Letteratura scientifica selezionata sul tema "IDO/TDO"
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Articoli di riviste sul tema "IDO/TDO":
1
Oweira, Hani, Imad Lahdou, Stefan Mehrle, Elias Khajeh, Rajan Nikbakhsh, Omid Ghamarnejad, Peter Terness, Christoph Reißfelder, Mahmoud Sadeghi e Ali Ramouz. "Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepG2 Tumor Cells". Journal of Clinical Medicine 11, n. 16 (16 agosto 2022): 4794. http://dx.doi.org/10.3390/jcm11164794.
Abstract (sommario):
There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.
2
Terai, Londin, Rochani, Link, Lam, Kaushal, Bhushan, Orloff e Sato. "Expression of Tryptophan 2,3-Dioxygenase in Metastatic Uveal Melanoma". Cancers 12, n. 2 (10 febbraio 2020): 405. http://dx.doi.org/10.3390/cancers12020405.
Abstract (sommario):
Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all hepatic metastasis. TDO was positive in both normal hepatocytes and the tumor cells with relatively higher expression in tumor cells. On the other hand, IDO protein remained undetectable in all of the MUM specimens. UM cell lines established from metastasis also expressed TDO protein and increasing kynurenine levels were detected in the supernatant of MUM cell culture. In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3. These results indicate that TDO might be one of the key mechanisms for resistance to immunotherapy in UM.
3
Kim, Chan, Joo Hoon Kim, Jin Sung Kim, Hong Jae Chon e Joo-Hang Kim. "A novel dual inhibitor of IDO and TDO, CMG017, potently suppresses the kynurenine pathway and overcomes resistance to immune checkpoint inhibitors." Journal of Clinical Oncology 37, n. 15_suppl (20 maggio 2019): e14228-e14228. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14228.
Abstract (sommario):
e14228 Background: Kynurenine production by indoleamine 2,3-dioxygenase (IDO) is critical for tumor immune suppression through effector T cell anergy and regulatory T cell proliferation. This has led to the rapid development of IDO inhibitors for cancer immunotherapy. However, results from recent clinical trials have been disappointing and this is partly due to pathway redundancy. Tryptophan 2,3-dioxygenase (TDO), another important enzyme of the kynurenine pathway, plays a compensatory role in the absence of IDO activity. Therefore, we developed a dual inhibitor of IDO and TDO to achieve maximal inhibition of the kynurenine pathway and alleviate tumor immune suppression. Methods: Small-molecule inhibitors of IDO and TDO were synthesized and evaluated using in vitro cell-based assays. Pharmacokinetic and pharmacodynamic profiles were assessed for these inhibitors. Tumor-bearing mice were treated with CMG017 per os, either alone or in combination with immune checkpoint inhibitors (ICIs). The tumor microenvironment (TME) was assessed through histological, flow-cytometric, and Nanostring immune profiling analyses. Results: CMG017 suppressed kynurenine production more effectively than inhibitors targeting either IDO or TDO alone, in various human and murine cancer cell lines. Single administration of CMG017 showed favorable pharmacokinetic profiles compared with an IDO1 selective inhibitor. Repeated once-daily per os administration of CMG017 decreased kynurenine concentration in both tumors and plasma of tumor-bearing mice and delayed tumor growth without significant toxicity. CMG017 induced dramatic changes in immune-related genes in TME and enhanced intratumoral infiltration of CD8+ effector T cells. The anti-tumor activity of CMG017 was almost negated when T cells were depleted, indicating the importance of adaptive immunity for the in vivo efficacy of CMG017. Of note, combination immunotherapy of CMG017 with ICIs (anti-PD-1 and anti-CTLA-4) led to durable tumor regression and long-term overall survival. Mice with complete tumor regression were immune to tumor re-challenge, indicating the establishment of immunological memory. Conclusions: CMG017, a dual inhibitor of IDO and TDO, potently suppressed the kynurenine pathway and showed promising anti-cancer efficacy, with favorable pharmacologic profiles.
4
Campesato, Luis Felipe, Sadna Budhu, Jeremy Tchaicha, Abhinav Jaiswal, Mathieu Gigoux, Stephane Pourpe, Cailian Liu et al. "Blockade of IDO/TDO downstream effectors restricts cancer immune suppression". Journal of Immunology 202, n. 1_Supplement (1 maggio 2019): 137.3. http://dx.doi.org/10.4049/jimmunol.202.supp.137.3.
Abstract (sommario):
Abstract Immune checkpoint blockade (ICB) results in clinical benefit for a subset of cancer patients, yet multiple mechanisms of resistance can impair optimal response. The catabolism of tryptophan into metabolites known as kynurenines (Kyn) by the expression of enzymes such as IDO or TDO is a frequent phenomenon that plays a suppressive role in tumor immunity. Recently it was shown that Kyn acts as agonist of the aryl hydrocarbon receptor (AHR). Here we sought to characterize the mechanisms of immune suppression associated with the AHR pathway and to evaluate its potential as therapeutic target. RNAseq analysis of human cancers revealed a correlation between the expressions of AHR-related genes with markers associated with immunotherapy resistance (PD-1, FOXP3, CD206). By using IDO or TDO-overexpressing variants of a melanoma cell model (B16-F10), we found that myeloid cells, such as tumor-associated macrophages (TAMs) and dendritic cells (DCs), present up-regulation of the AHR. IDO-expressing tumors (B16-IDO) show higher myeloid cell infiltration, which present a tolerogenic phenotype. Tumor-antigen specific CD8T cells present reduced expression of activation markers and proliferation rate when primed by Kyn-treated BMDCs. Treatment of B16-IDO-bearing mice with an AHR-specific antagonist (CH-223191) leads to an increase of MHC II in TAMs, of activation markers in CD8 T cells and reduced frequency of T-regs. AHR inhibition delays progression of tumors with an active IDO/TDO/Kyn pathway (B16-IDO and B16-TDO), and efficacy is further improved when ICB is used in combination. In summary, our findings demonstrate that targeting the Kyn pathway through AHR inhibition could overcome key suppressive mechanisms and sensitize tumors to ICB.
5
Thackray, Sarah J., Christopher G. Mowat e Stephen K. Chapman. "Exploring the mechanism of tryptophan 2,3-dioxygenase". Biochemical Society Transactions 36, n. 6 (19 novembre 2008): 1120–23. http://dx.doi.org/10.1042/bst0361120.
Abstract (sommario):
The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes.
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Oxenkrug, G. "Genetic and Environmental Impacts in Major Depressive Disorder are Mediated Via Kynurenine Pathway of Tryptophan Metabolism". European Psychiatry 24, S1 (gennaio 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70899-5.
Abstract (sommario):
We were first to propose up-regulation of KYN pathway of TRY metabolism as an etiological factor in depression: “in depression metabolism of TRY is shunted away from serotonin production, and towards KYN production” since “activity of liver TRY-pyrrolase is stimulated by raised blood corticosteroids levels” (Lapin & Oxenkrug, Lancet, 1969). TRY-pyrrolase, i.e., tryptophan-2,3-dioxygenase (TDO) was the only known enzyme catalyzing TRY conversion into KYN. TDO is mostly located in liver and activated by cortisol and prolactin. Seven years later another enzyme catalyzing TRY conversion into KYN, indoleamine-2,3-dioxygenase (IDO), was discovered. IDO is located in microglia, astrocytes and macrophages, and transcriptionally induced by pro-inflammatory cytokines. Discovery of neurotropic activity of kynurenines suggested that upregulation of TRY - KYN pathway not only augments serotonin deficiency but also underlines depression-associated anxiety, psychosis and cognitive decline. Simultaneous presence of high promoters alleles of pro-inflammatory cytokines genes (IFNG and TNF-alpha) determines genetic predisposition to depression via up-regulation of IDO while impact of environmental stresses is mediated via hormonal activation of TDO. Potentiation of IFNG-induced up-regulation of IDO by stress hormones further underscores the importance TRY-KYN pathway as major meeting point of gene-environment interaction in depression and as a new target for pharmacological intervention.
7
SUZUKI, Sachiko, Shigenobu TONÉ, Osamu TAKIKAWA, Toshikazu KUBO, Ichiro KOHNO e Yohsuke MINATOGAWA. "Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti". Biochemical Journal 355, n. 2 (6 aprile 2001): 425–29. http://dx.doi.org/10.1042/bj3550425.
Abstract (sommario):
Indoleamine 2,3-dioxygenase (IDO)-initiated tryptophan degradation in the placenta has been implicated in the prevention of the allogeneic fetus rejection [Munn, Zhou, Attwood, Bondarev, Conway, Marshall, Brown, and Mellor (1998) Science 281, 1191-1193]. To determine how IDO is associated with the development of the fetus and placenta, the time course of IDO expression (tryptophan-degrading activity, IDO protein and IDO mRNA) in the embryonic and extra-embryonic tissues as well as maternal tissues of mice was examined. A high tryptophan-degrading activity was detected in early concepti on days 6.5 and 7.5, whereas IDO protein and its mRNA were not expressed during early gestation, but appeared 2-3 days later, lasted for about 3 days and declined rapidly thereafter. The expression of IDO basically coincided with the formation of the placenta. On the contrary, the early tryptophan-degrading activity was due to gene expression of tryptophan 2,3-dioxygenase (TDO), as shown by Northern and Western analysis. These findings indicate that IDO is transiently expressed in the placenta but that the expression does not last until birth, and that the IDO expression is preceded by expression of another tryptophan-degrading enzyme, TDO, in the maternal and/or embryonic tissues in early concepti.
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Nienhaus, Karin, e G. Ulrich Nienhaus. "Co Recombination in Human IDO and TDO - A Comparison". Biophysical Journal 106, n. 2 (gennaio 2014): 676a. http://dx.doi.org/10.1016/j.bpj.2013.11.3744.
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Sacramento, Jireh Joy D., e David P. Goldberg. "Oxidation of an indole substrate by porphyrin iron(iii) superoxide: relevance to indoleamine and tryptophan 2,3-dioxygenases". Chemical Communications 56, n. 20 (2020): 3089–92. http://dx.doi.org/10.1039/c9cc10019a.
Abstract (sommario):
Reaction of FeIII(O2˙−)(TPP) with 2,3-dimethylindole at low temperature leads to the ring-cleaved, dioxygenated product, N-(2-acetyl-phenyl)-acetamide, analogous to TDO/IDO enzymes.
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Paccosi, Sara, Marta Cecchi, Angela Silvano, Sergio Fabbri e Astrid Parenti. "Different effects of tryptophan 2,3-dioxygenase inhibition on SK-Mel-28 and HCT-8 cancer cell lines". Journal of Cancer Research and Clinical Oncology 146, n. 12 (10 agosto 2020): 3155–63. http://dx.doi.org/10.1007/s00432-020-03351-2.
Abstract (sommario):
Abstract Purpose Indoleamine 2,3-dioxygenase-1 (IDO1) and more recently, tryptophan 2,3-dioxygenase (TDO), are tryptophan-catabolizing enzymes with immunoregulatory properties in cancer. IDO1 is more expressed than TDO in many tumours including melanomas; however, IDO inhibitors did not give expected results in clinical trials, highlighting the need to consider TDO. We aimed to characterize both TDO expression and function in a melanoma cell line, named SK-Mel-28, with the purpose to compare it with a colon cancer cell line, HCT-8, and with a human endothelial cell line (HUVEC). Methods TDO expression was assessed as real time-PCR and western blot, for mRNA and protein expression, respectively. While cell proliferation was assessed as cell duplication, cell apoptosis and cell cycle were analysed by means of flow cytometry. Results SK-Mel-28 cells showed higher TDO levels compared to HCT-8 and to HUVEC cells. A selective TDO inhibitor, 680C91, significantly impaired cell proliferation in a concentration-dependent manner, by inducing cell arrest during the G2 phase for SK-Mel-28 and HUVEC cells, while an early apoptosis was increasing in HCT-8 cells. No toxic effects were observed. These data demonstrated that TDO is highly expressed in SK-Mel-28 cells and may be involved in the regulation of their proliferation. Conclusion TDO may directly modulate cancer cell function rather than immune suppression and can be considered as a target for melanoma progression together with IDO1.
Tesi sul tema "IDO/TDO":
1
Julio, Ariane Rivellis. "Desenvolvimento e validação de métodos bioanalíticos para o monitoramento dos produtos das vias metabólicas do triptofano em linhagem celular de glioma humano". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-28042016-105250/.
Abstract (sommario):
O metabolismo do triptofano (Trp) se dá pela via das quinureninas (QUIN), pela via serotoninérgica (SER) e pela via das aminas traço. A primeira gera QUIN e uma variedade de outros metabólitos secundários. Quando conduzida pela enzima indolamina 2,3 dioxigenase (IDO) contribui para os fenômenos de tolerância e imune escape de células tumorais; e quando conduzida pela triptofano 2,3 dioxigenase (TDO) no fígado, participa na síntese da niacina e NAD. A via SER leva à formação do neurotransmissor serotonina (SER), que pode gerar o hormônio melatonina (MEL), respectivamente e outros metabólitos biologicamente ativos. Outra via menos estudada, a via das aminas traço, produz produtos neuroativos. Dada a abrangência e importância das rotas metabólicas do Trp, nós desenvolvemos e validamos uma metodologia bioanalítica robusta, seletiva e sensível por cromatografia líquida de alta eficiência (HPLC), acoplado espectrometria de massas (MS) para a determinação simultânea do Trp e seus 15 metabólitos. Para tanto, escolhemos para a avaliação das três vias, linhagens de glioma humano. A escolha por este tipo celular deveu-se ao grande interesse de estudos de metabolismo de Trp em células tumorais, no qual células de glioma tem sido modelo. Nos ensaios com as células de glioma acompanhamos os efeitos de um indutor e inibidores da primeira etapa de metabolização do Trp pela via das quinureninas, ou seja, IFN-γ (indutor da IDO), 1-metiltriptofano (1-MT; inibidor competitivo da IDO) e 680C91 (inibidor seletivo da TDO). Pudemos observar o impacto que a indução ou a inibição do primeiro passo teve sobre os metabólitos subsequentes e as diferenças no metabolismo das duas linhagens estudadas, A172 e T98G. A linhagem T98G só tem atividade de IDO, enquanto que a A172 tem tanto atividade IDO quanto TDO. A indução por IFN-γ mostrou que essa citocina não só atua na formação da via QUIN, mas possui um impacto modesto nas demais rotas. Observamos também que a inibição do 1-MT mostrou seu impacto nos metabólitos invdividualmente, do que a simples relação Trp-QUIN. Contudo, nosso resultados nos permitiu mostrar pela primeira vez a descrição completa dessas vias, em especial nessas linhagens celulares, podendo supor estratégias terapêuticas nessas rotas que estão relacionadas a progressão ou não tumoral.The tryptophan metabolism (Trp) takes place by means of kynurenine (QUIN), by the serotonin pathway (SER) and by the pathway of trace amines synthesis. The first generates QUIN and a variety of other secondary metabolites. When driven by the enzyme indoleamine 2,3 dioxygenase (IDO) contributes to the phenomena of tolerance and immune escape of tumor cells; and when conducted by tryptophan 2,3 -dioxygenase (TDO) in the liver, participates in the niacin synthesis NAD. The SER pathway leads to the serotonin neurotransmitter (SER) formation, which can generate the hormone melatonin (MEL), respectively and other biologically active metabolites. Another less studied amines trace synthesis pathway produces neuroactive products. Given the scope and importance of Trp metabolic pathways,we developed and validated a robust, sensitive and selective bioanalytical method by high performance liquid chromatography (HPLC) coupled mass spectrometry (MS) for simultaneous determination of TRP and its 16 metabolites. Therefore, we chose to evaluate the three routes, glioma cell lines. The initial choice of this type of cell was due to the great interest in Trp metabolism studies in tumor cells, which glioma cells has been a model. In assays with glioma cells, we followed the effects of an inductor and inhibitors of the first stage of Trp metabolism, via the kynurenine pathway, or IFN -γ (IDO inducer) 1- methyltryptophane (1- MT; competitive IDO inhibitor) and 680C91 (selective TDO inhibitor). We could observe the first step induction or inhibition impact had over the further metabolites and the metabolism differences between the two studied strains, A172 and T98G. The T98G glioma cell has only IDO activity, while the A172 has both IDO and TDO activity as well. The IFN-γ indution showed that this cytokine not only acts in the formation of QUIN route, but has a modest impact on the others routes. Inhibition of IDO showed that the competitive inhibitor has activity in itself than a simple Trp-QUIN relationship. However, our results allow us to show the first time the complete description of these pathways, in particular, in these cell lines that can assume therapeutic strategies in these routes that are related or not with tumor progression.
2
Pantouris, Georgios. "Insights into inhibition of heme-dependent dioxygenases". Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/7714.
Abstract (sommario):
Tryptophan 2,3-dioxygenase (TDO), along with indoleamine 2,3-dioxygenase (IDO) and indoleamine 2,3-dioxygenase-2 (IDO2) are the three enzymes that catalyse oxidation of L-tryptophan (L-Trp) in the first step of the kynurenine pathway. Despite the fact that all three catalyse the same reaction, they were detected and characterized in different chronological periods; TDO, IDO and IDO2 were discovered in 1936, 1967 and 2007 respectively. Years of studies showed that abnormal regulation of L-Trp, in the first step of kynurenine pathway, is related with several disorders, including cancer. Regardless of their distinct dissimilarities, TDO, IDO and IDO2 were all detected in various cancers, supporting tumour escape and survival. The early identification of IDO immunomodulatory action (1990s) led to intense research for the development of IDO inhibitors, but not TDO. Despite this effort, the most pharmacologically suitable IDO inhibitor, 1-methyltryptophan (1- MT), appears to be ineffective as monotherapeutic drug. Discovery of IDO2 showed that 1-MT action is not fully understood, raising questions about the biological significance of IDO2. The ultimate goal of the current study was to address the problems outlined above. Because TDO and IDO are two druggable molecular targets, the discovery of a new class of effective inhibitors was pursued. Plate screening of ~2800 potential inhibitor compounds obtained from National Cancer Institute (NCI), USA, indicated seven promising compounds that inhibit both TDO and IDO in either nanomolar or low micromolar range. Interestingly, of these seven inhibitors, six have been identified to have cytotoxic action against several types of tumour cell lines (NCI data). NSC 26326, known as b-lapachone, is a natural occurring quinone and the strongest inhibitor of all seven. This NCI compound inhibits both TDO and IDO with inhibition constants of ~30-70 nM and 97 ± 14 nM respectively. Like NSC 26326, NSC 36398 is another natural occurring product and the only compound that showed selectivity against TDO with inhibition constant of 16.3 ± 3.8 μM. Among the seven compounds that displayed promise as inhibitors of TDO and IDO was mitomycin C. Mitomycin C, which is an approved oncology drug and a known inhibitor of IDO (Ki = 24.2 ± 1.2 μM), is also inhibitor of TDO with inhibition constant of 2.86 ± 0.03 μM. Another major goal of the current work was the discovery of isatin derivatives as inhibitors of TDO and IDO. Using the tryptophan-like structure of isatin as starting point, a number of structural modifications were carried out (structureactivity relationship (SAR)) succeeding the optimization of their inhibition activity. This new family of TDO and IDO inhibitors demonstrated inhibition potencies in the low micromolar range with 5,7-dicholoisatin to reach the nanomolar range (in the case of TDO). Halogenation of isatin and its derivatives was found to increase noticeably the inhibition potencies of these molecules by 12fold and 6fold for TDO and IDO respectively while breakdown of isatin’s pyrrolidine ring had a disastrous result on the inhibition of both enzymes. Combinations of 1-MT with either the newly-identified NCI inhibitors or the isatin derivatives were also examined. The in vitro combinations of 1-MT with either the NCI inhibitors or the isatin derivatives revealed an additive effect without though excluding the possibility of synergistic effect in vivo. The specificity of TDO, IDO and IDO2 against the two stereoisomers of 1- MT was also investigated, with interesting results. While IDO is inhibited only by the L-isoform of 1-MT (Ki = 18.0 ± 3.4 μM), IDO2 is inhibited by both 1-Me-L-Trp and 1-Me-D-Trp with inhibition constants of 306 ± 17 μM and 3419 ± 259 μM respectively. Biochemical characterization of human IDO2 was another goal of the current thesis, which completed successfully. Kinetic, redox and inhibition study of human IDO2 indicated significant differences in comparison with human IDO something which suggests the potential implication of IDO2 in an identified biological pathway (other than tryptophan catabolism function).The findings presented herein help to solve the mystery of 1-MT action, at least in vitro, give answers in regards to IDO2 function, and provide a number of new, promising inhibitors for TDO and IDO.
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Branquinho, Maryana Stephany Ferreira. "Efeitos dos inibidores de IDO e TDO na proliferação, migração e invasão de melanomas humanos e na atividade tumoricida de células mononucleares". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-11112015-142104/.
Abstract (sommario):
No câncer, o aumento da expressão das enzimas indolamina 2,3-dioxigenase 1 (IDO1) e triptofano 2,3-dioxigenase (TDO), que convertem o triptofano (Trp) em quinurenina (QUIN), tem sido associado ao mecanismo de imuno escape tumoral e inibidores destas enzimas têm sido considerados como imunoadjuvantes na terapia antitumoral. O mais conhecido deles é o 1-metil-triptofano (1-MT), um inibidor competitivo da IDO e alvo de estudos clínicos. O 1-MT é encontrado nas formas enantioméricas D- e L- e embora o enantiômero 1-L-MT seja mais eficiente na inibição da IDO1 (a isoforma mais ativa em tumores), é o 1-D-MT o enantiômero mais eficiente na redução experimental de tumores. Esse dado sugere que o 1-MT pode ter ações adicionais à inibição da IDO. Neste estudo avaliamos os efeitos diretos dos estereoisomeros, 1-D-MT, 1-L-MT, 1-DL-MT, sobre melanomas humanos e também do composto 680C91 (um inibidor de TDO). Proliferação, migração e invasão são os ensaios usuais in vitro para avaliar como um determinado composto afetaria a progressão tumoral. Observamos que todos os compostos testados possuem algum efeito direto sobre pelo menos um desses parâmetros, sendo que esse efeito varia de acordo com a linhagem. Logo, todos eles possuem ação direta sobre a célula tumoral que deve contribuir com a atividade antineoplásica. Também analisamos os efeitos destes compostos sobre a ação tumoricida de células mononucleares de sangue periférico humano (PBMC). Em co-culturas, observamos que o 1-MT foi capaz de potencializar a atividade tumoricida de PBMC\'s e levou à diminuição da produção de IFN-γ e TNF-α e aumento de IL-10. Essas alterações não cursam com a inibição da produção de QUIN, o que nos faz pensar que esta ação de 1-MT sobre IFN-γ ocorre independente da enzima IDO e que parte dos efeitos antitumorais da 1-MT seja consequência de sua ação sobre a liberação destas citocinas. 1-MT também levou a modificações na concentração de outros metabólitos do Trp. Por fim, a co-cultura por si só aumentou o consumo de ácido xanturênico (XA) e aumentou a produção de ácido quinurênico (KA). Esse resultado parece significativo para a imunologia de tumores dado os efeitos biológicos destes compostos.In cancer, the increased expression of the enzymes indolamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), that convert tryptophan (Trp) to kynurenine (KYN), has been associated with the mechanism of immune escape of tumoral cells and inhibitors of these enzymes have been considered as immuno-adjuvants in antitumor therapy. The most known is the 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO and a target in clinical trials. 1-MT is found in the enantiomeric forms D- and L- and although 1-L-MT is more efficient to inhibit IDO1 (the isoform more active in tumors), 1-D-MT is more efficient in experimental models. This fact suggests that 1-MT may have additional actions beyond IDO inhibition. In this study, we evaluated the direct effects of 1-D-MT, 1-L-MT and 1-DL-MT on human melanomas. We also tested the effects of the compound 680C91 (an inhibitor of TDO). Proliferation, migration and invasion are the usual in vitro tests to evaluate how a specific compound affects tumor progression. We observed that all of the tested compounds have some direct effect on at least one of these parameters depending on the cell lineage. Therefore, direct effects on proliferation, migration and invasion must compose the antineoplastic activity of these compounds. In co-cultures, we observed that 1-MT was able to potentiate the tumoricidal activity of peripheral blood mononuclear cells (PBMC) and led to a decreased production of IFN-γ and TNF-α, and an increase in IL-10. These changes were not linked with the inhibition of KYN production, and led us to consider that the effect of 1-MT on cytokine production occurs independently of the enzyme IDO and is part of its antitumor effects. 1-MT also led to changes in the concentration of other Trp metabolites. Finally, the co-culture by itself led to an increased consumption of xanthurenic acid (XA) and increased production of kynurenic acid (KA). This result seems significant to the immunology of tumors given the biological effects of these compounds.
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Venancio, Paloma Almeida. "Expressão de indoleamina 2,3-dioxigenase (IDO) e triptofano 2,3-dioxigenase(TDO) no ambiente cervicovaginal normal, na vaginose bacteriana e nas lesões cervicais associadas ao HPV". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/9/9142/tde-12112018-124550/.
Abstract (sommario):
Neste estudo avaliamos o papel do metabolismo do triptofano (Trp) na homeostasia, na vaginose bacteriana e nas lesões cervicais associadas ao HPV. A importância do metabolismo do Trp se deve a sua ação na proliferação de microrganismos e de células do sistema imune. O consumo de triptofano tem sido identificado como uma forma de controlar o crescimento bacteriano limitando a infecção. Por outro lado, a oxidação de Trp produz quinurenina (QUIN), que tem papel chave na tolerância imunológica. A formação de QUIN se dá através das enzimas indoleamina 2,3-dioxigenase (IDO) e triptofano 2,3- dioxigenase (TDO). A mais estudada delas no âmbito das infecções/ imuno escape é a enzima IDO. Mais recentemente, tem-se dado ênfase ao papel da TDO no câncer. Nesta dissertação, o interesse foi avaliar a expressão da IDO no epitélio cervicovaginal de mulheres com vaginose bacteriana e de IDO e TDO em amostras cervicais de mulheres com diferentes graus de lesão cervical associada ao HPV. Foram incluídas 165 mulheres atendidas no CAISM/UNICAMP, as quais foram divididas em dois grupos: grupo caso composto por mulheres com lesão de baixo ou alto grau e carcinoma invasor (n=42) e grupo controle composto por mulheres com citologia oncológica normal, independente de apresentar infecção genital (n=123). IDO foi avaliada por imunocitoquímica em citologia em base líquida e IDO e TDO em biópsias cervicais. Mulheres com vaginose bacteriana apresentaram expressão aumentada de IDO em células escamosas em comparação às mulheres sem vaginose bacteriana (OR=7.41; IC 95%= 2.50 a 21.4; p <0.0001). No epitélio vaginal normal com ou sem infecção por HPV houve uma expressão leve de IDO em células escamosas. Na presença de lesões ou carcinoma, houve um aumento no número de células escamosas displásicas e de leucócitos IDO-positivos; aumento de IDO também pôde ser observada em culturas de pele organotípicas transduzidas com as oncoproteínas E6/ E7 do HPV16. Nas lesões cervicais, assim como visto para a IDO, a TDO esteve expressa em leucócitos, especialmente os infiltrados na região estromal e na parede dos vasos sanguíneos. A expressão basal de IDO no epitélio cervical normal e sua regulação positiva na infecção por HPV e lesões associadas sugerem a participação do metabolismo do Trp nos mecanismos imunossupressores envolvidos na doença. Embora o papel do IDO já tenha sido abordada anteriormente, até onde sabemos esta é a primeira evidência da expressão de TDO no epitélio vaginal, na neoplasia intraepitelial cervical e carcinoma de células escamosas. Ainda, em leucócitos, especialmente aqueles com morfologia típica de polimorfonucleares, parecem ser importantes fontes de IDO na cérvix uterina.In this study we evaluated the role of tryptophan (Trp) metabolism in cervix homeostasis, bacterial vaginosis and HPV-associated lesions. The importance of Trp metabolism is due to its action on microorganisms and immune cells. Tryptophan consumption has been identified as a way to controlling bacterial growth limiting infection. On the other hand, the oxidation of Trp produces kynurenine (Kyn) which plays a key role in immunological tolerance. The formation of Kyn occurs through the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). IDO is the most studied of them within the context of infections / immune escape. More recently, TDO has also been considered in studies of cancer progression. In this thesis, we were interested in cervicovaginal epithelium IDO expression in women with bacterial vaginosis and of IDO and TDO in cervical samples of women with different degrees of cervical lesion associated with HPV. A total of 165 women attended at CAISM/UNICAMP were divided into two groups: a case group composed of women with low or high grade lesions and invasive carcinoma (n = 42) and a control group composed of women with normal cytology, independent to present genital infection (n =123). IDO was evaluated by immunocytochemistry in liquid-based cytology and IDO and TDO in cervical biopsies. Women with bacterial vaginosis had increased IDO expression in squamous cells compared to women without bacterial vaginosis (OR = 7.41, 95% CI = 2.50- 21.74; p<0.0001). In normal vaginal epithelium with or without HPV infection there was a mild IDO expression in squamous cells. In the presence of cervical intraepithelial lesions or squamous cell carcinoma, there was an increase in the number of IDO-positive dysplastic squamous cells and leukocytes; increase in IDO can also be observed in organotypic skin cultures transduced with HPV-16 E6/E7 oncoproteins. In cervical lesions, as observed for IDO, TDO was expressed in leukocytes, especially infiltrates in the stromal region and in the wall of blood vessels. The basal expression of IDO in the normal cervical epithelium and its positive regulation in HPV infection and associated lesions suggests the participation of Trp metabolism in the immunosuppressive mechanisms involved in the disease. Although some previous data have already considered the role of IDO, as far as we know this is the first evidence of the participation of TDO in the vaginal epithelium, cervical intraepithelial neoplasia and squamous cell carcinoma. In addition, in leukocytes, especially those with a typical polymorphonuclear morphology, appear to be important sources of IDO in the uterine cervix.
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Parigiani, Mattia. "Accorgimenti nutrizionali volti all'ottimizzazione del metabolismo del triptofano in condizioni fisiologiche e patologiche". Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amslaurea.unibo.it/22079/.
Abstract (sommario):
Il triptofano è un aminoacido essenziale che si trova in fonti alimentari proteiche di origine sia vegetale (legumi, cereali integrali e semi oleosi) che animale (prodotti carnei e lattiero-caseari). Come gli altri aminoacidi, partecipa alla sintesi proteica ma la sua importanza risiede particolarmente nel fatto di essere precursore di molecole funzionali tra cui il neurotrasmettitore serotonina, l’ormone melatonina e la vitamina niacina. Diversi studi hanno evidenziato un’alterazione del metabolismo del triptofano in casi di infiammazione sistemica di basso grado, condizione associata ad obesità e sindrome metabolica.
Ad oggi, nessun claim salutistico concernente triptofano, L-triptofano o 5-idrossitriptofano, il precursore della serotonina, è stato autorizzato da EFSA in quanto non esistono ancora evidenze scientifiche certe sul ruolo funzionale di questo aminoacido. Questo elaborato riporta lo stato attuale delle conoscenze sull’argomento nella considerazione che in un futuro, con l’ampliarsi delle stesse, il triptofano potrebbe rappresentare una nuova possibilità per la formulazione e produzione di alimenti arricchiti.
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Michel, Marion. "Conception, synthèse et validation de molécules hétérocycliques fluorées ciblant IDO et/ou TDO pour le traitement de la neuroinflammation et son diagnostic par imagerie 18F-TEP". Electronic Thesis or Diss., Orléans, 2023. http://www.theses.fr/2023ORLE1051.
Abstract (sommario):
Le vieillissement de la population actuelle engendre une augmentation du nombre de personnes souffrant de maladies neurodégénératives se heurtant, par la même occasion, à l'absence de traitements curatifs. Par conséquent, le développement de nouveaux outils diagnostiques et thérapeutiques, en vue d'une amélioration de la prise en charge de ces patients, est devenu un enjeu majeur de la recherche.Nombre de ces pathologies dont la maladie d'Alzheimer, la maladie de Parkinson, ou encore la maladie de Charcot suivent le même processus pathophysiologique, appelé neuroinflammation. Ce mécanisme de l'immunité cérébrale, faisant surface dès les premiers instants de la maladie, a dernièrement été placé au cœur des efforts de la communauté scientifique. À cette occasion, l'Indoleamine 2,3-dioxygénase (IDO) et la Tryptophane 2,3-dioxygénase (TDO), enzymes participant au catabolisme du tryptophane, ont été reconnues comme étant surexprimées dans ce contexte de neuroinflammation et semblent y jouer un rôle clé.La tomographie par émission de positons (TEP) est une technique d'imagerie de précision donnant accès à l'étude fonctionnelle de nos organes comme le cerveau. Cette technique de choix non invasive trouve ainsi son utilité chez l'Homme dans le diagnostic, le suivi, et la quantification de ces maladies du système nerveux central (SNC) grâce à l'administration de radiotraceurs définis, ciblant cette zone.Afin de concevoir de puissants radioligands fluorés, spécifiques des enzymes IDO et TDO, nous avons tout d'abord amorcé ce projet de recherche par la transposition de ligands d'IDO, issus de la littérature, en radioligands marqués au 18F nouveaux. Nous avons par la suite développé des séries chimiques originales de types [6-5] et [6-5-5] permettant l'obtention de composés mixtes ou sélectifs de TDO. Pour terminer, l'exploration de l'espace chimique en série hétérocyclique nous a conduit à la conception inédites de ligands fluorés sélectifs de TDO à fort potentiel de valorisationThe ageing of the global population has led to an increase in the number of people suffering from neurodegenerative diseases, with the concomitant lack of curative treatments. Consequently, the development of new diagnostic and therapeutic tools to improve care for these patients has become a major research challenge.Many of these diseases, including Alzheimer's, Parkinson's and Lou Gehrig's disease, follow the same pathophysiological process known as neuroinflammation. This mechanism of cerebral immunity, which emerges at the earliest stages of the disease, has recently become the focus of scientific interest. Indoleamine 2,3-dioxygenase (IDO) and Tryptophan 2,3-dioxygenase (TDO) enzymes, involved in the catabolism of tryptophan, have been identified as being over-expressed in the context of neuroinflammation and appear to play a key role in it.Positron emission tomography (PET) is a precision imaging-technique giving access to the functional study of organs such as the brain. This non-invasive technique can thus be used for the diagnosis, monitoring and quantification of CNS diseases by the administration of specific radiotracers targeting this area.In order to design powerful fluorinated radioligands specific to the IDO and TDO enzymes, we began this research project by transposing IDO ligands form the literature into new 18F-labelled radioligands. We then developed original chemical series with a [6-5] or [6-5-5] scaffold to obtain mixed or selective TDO ligands. Finally, the exploration of the chemical space in the heterocyclic domain led us to the novel design of fluorinated TDO-selective ligands with a high potential for development
Capitoli di libri sul tema "IDO/TDO":
1
Prendergast, George C., William J. Malachowski, Arpita Mondal, Peggy Scherle e Alexander J. Muller. "IDO/TDO Inhibition in Cancer". In Oncoimmunology, 289–307. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-62431-0_17.
Atti di convegni sul tema "IDO/TDO":
1
Coma, Silvia, Jill Cavanaugh, James Nolan, Jeremy Tchaicha, Karen McGovern, Everett Stone, Candice Lamb et al. "Abstract 3757: Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine". In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3757.
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Tchaicha, Jeremy, Karen McGovern, Luis Felipe Campesato, Silvia Coma, Xiaoyan Michelle Zhang, Meghan Walsh, Jill Cavanaugh, Taha Merghoub, Jedd Wolchok e Mark Manfredi. "Abstract 4723: Targeting the IDO and TDO pathway through inhibition of the aryl hydrocarbon receptor". In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-4723.
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Campesato, Luis F., Sadna Budhu, Mathieu Gigoux, Jeremy Tchaicha, Stephane Pourpe, Cailian Liu, Dmitriy Zamarin et al. "Abstract PR05: Blockade of AHR activation by IDO/TDO-derived kynurenine restricts cancer immune suppression". In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 27-30, 2018; Miami Beach, FL. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2326-6074.tumimm18-pr05.
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Zhang, Michelle, Everett Stone, Todd A. Triplett, Kendra Triplett, Candice Lamb, Christos S. Karamitros, John Blazek, George Georgiou e Mark G. Manfredi. "Abstract 5570: A novel approach to targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine". In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-5570.
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Mautino, Mario R., Richard A. Metz, Firoz Jaipuri, Jesse Waldo, Sanjeev Kumar, Agnieszka Marcinowicz-Flick, Hima Potturi et al. "Abstract 1633: Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy". In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-1633.
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Noubade, Rajkumar, Holbrook Kohrt, Lisa Marshall, Idit Sagiv-Barfi, Jonathan Hebb, Cariad Chester, Amanda Rajapaksa et al. "Abstract 3648: Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics". In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-3648.
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Wise, Alan, Barry E. McGuinness, Sarah C. Trewick, Phillip M. Cowley, Nicola Bevan, Clare Szybut e Thomas J. Brown. "Abstract 4292: In vitro kynurenine modulation by novel dual-acting and selective tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) inhibitors". In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-4292.
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Sordillo, Laura A., Lin Zhang, Peter Sordillo e Robert R. Alfano. "Alzheimer’s disease: label-free fluorescence shows increases in indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO) activity in affected areas of the brain". In Optical Biopsy XVII: Toward Real-Time Spectroscopic Imaging and Diagnosis, a cura di Robert R. Alfano, Stavros G. Demos e Angela B. Seddon. SPIE, 2019. http://dx.doi.org/10.1117/12.2513384.