means of an artificial intelligence generative framework. Finally, selectivity of the optimized molecules was assessed and the top 4 lead molecules were filtered through PAINS, Brenk and NIH filters. Results indicated that phenyloxalamide, fluoroquinoline, and 3-bromo-4-fluroaniline confer selectivity towards the IDO inhibition. Correspondingly, 1-benzyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione was found to be an integral fragment for the selective inhibition of the TDO by constituting a coordination bond with the Fe atom of heme. In addition, furo[2,3-c]pyridine-2,3-diamine was found as a common fragment for inhibition of the both targets and can be used in the design of the dual target inhibitors of the IDO and TDO. The new fragments introduced here can be a useful building blocks for incorporation into the selective TDO or dual IDO/TDO inhibitors.
Asunto(s)
Quimioinformática , Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Aprendizaje Automático , Triptófano Oxigenasa , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Triptófano Oxigenasa/antagonistas & inhibidores , Triptófano Oxigenasa/metabolismo , Triptófano Oxigenasa/química , Humanos , Quimioinformática/métodos , Inhibidores Enzimáticos/química , Simulación del Acoplamiento MolecularRESUMEN
For mammary carcinomas in pet rabbits, prognostic biomarkers are poorly defined, and treatment is limited to surgical excision. Additional treatment options are needed for rabbit patients for which surgery is not a suitable option. In human breast cancer, the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) represents a prognostic biomarker and possible therapeutic target. This retrospective immunohistochemical study examined IDO1 in 96 pet rabbit mammary carcinomas with known mitotic count, hormone receptor status, and percentage of stromal tumor infiltrating lymphocytes (TILs). Tumors were obtained from 96 pet rabbits with an average of 5.5 years. All rabbits with reported sex (n = 88) were female or female-spayed. Of the carcinomas, 94% expressed IDO1, and 86% had sparse TILs consistent with cold tumors. Statistically significant correlations existed between a higher percentage of IDO1-positive tumor cells, lower mitotic counts, and increased estrogen receptor expression. The threshold for significance was IDO1 staining in >10% of tumor cells. These results lead to the assumption that IDO1 expression contributes to tumorigenesis and may represent a prognostic biomarker and possible therapeutic target also in pet rabbit mammary carcinomas. They also support the value of rabbits for breast cancer research.
RESUMEN
(1) Background: Kidney transplantation is the best therapy for patients with end-stage renal disease, but the risk of rejection complicates it. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme involved in immune response modulation, has been suggested to play a role in transplant immunological injury. The aim of the study was to explore the expression of IDO1 in the interstitial foci of transplanted kidneys and its potential association with rejection episodes. (2) Methods: This retrospective study analysed kidney transplant biopsies from 121 patients, focusing on IDO1 expression in interstitial foci. Immunohistochemistry was used to detect IDO1, and patients were categorised based on IDO1 presence (IDO1-IF positive or negative). The incidence of rejection was compared between these groups. (3) Results: Patients with IDO1 expression in interstitial foci (IDO1-IF(+)) exhibited higher incidences of rejection 46/80 (57.5%) vs. 10/41 (24.34%) patients compared to IDO1-IF(-) patients, which was statistically significant with p = 0.0005. The analysis of antibody-mediated rejection showed that IDO1-IF(+) patients developed AMR at 12/80 (15%), while only 1 IDO1-IF(-) negative patient did (2,44%), with p = 0.035. T-cell-mediated rejection was also more common in IDO1-IF(+) patients 43/80 (53.75%) than in IDO1-IF(-) patients 7/41 (17.07%), with p = 0.0001. (4) Conclusions: IDO1 expression in interstitial foci of renal transplant biopsies is associated with a higher incidence of rejection, suggesting that IDO1 could serve as a potential biomarker for transplant rejection. These findings highlight the importance of IDO1 in immune regulation and its potential utility in improving the management of kidney transplant recipients.
RESUMEN
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.
RESUMEN
BACKGROUND/AIM: Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme in tryptophan metabolism and plays an important role in immunosuppression. The effects of IDO1 on tumor invasion and metastasis have been studied in several types of malignancies. However, the role of IDO1 in these steps in colorectal cancer (CRC) has not been elucidated. Therefore, we aimed to investigate the effects of IDO1 on invasion, migration, and epithelial-mesenchymal transition (EMT) in CRC cells. MATERIALS AND METHODS: All experiments were performed using the DLD-1 colon cancer cell line that expresses IDO1. We conducted a scratch wound healing assay and Boyden chamber assay to investigate the impact of IDO1 on DLD-1 cell migration and invasion, respectively, in the presence and absence of the IDO1 inhibitor L-1-methyl-tryptophan (L-1-MT). Additionally, western blotting was performed to analyze alterations in the expression of EMT-related markers caused by L-1-MT. RESULTS: High expression of IDO1 was confirmed in the cytoplasm of DLD-1 by immunofluorescence staining. In the scratch wound healing assay, the invasion ability of DLD-1 cells decreased to 62% after treatment with L-1-MT at 1,000 µM for 24 h. In the Boyden chamber assay, the migration of DLD-1 cells was suppressed by 85% after treatment with L-1-MT at 2,500 µM for 24 h. L-1-MT treatment increased the expression level of E-cadherin and decreased the expression levels of vimentin, Snail, and Slug. CONCLUSION: IDO1 inhibition reduced the invasion and migration ability of IDO1-expressing DLD-1 colon cancer cells, which was accompanied by altered expression of EMT-related proteins. IDO1 could be a potential target for the treatment of advanced CRC.
Asunto(s)
Movimiento Celular , Neoplasias del Colon , Transición Epitelial-Mesenquimal , Indolamina-Pirrol 2,3,-Dioxigenasa , Invasividad Neoplásica , Triptófano , Humanos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Línea Celular Tumoral , Triptófano/análogos & derivados , Triptófano/farmacología , Triptófano/metabolismo , Inhibidores Enzimáticos/farmacologíaRESUMEN
Soil and groundwater were investigated for the genes encoding soluble and particulate methane monooxygenase/ammonia monooxygenase (sMMO, pMMO/AMO), toluene 4-monooxygenase (T4MO), propane monooxygenase (PMO) and phenol hydroxylase (PH). The objectives were (1) to determine which subunits were present, (2) to examine the diversity of the phylotypes associated with the biomarkers and (3) to identify which metagenome associated genomes (MAGs) contained these subunits. All T4MO and PH subunits were annotated in the groundwater metagenomes, while few were annotated in the soil metagenomes. The majority of the soil metagenomes included only four sMMO subunits. Only two groundwater metagenomes contained five sMMO subunits. Gene counts for the pMMO subunits varied between samples. The majority of the soil metagenomes were annotated for all four PMO subunits, while three out of eight groundwater metagenomes contained all four PMO subunits. A comparison of the blast alignments for the sMMO alpha chain (mmoX) indicated the phylotypes differed between the soil and groundwater metagenomes. For the pMMO/AMO alpha subunit (pmoA/amoA), Nitrosospira was important for the soil metagenomes, while Methylosinus and Methylocystis were dominant for the groundwater metagenomes. The majority of pmoA alignments from both metagenomes were from uncultured bacteria. High quality MAGs were obtained from the groundwater data. Four MAGs (Methylocella and Cypionkella) contained sMMO subunits. Another three MAGs, within the order Pseudomonadales, contained all three pMMO subunits. All PH subunits were detected in seven MAGs (Azonexus, Rhodoferax, Aquabacterium). In those seven, all contained catechol 2,3-dioxagenase, and Aquabacterium also contained catechol 1,2-dioxygenase. T4MO subunits were detected in eight MAGs (Azonexus, Rhodoferax, Siculibacillus) and all, except one, contained all six subunits. Four MAGs (Rhodoferax and Azonexus) contained all subunits for PH and T4MO, as well as catechol 2,3-dixoygenase. The detection of T4MO and PH in groundwater metagenomes and MAGs has important implications for the potential oxidation of groundwater contaminants.
Asunto(s)
Agua Subterránea , Metagenoma , Oxigenasas , Filogenia , Microbiología del Suelo , Agua Subterránea/microbiología , Agua Subterránea/química , Oxigenasas/genética , Oxigenasas/metabolismo , Bacterias/genética , Bacterias/clasificación , Bacterias/enzimología , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Citocromo P-450 CYP4A/genética , Citocromo P-450 CYP4A/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Oxigenasas de Función MixtaRESUMEN
Di-n-butyl phthalate (DBP) is one of the important phthalates detected commonly in soils and crops, posing serious threat to human health. Pseudochrobactrum sp. XF203 (XF203), a new strain related with DBP biodegradation, was first identified from a natural habitat lacking human disturbance. Genomic analysis coupled with gene expression comparison assay revealed this strain harbors the key aromatic ring-cleaving gene catE203 (encoding catechol 2,3-dioxygenase/C23O) involved DBP biodegradation. Following intermediates identification and enzymatic analysis also indicated a C23O dependent DBP lysis pathway in XF203. The gene directed ribosome engineering was operated and to generate a desirable mutant strain XF203R with highest catE203 gene expression level and strong DBP degrading ability. The X203R removed DBP in soil jointly by reassembling bacterial community. These results demonstrate a great value of XF203R for the practical DBP bioremediation application, highlighting the important role of the key gene-directed ribosome engineering in mining multi-pollutants degrading bacteria from natural habitats where various functional genes are well conserved.
Asunto(s)
Biodegradación Ambiental , Dibutil Ftalato , Ribosomas , Contaminantes del Suelo , Contaminantes del Suelo/metabolismo , Dibutil Ftalato/metabolismo , Ribosomas/metabolismo , Microbiología del Suelo , Expresión Génica , Burkholderiaceae/metabolismo , Burkholderiaceae/genéticaRESUMEN
Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.