Both pre-clinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurological and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate oxidase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. Significance Statement Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurological and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. In this review, we endeavor to describe these processes in detail.

2024-06-12·Journal of Biomolecular Structure and Dynamics

Human indoleamine-2,3-dioxygenase 2 cofactor lability and low substrate affinity explained by homology modeling, molecular dynamics and molecular docking

Article

作者: Wouters, Johan ; Leherte, Laurence ; Mirgaux, Manon

The human indoleamine-2,3-dioxygenase 2 (hIDO2) protein is growing of interest as it is increasingly implicated in multiple diseases (cancer, autoimmune diseases, COVID-19). However, it is only poorly reported in the literature. Its mode of action remains unknown because it does not seem to catalyze the reaction for which it is attributed: the degradation of the L-Tryptophan into N-formyl-kynurenine. This contrasts with its paralog, the human indoleamine-2,3-dioxygenase 1 (hIDO1), which has been extensively studied in the literature and for which several inhibitors are already in clinical trials. Yet, the recent failure of one of the most advanced hIDO1 inhibitors, the Epacadostat, could be caused by a still unknown interaction between hIDO1 and hIDO2. In order to better understand the mechanism of hIDO2, and in the absence of experimental structural data, a computational study mixing homology modeling, Molecular Dynamics, and molecular docking was conducted. The present article highlights an exacerbated lability of the cofactor as well as an inadequate positioning of the substrate in the active site of hIDO2, which might bring part of an answer to its lack of activity.Communicated by Ramaswamy H. Sarma.

2024-05-01·Tuberculosis

Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis

Article

作者: van der Wel, Nicole N ; Bugiani, Marianna ; Grootemaat, Anita E ; Guo, Lihui ; Zaharie, Stefan-Dan ; Lutter, René ; van der Kuip, Martijn ; Marceline van Furth, A ; Kruger, Mariana ; Zhang, Lin

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%. Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

项与 IDO1 x IDO2 相关的新闻（医药）

2024-03-04

·BioSpace

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

免疫疗法

2023-03-06

·BioSpace

Therapeutic Solutions International Announces Plans to Initiate Breast Cancer Clinical Trial Using FloraStilbene™ Immune Stimulator Through Res Nova Bio Subsidiary

Company Receives Institutional Review Board Approval for 10 Patient Proof of Concept Oncology Trial ELK CITY, Idaho--(BUSINESS WIRE)-- Therapeutic Solutions International (TSOI) announced today plans to initiate ten patient proof-of-concept clinical trial aimed at demonstrating the ability of FloraStilbene™ to stimulate the immune system in advanced breast cancer patients. The Company has previously been granted a patent on utilization of pterostilbene and pterostilbene compositions for synergy with cancer immunotherapy such as interleukin-21, as well as suppression of cancer derived immune inhibitory agent enzymes such as indolamine 2,3 dioxygenase2. By combining previous experiences with immune modulation, the Company announced the creation of a novel immune stimulatory adjuvant combining pterostilbene with RU-486, termed “FloraStilbene”. Preclinical data, for which intellectual property has been demonstrated FloraStilbene overcame immune suppression induced in the 4T1 mouse model of triple negative breast cancer. “FloraStilbene™ represents a non-toxic approach to overcoming breast cancer induced immune suppression, which acts as a significant barrier to efficacy of oncology immunotherapy,” said Dr. James Veltmeyer, Chief Medical Officer of the Company. “I am eager to lead this clinical trial, which if successful, will serve as the basis for a new approach to increase efficacy of drugs such as Herceptin and checkpoint inhibitors.” “Therapeutic Solutions International has been working on, and filing patents, in the area of cancer immunotherapy with internationally renowned opinion leaders such as Dr. Santosh Kesari since 2015,” said Famela Ramos, President and Chief Executive Officer of Res Nova Bio. “We are excited to leverage these deep and broad resources to rapidly enter the clinic to address such a major unmet medical need.” “One of the guiding principles of our Company has been to bring hope to patients for which limited options exist,” said Timothy Dixon, President, and Chief Executive Officer of Therapeutic Solutions International. “We strongly believe that immuno-adjuvant approaches such as FloraStilbene™ will greatly increase the potency of numerous existing therapies, as well as reducing various toxicities.” 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 . About Res Nova Bio, Inc. Res Nova Bio is a San Diego Biotechnology Cancer Immunotherapy Company dedicated to addressing the unmet medical need in the treatment of advanced breast cancer. Our Company is a place where problems get solved and the lives, of our employees and our patients, are transformed. The Company's corporate website is . 1 Augmentation of oncology immunotherapies by pterostilbene containing compositions 2 Nutraceuticals for suppressing indolamine 2,3 deoxygenase

免疫疗法临床研究

2023-01-06

·生物制药小编

免疫代谢与ICI治疗耐药

免疫抑制剂（ICI）治疗为多种肿瘤带来的非常有希望的治疗效果，但是对ICI的原发和继发性耐药仍然是我们正在面临的主要问题。肿瘤微环境（TME）和宿主生理过程的代谢改变是肿瘤发生时的一个重要标志，这不但能够为肿瘤创造生存条件，同时还会促进免疫抑制环境的形成，是ICI耐药性产生的重要原因。ICI耐药的产生涉及多种代谢通路，通路的的异常改变能够通过改变肿瘤部位免疫细胞的状态和功能而使ICI治疗效果变差。腺苷通路腺苷是外周组织免疫反应的主要抗炎调节剂，它2核外核苷酸酶CD39+和CD73+催化ATP产生。在发生肿瘤的情况下，胞外腺苷浓度可升高100多倍，并不断积聚，会抑制多种免疫细胞的功能而导致肿瘤免疫降低。腺苷受体（AR）包含4种（A1R、A2AR、A2BR、A3R），被激活后会：诱导单核细胞分化为巨噬细胞，促进巨噬细胞产生IL-12和TNFα导致免疫耐受。影响嗜中性粒细胞的活性，减少其粘附、迁移、脱颗粒作用，最终导致Fc受体介导的吞噬作用被抑制，并减少超氧化物的生成。已有研究证明CD73+肿瘤细胞对于抗PD-1阻断剂具有治疗抗性，因此同时阻断CD73和PD-1能够增强瘤内CD8+T细胞的浸润和肿瘤治疗效果。Clin Cancer Res. 2013 Oct 15;19(20):5626-35. 同时，靶向CD39和CD73以及抗AR药物在临床前模型中已被证明有效。并且针对该途径的新型抗体和小分子药物正在进行联合ICI治疗的临床前研究。【36,37】Int J Mol Sci. 2020 Jun 21;21(12):4414. 血管生成脉管系统由血管和淋巴管组成，其中充斥着大量的免疫细胞和间质细胞（如癌症成纤维细胞CAF），异常的脉管系统有利于形成低pH和高度缺氧环境，对多种免疫细胞产生影响：抑制DC成熟。抑制CD8+T细胞增殖、迁移和免疫功能，并导致其发生耗竭。促进TAM由抗癌M1表型向免疫抑制M2表型极化。诱导髓源性抑制细胞（MDSC）的生长和免疫抑制活性。因此使用抗血管生成药物能够减轻免疫抑制，增加CD8+T细胞的浸润来增强ICI药物效果。VEGF联合抗PD-L1、抗PD-1、抗CTLA-1疗法已在多类肿瘤中进行了试验。Nat Rev Clin Oncol. 2018 May;15(5):310-324. 色氨酸分解代谢通路色氨酸-犬尿氨酸-芳基烃受体（Trp-Kyn-AhR）通路参与生理性免疫抑制的形成，该通路包括三种酶，分别是IDO1、TDO、IDO2，其中IDO1对免疫治疗耐药的形成起主要作用。IDO1的生理作用是诱导获得性免疫耐受，它能够促进色氨酸的消耗以及犬尿氨酸积累，对免疫细胞产生影响：促进Treg活化抑制T细胞活化诱导T细胞无能状态黑色素瘤患者前哨淋巴结中IOD1高表达降低了抗CTLA1-4和抗PD1/PDL1治疗效果，并且导致肿瘤部位淋巴细胞浸润程度降低以及预后较差，在多种肿瘤中均观察到了相同的现象。Br J Dermatol. 2014 Nov;171(5):987-95. 无论是敲除IDO基因或者使用IDO抑制剂，与ICI联用均能使肿瘤小鼠存活时间延长。PI3K/AKT/mTOR通路该通路参与细胞生长、存活、代谢、运动，是生理活动的重要通路。除正常功能外，约30%的癌症中发现了该通路功能失调，通过多种机制介导肿瘤发生、进展、耐药。PTEN是PI3K/AKT通路的主要负调控因子，其突变导致免疫抑制细胞因子表达水平升高、CD8+T细胞浸润程度降低、毒性降低。并且PTEN突变型三阴性乳腺癌（TNBC）和CRC中观察到了高水平的PD-L1。参与调节MDSC分化。PI3Kδ高表达与FOXP3+Treg细胞数量增加相关。使效应CD8+T细胞转化为记忆T细胞，并调节肿瘤相关巨噬细胞（TAM）的免疫刺激和免疫抑制开关。该通路已常威多种肿瘤的的治疗靶点，相关药物如PI3K抑制剂、mTOR抑制剂、PI3K-mTOR双重抑制剂已被批准用于治疗不同肿瘤。PI3K/AKT/mTOR抑制剂与ICI药物联用的多项临床试验正在进行中。Int J Mol Sci. 2020 Jun 21;21(12):4414. 小结代谢途径对ICI原发和获得性耐药至关重要，从根本上了解耐药的产生原因可能发现用于预测ICI疗效的标志物，并同时可以为“冷”肿瘤和耐药患者提供治疗帮助以提高ICI治疗效果。参考资料Allard B et al. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013 Oct 15;19(20):5626-35. Giannone G et al. Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy. Int J Mol Sci. 2020 Jun 21;21(12):4414. Khan KA et al. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018 May;15(5):310-324. Chevolet I et al. Peritumoral indoleamine 2,3-dioxygenase expression in melanoma: an early marker of resistance to immune control? Br J Dermatol. 2014 Nov;171(5):987-95.

免疫疗法