Author: Bal, Salih Haldun ; Karaca, Mert ; Yilmaz, Emel ; Özkalemkaş, Fahir ; Kunt Uzaslan, Esra ; Budak, Ferah ; Arslan, Gözde ; Oral, Haluk Barbaros ; Akalin, Halis ; Yilmaztepe Oral, Arzu ; Yöyen Ermiş, Diğdem ; Macunluoğlu, Aslı Ceren

Kinürenin yolağı, yol boyunca oluşan metabolitler ve enzimler aracılığıyla neredeyse tüm bağışıklık tepkileriyle etkileşime girmektedir. Hız sınırlayıcı enzim olan indolamin 2,3-dioksijenaz (IDO), yolağın başlangıç adımında oksidoredüktaz olarak görev yapmakta olup triptofanın kinürenine dönüşümünü katalizler ve çeşitli enfeksiyöz hastalıkların patogeneziyle ilişkilendirilmiştir. Bu çalışmada, koronavirüs hastalığı 2019 [coronavirus diseases-2019 (COVID-19)] hastalarının serum IDO-1 düzeyleri, Th1-2- 17 ile ilişkili sitokinlerin düzeyleri ve hematolojik parametreler, hastalığın şiddeti (hafif, orta, şiddetli) göz önünde bulundurularak araştırılması amaçlanmıştır. Yüz otuz hasta ve 91 sağlıklı kontrol için IDO1 serum seviyeleri enzim ilişkili immünsorban assay [enzyme linked immunosorbant assay (ELISA)] yöntemi kullanılarak ölçülmüş ve karşılaştırılmıştır. IDO gen lokusundaki daha önce enflamasyonla ilişkilendirilmiş olan tek nükleotit polimorfizm [single nucleotid polymorphism (SNP)] bölgesi taranmıştır. SNP analizleri, erime eğrisi (melting curve) analiziyle gerçekleştirilmiştir. Kırk COVID-19 hastasının IDO-1 intronik varyant rs7820268 ve IDO-2 inaktivitesinden sorumlu rs4503083 SNP bölgeleri, elli iki sağlıklı kontrol ile karşılaştırmalı olarak incelenmiştir. Tüm sonuçlar istatistiksel olarak analiz edilmiş ve karşılaştırılmıştır. IDO-1 serum konsantrasyonları hasta grubunda sağlıklı kontrol grubuna göre anlamlı olarak düşük bulunmuştur (p< 0.0001). Ayrıca, şiddetli hasta grubundaki IDO-1 serum seviyeleri, hafif hasta grubundan daha düşük olarak belirlenmiştir (p= 0.026). Hasta grubunda IL-4, IL-6, IL-10, TNF-α serum seviyeleri anlamlı derecede yüksek bulunurken, IFN-γ seviyeleri düşük olarak tespit edilmiştir. IDO1 ve IL-6 seviyeleri arasında ise negatif bir korelasyon bulunmuştur (r= -0.3503, p= 0.0391). Hastalık şiddetine göre sınıflandırılan hasta gruplarında lenfosit, monosit, nötrofil ve akut faz reaktan değerleri karşılaştırıldığında anlamlı farklılıklar bulunmuştur. SNP analizi sonucunda, rs7820268 IDO-1 bölgesi için CC genotipi COVID-19 hasta grubunda sağlıklı kontrol grubuna göre önemli ölçüde daha yüksek bulunmuştur (p= 0.0017). Bu veriler, IDO-1 rs7820268 SNP bölgesindeki polimorfizmin COVID-19'a duyarlılıkla ilişkili olabileceğini düşündürmektedir.

01 Mar 2025·Cancer Medicine

The Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression

Review

Author: Wang, Guoying ; Zhang, Jia ; Zhang, Chengcheng ; Wang, Zhongqi ; Lu, Zhanhui ; Su, Wan

ABSTRACTTryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine‐2,3‐dioxygenase 1 (IDO1), IDO2, and Trp‐2,3‐dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non‐enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.

01 Jan 2025·Acta Neuropsychiatrica

Gene expression of kynurenine pathway enzymes in depression and following electroconvulsive therapy

Article

Author: Corrigan, Myles ; Murphy, Therese M ; McLoughlin, Declan M. ; Ryan, Karen M ; Murphy, Therese M. ; Ryan, Karen M. ; Harkin, Andrew ; McLoughlin, Declan M

AbstractObjective:This study aimed to investigate changes in mRNA expression of the kynurenine pathway (KP) enzymes tryptophan 2, 3-dioxygenase (TDO), indoleamine 2, 3-dioxygenase 1 and 2 (IDO1, IDO2), kynurenine aminotransferase 1 and 2 (KAT1, KAT2), kynurenine monooxygenase (KMO) and kynureninase (KYNU) in medicated patients with depression (n = 74) compared to age- and sex-matched healthy controls (n = 55) and in patients with depression after electroconvulsive therapy (ECT). Associations with mood score (24-item Hamilton Depression Rating Scale, HAM-D24), plasma KP metabolites and selected glucocorticoid and inflammatory immune markers known to regulate KP enzyme expression were also explored.Methods:HAM-D24 was used to evaluate depression severity. Whole blood mRNA expression was assessed using quantitative real-time polymerase chain reaction.Results:KAT1, KYNU and IDO2 were significantly reduced in patient samples compared to control samples, though results did not survive statistical adjustment for covariates or multiple comparisons. ECT did not alter KP enzyme mRNA expression. Changes in IDO1 and KMO and change in HAM-D24 score post-ECT were negatively correlated in subgroups of patients with unipolar depression (IDO1 only), psychotic depression and ECT responders and remitters. Further exploratory correlative analyses revealed altered association patterns between KP enzyme expression, KP metabolites, NR3C1 and IL-6 in depressed patients pre- and post-ECT.Conclusion:Further studies are warranted to determine if KP measures have sufficient sensitivity, specificity and predictive value to be integrated into stress and immune associated biomarker panels to aid patient stratification at diagnosis and in predicting treatment response to antidepressant therapy.

News (Medical) associated with IDO1 x IDO2

04 Mar 2024

·www.biospace.com

Therapeutic Solutions International Granted Patent on Commercially Available QuadraMune® Nutraceutical for Increasing Natural Killer Cell Immunity in COVID-19 Patients

Latest Patent to Complement Issued Claims on Viral Inhibition, Adaptive Immune Stimulation, and Brain Protection/Regeneration ELK CITY, Idaho--(BUSINESS WIRE)-- Therapeutic Solutions International, Inc. (TSOI), a clinical-stage stem cell and immunotherapy company, announced today the granting of a patent covering the ability of QuadraMune® and similar compositions, to stimulate natural killer (NK) cell activity in patients with COVID-19. NK cells are the first line of defense against viruses and cancers1. The Company was previously awarded by the United States Patent and Trademark Office the following QuadraMune® related patents: Patent #11,229,674, covering inhibition of the immune suppressing enzyme indolamine 2,3 dioxygenase2. It is published that this enzyme plays a fundamental role in immune suppression by cancer3, as well as numerous viruses including SARS-CoV-2, the causative agent of COVID-194. Patent #11,266,707, “Nutraceuticals for the prevention, inhibition, and treatment of SARS-CoV-2 and associated COVID-19”5. Patent #11,504,410, covering use of QuadraMune® and its derivatives for protecting and restoring brain function after neurological damage, including Long COVID6. Patent #11759495, covering upregulation of T regulatory cells for suppression of suicidal ideation7. “In addition to this important validation from the USPTO, the fact that the ingredients in QuadraMune® have been reported by institutions such as Johns Hopkins University to suppress SARS-CoV-2 is strongly encouraging,” said Famela Ramos, Vice President of Business Development for the Company. “Our Company is driven by a desire to address unmet medical needs, whether it is through developing state of the art stem cell and gene therapies, or science-backed nutraceuticals,” said Timothy Dixon, President, and CEO of the Company. “The importance of NK cells in protecting the body against cancer and viruses is well known, the fact that this can be performed using a low-cost nutraceutical approach has implications in both oncology and virology.” About Therapeutic Solutions International, Inc. Therapeutic Solutions International is focused on immune modulation for the treatment of several specific diseases. The Company's corporate website is . 1 Cerwenka and Lanier. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001 Oct;1(1):41-9. 2 3 Ricuitti et al. Targeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence. Pharmacol Ther. 2019 Apr:196:105-116. 4 Guo et al. Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19. J Pathol. 2022 Mar;256(3):256-261. 5 6 7 8 Johns Hopkins University Publishes Efficacy of QuadraMune™ Ingredient Sulforaphane at Inhibiting Coronavirus in Laboratory Studies | BioSpace

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