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Addanki S, Kim L, Stevens A. Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review. Cancers (Basel) 2025; 17:1355. [PMID: 40282531 PMCID: PMC12025543 DOI: 10.3390/cancers17081355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/05/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.
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Affiliation(s)
- Sridevi Addanki
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Alexandra Stevens
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Wang Y, Wu W, Zeng F, Meng X, Peng M, Wang J, Chen Z, Liu W. The role of kynurenine pathway metabolism mediated by exercise in the microbial-gut-brain axis in Alzheimer's disease. Exp Neurol 2025; 384:115070. [PMID: 39603488 DOI: 10.1016/j.expneurol.2024.115070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/14/2024] [Accepted: 11/18/2024] [Indexed: 11/29/2024]
Abstract
In recent years, the role of the microbiome-gut-brain axis in the pathogenesis of Alzheimer's disease (AD) has garnered increasing attention. Specifically, tryptophan metabolism via the kynurenine pathway (KP) plays a crucial regulatory role in this axis. This study reviews how exercise regulates the microbiome-gut-brain axis by influencing kynurenine pathway metabolism, thereby exerting resistance against AD. This paper also discusses how exercise positively impacts AD via the microbiome-gut-brain axis by modulating the endocrine, autonomic nervous, and immune systems. Although the specific mechanisms are not fully understood, research indicates that exercise may optimize tryptophan metabolism by promoting the growth of beneficial microbiota and inhibiting harmful microbiota, producing substances that are beneficial to the nervous system and combating AD. The aim of this review is to provide new perspectives and potential intervention strategies for the prevention and treatment of AD by exploring the links between exercise, KP and the gut-brain axis.
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Affiliation(s)
- Yiyang Wang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Weijia Wu
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Fanqi Zeng
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Xiangyuan Meng
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Mei Peng
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Juan Wang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Zeyu Chen
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Wenfeng Liu
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China; Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, Hunan Normal University, Changsha 410081, China.
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Edgar CD, Blair A, Tate WP. Measurement of Genetic Variations in ME/CFS Patients in the IDO2 Gene Encoding an Enzyme Metabolizing Tryptophan. Methods Mol Biol 2025; 2920:247-256. [PMID: 40372687 DOI: 10.1007/978-1-0716-4498-0_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Genetic variations in the indoleamine 2,3-dioxygenase (IDO2) gene that are commonly found in the general population have been assessed for their frequency in myalgic encephalomyelitis/chronic fatigue (ME/CFS) patients compared with healthy controls. They have potential for being genetic variations that lead to susceptibility to developing ME/CFS following exposure to a triggering stressor like a viral infection or other major stress events. The IDO2 gene encodes an enzyme that is involved in the tryptophan-kynurenine pathway (TKP), and is activated if there are excessive amounts of tryptophan to prevent excessive serotonin production. The TKP pathway through production of NADH is involved in regulating the immune system and likely plays an important role in ME/CFS. A simple method was developed to evaluate the 5 commonly occurring mutations in this gene in ME/CFS patients and to determine if one or more were present at higher frequency than in healthy controls. This might indicate a susceptibility factor for developing ME/CFS. In this chapter we describe the techniques used to isolate peripheral blood mononuclear cells (PBMCs), extract the DNA, and then do touchdown PCR and DNA sequencing for the analysis.
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Affiliation(s)
- Christina D Edgar
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Anna Blair
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Warren P Tate
- Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
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Suvieri C, Belladonna ML, Volpi C. The Two Sides of Indoleamine 2,3-Dioxygenase 2 (IDO2). Cells 2024; 13:1894. [PMID: 39594642 PMCID: PMC11593294 DOI: 10.3390/cells13221894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 originated from gene duplication before vertebrate divergence. While IDO1 has a well-defined role in immune regulation, the biological role of IDO2 remains unclear. Discovered in 2007, IDO2 is located near the IDO1 gene. Because of their high sequence similarity, IDO2 was initially thought to be a tryptophan (Trp)-degrading enzyme like IDO1. Differently from what expected, IDO2 displays extremely low catalytic activity toward Trp. Nevertheless, many studies, often contradictory, have tried to demonstrate that IDO2 modulates immune responses by catabolizing Trp into kynurenine, an unconvincing hypothesis linked to an incomplete understanding of IDO2's activity. In this study, we review IDO2's functional role beyond Trp metabolism. IDO2's evolutionary persistence across species, despite being almost inactive as an enzyme, suggests it has some relevant biological importance. IDO2 expression in human normal cells is poor, but significant in various cancers, with two prevalent SNPs. Overall, the comparison of IDO2 to IDO1 as a Trp-degrading enzyme may have led to misunderstandings about IDO2's true physiological and pathological roles. New insights suggest that IDO2 might function more as a signaling molecule, particularly in cancer contexts, and further studies could reveal its potential as a target for cancer therapy.
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Affiliation(s)
| | | | - Claudia Volpi
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (M.L.B.)
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Cizmecioglu A, Eryavuz Onmaz D, Senturk S, Askin D, Unlu A, Korkmaz H, Gungor G. Kynurenine Pathway Dysregulation and Pain Perception in Acute Pancreatitis: Has the Connection Unraveled? Neurosci Lett 2024; 837:137902. [PMID: 39029612 DOI: 10.1016/j.neulet.2024.137902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024]
Abstract
AIM Tryptophan (TRP), an essential amino acid, undergoes catabolism through various pathways. Notably, the kynurenine pathway (KP), constituting one of these pathways, exhibits a unidirectional impact on immune response and energy metabolism. Nonetheless, its influence on pain sensation is characterized by biphasic dynamics. This study aims to scrutinize the influence of the KP pathway on pain sensation, particularly within the context of pancreatic inflammation. METHODS Our prospective case-control study involved individuals diagnosed with acute pancreatitis and a control group matched for gender and age. The patient cohort was subsequently subdivided into severe and non-severe subgroups. To assess metabolites within KP, two blood samples were collected from the patient cohort, one at the time of diagnosis and another during the recovery phase. Furthermore, for pain quantification, daily pain scores utilizing the Visual Analog Scale (VAS) were extracted from the patients' medical records. RESULTS The study incorporated 30 patients along with an equivalent number of controls. A noticeable distinction was evident between the patient and control groups, characterized by an increase in kynurenine levels and a decrease in the tryptophan/kynurenine ratio. Throughout the process of disease recovery, a uniform decrease was observed in all KP metabolites, excluding 3-Hydroxykynurenine. Elevated levels of Kynurenic acid (KYNA) were correlated with increased pain scores. Critically, no apparent distinctions in KP metabolites were discerned concerning pain severity in patients with comorbidities characterized by neural involvement. CONCLUSION Based on our results, the kynurenine pathway (KP) is activated in instances of acute pancreatitis. Elevated levels of KYNA were found to be associated with heightened pain scores. The operative stages within the KP responsible for pain modulation are impaired in cases characterized by neuropathy-induced pain sensation.
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Affiliation(s)
- Ahmet Cizmecioglu
- Department of Internal Medicine, Faculty of Medicine, Selcuk University, Konya, Turkiye.
| | - Duygu Eryavuz Onmaz
- Department of Biochemistry, Faculty of Medicine, Selcuk University, Konya, Turkiye.
| | - Suleyman Senturk
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Selcuk University, Konya, Turkiye.
| | - Dudu Askin
- Department of Internal Medicine, Alanya Sifa Private Medical Center, Antalya, Turkiye.
| | - Ali Unlu
- Department of Biochemistry, Faculty of Medicine, Selcuk University, Konya, Turkiye.
| | - Huseyin Korkmaz
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Selcuk University, Konya, Turkiye.
| | - Gokhan Gungor
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Selcuk University, Konya, Turkiye.
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Ren C, Zhang S, Chen Y, Deng K, Kuang M, Gong Z, Zhang K, Wang P, Huang P, Zhou Z, Gong A. Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary. FASEB J 2024; 38:e23804. [PMID: 39037422 DOI: 10.1096/fj.202400453r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/31/2024] [Accepted: 06/26/2024] [Indexed: 07/23/2024]
Abstract
Natural Nicotinamide Adenine Dinucleotide (NAD+) precursors have attracted much attention due to their positive effects in promoting ovarian health. However, their target tissue, synthesis efficiency, advantages, and disadvantages are still unclear. This review summarizes the distribution of NAD+ at the tissue, cellular and subcellular levels, discusses its biosynthetic pathways and the latest findings in ovary, include: (1) NAD+ plays distinct roles both intracellularly and extracellularly, adapting its distribution in response to requirements. (2) Different precursors differs in target tissues, synthetic efficiency, biological utilization, and adverse effects. Importantly: tryptophan is primarily utilized in the liver and kidneys, posing metabolic risks in excess; nicotinamide (NAM) is indispensable for maintaining NAD+ levels; nicotinic acid (NA) constructs a crucial bridge between intestinal microbiota and the host with diverse functions; nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase NAD+ systemically and can be influenced by delivery route, tissue specificity, and transport efficiency. (3) The biosynthetic pathways of NAD+ are intricately intertwined. They provide multiple sources and techniques for NAD+ synthesis, thereby reducing the dependence on a single molecule to maintain cellular NAD+ levels. However, an excess of a specific precursor potentially influencing other pathways. In addition, Protein expression analysis suggest that ovarian tissues may preferentially utilize NAM and NMN. These findings summarize the specific roles and potential of NAD+ precursors in enhancing ovarian health. Future research should delve into the molecular mechanisms and intervention strategies of different precursors, aiming to achieve personalized prevention or treatment of ovarian diseases, and reveal their clinical application value.
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Affiliation(s)
- Caifang Ren
- School of Medicine, Jiangsu University, Zhenjiang, China
- Hematological Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Shuang Zhang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yanyan Chen
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Kaiping Deng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Meiqian Kuang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zihao Gong
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ke Zhang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Panqi Wang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Pan Huang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhengrong Zhou
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Aihua Gong
- School of Medicine, Jiangsu University, Zhenjiang, China
- Hematological Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
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Mirgaux M, Leherte L, Wouters J. Human indoleamine-2,3-dioxygenase 2 cofactor lability and low substrate affinity explained by homology modeling, molecular dynamics and molecular docking. J Biomol Struct Dyn 2024; 42:4475-4488. [PMID: 37301605 DOI: 10.1080/07391102.2023.2220830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023]
Abstract
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.
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Affiliation(s)
- Manon Mirgaux
- Department of Chemistry, Laboratoire de Chimie Biologique Structurale (CBS), Namur Institute of Structured Matter (NISM), Namur Research Institute for Life Science (NARILIS), University of Namur (UNamur), Namur, Belgium
| | - Laurence Leherte
- Department of Chemistry, Laboratoire de Chimie Biologique Structurale (CBS), Namur Institute of Structured Matter (NISM), Namur Research Institute for Life Science (NARILIS), University of Namur (UNamur), Namur, Belgium
| | - Johan Wouters
- Department of Chemistry, Laboratoire de Chimie Biologique Structurale (CBS), Namur Institute of Structured Matter (NISM), Namur Research Institute for Life Science (NARILIS), University of Namur (UNamur), Namur, Belgium
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Liang J, Cheng ZY, Shan F, Cao Y, Xia QR. Serum indoleamine 2, 3-dioxygenase and tryptophan-2, 3-dioxygenase: potential biomarkers for the diagnosis of major depressive disorder. Psychopharmacology (Berl) 2024; 241:1093-1099. [PMID: 38286858 DOI: 10.1007/s00213-024-06542-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 01/22/2024] [Indexed: 01/31/2024]
Abstract
OBJECTIVE The objective of this study was to observe the changes in the levels of indoleamine 2, 3-dioxygenase (IDO) and tryptophan-2, 3-dioxygenase (TDO) in patients with major depressive disorder (MDD) and investigate their potential role as novel biomarkers for diagnosing MDD. METHODS A total of 55 MDD patients and 55 healthy controls (HC) were enrolled in the study. The severity of MDD was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24) before and after treatment. The serum concentrations of IDO and TDO were measured at baseline and after treatment. The correlations between the serum levels of IDO and TDO and HAMD-24 scores were evaluated using Pearson's correlation test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the area under the curve (AUC) of serum levels of IDO and TDO for discriminating MDD patients from HC. RESULTS The serum IDO and TDO concentrations were significantly higher in patients with MDD at baseline than in healthy controls, and decreased significantly after 2 weeks or 1 month of treatment. The levels of IDO and TDO were significantly positively correlated with HAMD-24 scores. Furthermore, the AUC values for IDO and TDO were 0.999 and 0.966, respectively. CONCLUSION The study suggests that serum IDO and TDO may serve as novel biomarkers for diagnosing MDD. These findings may lead to a better understanding of the pathogenesis of MDD and the development of new therapeutic targets.
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Affiliation(s)
- Jun Liang
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Zhuo-Yu Cheng
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Feng Shan
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Yin Cao
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Qing-Rong Xia
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China.
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China.
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China.
- Anhui Clinical Research Center for Mental Disorders, Hefei, China.
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Wu HX, Long CR, Zhang ZH, Chen YL, Wang YY, Xiang SJ, Zhou BJ. Tryptophan metabolism and liver fibrosis. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:192-198. [DOI: 10.11569/wcjd.v32.i3.192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2024]
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Engin AB, Engin A. Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:629-655. [PMID: 39287867 DOI: 10.1007/978-3-031-63657-8_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
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-β 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.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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Suvieri C, De Marchis F, Mandarano M, Ambrosino S, Rossini S, Mondanelli G, Gargaro M, Panfili E, Orabona C, Pallotta MT, Belladonna ML, Volpi C. Membrane Localization and Phosphorylation of Indoleamine 2,3-Dioxygenase 2 (IDO2) in A549 Human Lung Adenocarcinoma Cells: First Steps in Exploring Its Signaling Function. Int J Mol Sci 2023; 24:16236. [PMID: 38003426 PMCID: PMC10671178 DOI: 10.3390/ijms242216236] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/05/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Indoleamine 2,3-dioxygenase 2 (IDO2) is a paralog of Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-degrading enzyme producing immunomodulatory molecules. However, the two proteins are unlikely to carry out the same functions. IDO2 shows little or no tryptophan catabolic activity and exerts contrasting immunomodulatory roles in a context-dependent manner in cancer and autoimmune diseases. The recently described potential non-enzymatic activity of IDO2 has suggested its possible involvement in alternative pathways, resulting in either pro- or anti-inflammatory effects in different models. In a previous study on non-small cell lung cancer (NSCLC) tissues, we found that IDO2 expression revealed at the plasma membrane level of tumor cells was significantly associated with poor prognosis. In this study, the A549 human cell line, basally expressing IDO2, was used as an in vitro model of human lung adenocarcinoma to gain more insights into a possible alternative function of IDO2 different from the catalytic one. In these cells, immunocytochemistry and isopycnic sucrose gradient analyses confirmed the IDO2 protein localization in the cell membrane compartment, and the immunoprecipitation of tyrosine-phosphorylated proteins revealed that kinase activities can target IDO2. The different localization from the cytosolic one and the phosphorylation state are the first indications for the signaling function of IDO2, suggesting that the IDO2 non-enzymatic role in cancer cells is worthy of deeper understanding.
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Affiliation(s)
- Chiara Suvieri
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Francesca De Marchis
- Institute of Biosciences and Bioresources, Research Division of Perugia, National Research Council (CNR), 06128 Perugia, Italy;
| | - Martina Mandarano
- Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy;
| | - Sara Ambrosino
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Sofia Rossini
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Giada Mondanelli
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Marco Gargaro
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Eleonora Panfili
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Ciriana Orabona
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Maria Teresa Pallotta
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Maria Laura Belladonna
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
| | - Claudia Volpi
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy; (C.S.); (S.A.); (S.R.); (G.M.); (M.G.); (E.P.); (C.O.); (M.T.P.); (M.L.B.)
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12
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Chilosi M, Doglioni C, Ravaglia C, Piciucchi S, Dubini A, Stefanizzi L, Poletti V. COVID-19. Biology, pathophysiology, and immunology: a pathologist view. Pathologica 2023; 115:248-256. [PMID: 38054899 DOI: 10.32074/1591-951x-954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 12/07/2023] Open
Abstract
Even if the SARS-CoV-2 pandemic has been declared over, several risks and clinical problems remain to be faced, including long-COVID sequelae and possible outbreaks of pathogenic variants. Intense research on COVID-19 has provided in these few years a striking amount of data covering different fields and disciplines, which can help to provide a knowledge shield against new potential infective spreads, and may also potentially be applied to other fields of medicine, including oncology and neurology. Nevertheless, areas of uncertainty still remain regarding the pathogenic mechanisms that subtend the multifaceted manifestations of the disease. To better clarify the pathogenesis of the disease, a systematic multidisciplinary evaluation of the many mechanisms involved in COVID-19 is mandatory, including clinical, physiological, radiological, immunological and pathological studies. In COVID-19 syndrome the pathological studies have been mainly performed on autopsy cases, and only a few studies are available on biopsies. Nevertheless, these studies have provided relevant information that can substantially contribute to decipher the complex scenario characterizing the different forms of COVID-19 and long-COVID-19. In this review the data provided by pathological investigations are recapitulated and discussed, in the light of different hypothesis and data provided by clinical, physiological and immunological data.
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Affiliation(s)
- Marco Chilosi
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy
| | - Claudio Doglioni
- Department of Pathology, San Raffaele Scientific Institute. Milan, Italy
| | - Claudia Ravaglia
- Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy
| | - Sara Piciucchi
- Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy
| | | | | | - Venerino Poletti
- Department of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy
- Department of Pathology, Ospedale GB Morgagni, Forlì, Italy
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13
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Wang Y, Song J, Yu K, Nie D, Zhao C, Jiao L, Wang Z, Zhou L, Wang F, Yu Q, Zhang S, Wen Z, Wu J, Wang CY, Wang DW, Cheng J, Zhao C. Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency Inhibits Pathological Cardiac Hypertrophy. Hypertension 2023; 80:2099-2111. [PMID: 37485661 DOI: 10.1161/hypertensionaha.122.20809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 07/10/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND Aberrant amino acid metabolism is implicated in cardiac hypertrophy, while the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive. Herein, we aimed to investigate the effect and potential mechanism of IDO1 (indoleamine 2,3-dioxygenase) and its metabolite kynurenine (Kyn) on pathological cardiac hypertrophy. METHODS Transverse aortic constriction was performed to induce cardiac hypertrophy in IDO1-knockout (KO) mice and AAV9-cTNT-shIDO1 mice. Liquid chromatography-mass spectrometry was used to detect the metabolites of tryptophan-Kyn pathway. Chromatin immunoprecipitation assay and dual luciferase assay were used to validate the binding of protein and DNA. RESULTS IDO1 expression was upregulated in both human and murine hypertrophic myocardium, alongside with increased IDO1 activity and Kyn content in transverse aortic constriction-induced mice's hearts using liquid chromatography-mass spectrometry analysis. Myocardial remodeling and heart function were significantly improved in transverse aortic constriction-induced IDO1-KO mice, but were greatly exacerbated with subcutaneous Kyn administration. IDO1 inhibition or Kyn addition confirmed the alleviation or aggravation of hypertrophy in cardiomyocyte treated with isoprenaline, respectively. Mechanistically, IDO1 and metabolite Kyn contributed to pathological hypertrophy via the AhR (aryl hydrocarbon receptor)-GATA4 (GATA binding protein 4) axis. CONCLUSIONS This study demonstrated that IDO1 deficiency and consequent Kyn insufficiency can protect against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.
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Affiliation(s)
- Yinhui Wang
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Jia Song
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.S.)
| | - Kun Yu
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Daan Nie
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (D.N.)
- Department of Cardiovascular Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China (D.N.)
| | - Chengcheng Zhao
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Liping Jiao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China (L.J.)
| | - Ziyi Wang
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Ling Zhou
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Feng Wang
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Qilin Yu
- The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Q.Y., S.Z., C.-Y.W.)
| | - Shu Zhang
- The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Q.Y., S.Z., C.-Y.W.)
| | - Zheng Wen
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Junfang Wu
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Cong-Yi Wang
- The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Q.Y., S.Z., C.-Y.W.)
| | - Dao Wen Wang
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Jia Cheng
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
| | - Chunxia Zhao
- Department of Internal Medicine, Division of Cardiology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Y.W., K.Y., Chengcheng Zhao, Z. Wang, L.Z., F.W., Z. Wen, J.W., D.W.W., J.C., Chunxia Zhao)
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14
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Shen J, Zhao W, Cheng J, Cheng J, Zhao L, Dai C, Fu Y, Li B, Chen Z, Shi D, Li H, Deng Y. Lipopolysaccharide accelerates tryptophan degradation in the ovary and the derivative kynurenine disturbs hormone biosynthesis and reproductive performance. JOURNAL OF HAZARDOUS MATERIALS 2023; 458:131988. [PMID: 37418963 DOI: 10.1016/j.jhazmat.2023.131988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 07/01/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023]
Abstract
Lipopolysaccharide (LPS), also known as endotoxin, is a component of the outer membrane of gram-negative bacteria. LPS is released into the surrounding environment during bacterial death and lysis. Due to its chemical and thermal stability, LPS can be detected anywhere and easily exposed to humans and animals. Previous studies have shown that LPS causes hormonal imbalances, ovarian failure, and infertility in mammals. However, the potential mechanisms remain unclear. In this study, we investigated the effects and mechanisms of LPS on tryptophan degradation, both in vivo and in vitro. The effects of kynurenine, a tryptophan derivative, on granulosa cell function and reproductive performance were explored. Results showed that p38, NF-κB, and JNK signaling pathways were involved in LPS-induced Ido1 expressions and kynurenine accumulation. Furthermore, the kynurenine decreased estradiol production, but increased granulosa cell proliferation. In vivo, experiments showed that kynurenine decreased estradiol and FSH production and inhibited ovulation and corpus luteum formation. Additionally, pregnancy and offspring survival rates decreased considerably after kynurenine treatment. Our findings suggest that kynurenine accumulation disrupts hormone secretion, ovulation, corpus luteal formation, and reproductive performance in mammals.
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Affiliation(s)
- Jie Shen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China; Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Weimin Zhao
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Juanru Cheng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Jinhua Cheng
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Lei Zhao
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China; Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Chaohui Dai
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Yanfeng Fu
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Bixia Li
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Zhe Chen
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Hui Li
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China.
| | - Yanfei Deng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China.
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15
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Shadboorestan A, Koual M, Dairou J, Coumoul X. The Role of the Kynurenine/AhR Pathway in Diseases Related to Metabolism and Cancer. Int J Tryptophan Res 2023; 16:11786469231185102. [PMID: 37719171 PMCID: PMC10503295 DOI: 10.1177/11786469231185102] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/12/2023] [Indexed: 09/19/2023] Open
Abstract
The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand's battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.
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Affiliation(s)
- Amir Shadboorestan
- Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Meriem Koual
- T3S, INSERM UMR-S 1124, Université Paris Cité, Paris, France
- Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France
| | - Julien Dairou
- CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, Paris, France
| | - Xavier Coumoul
- T3S, INSERM UMR-S 1124, Université Paris Cité, Paris, France
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16
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Girithar HN, Staats Pires A, Ahn SB, Guillemin GJ, Gluch L, Heng B. Involvement of the kynurenine pathway in breast cancer: updates on clinical research and trials. Br J Cancer 2023; 129:185-203. [PMID: 37041200 PMCID: PMC10338682 DOI: 10.1038/s41416-023-02245-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 03/04/2023] [Accepted: 03/17/2023] [Indexed: 04/13/2023] Open
Abstract
Breast cancer (BrCa) is the leading cause of cancer incidence and mortality in women worldwide. While BrCa treatment has been shown to be highly successful if detected at an early stage, there are few effective strategies to treat metastatic tumours. Hence, metastasis remains the main cause in most of BrCa deaths, highlighting the need for new approaches in this group of patients. Immunotherapy has been gaining attention as a new treatment for BrCa metastasis and the kynurenine pathway (KP) has been suggested as one of the potential targets. The KP is the major biochemical pathway in tryptophan (TRP) metabolism, catabolising TRP to nicotinamide adenine dinucleotide (NAD+). The KP has been reported to be elevated under inflammatory conditions such as cancers and that its activity suppresses immune surveillance. Dysregulation of the KP has previously been reported implicated in BrCa. This review aims to discuss and provide an update on the current mechanisms involved in KP-mediated immune suppression and cancer growth. Furthermore, we also provide a summary on 58 studies about the involvement of the KP and BrCa and five clinical trials targeting KP enzymes and their outcome.
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Affiliation(s)
- Hemaasri-Neya Girithar
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Ananda Staats Pires
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Seong Beom Ahn
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Gilles J Guillemin
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Laurence Gluch
- The Strathfield Breast Centre, Strathfield, NSW, Australia
| | - Benjamin Heng
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
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17
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Stone TW, Williams RO. Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation-Cancer Interface. Cancers (Basel) 2023; 15:cancers15112895. [PMID: 37296860 DOI: 10.3390/cancers15112895] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 06/12/2023] Open
Abstract
The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.
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Affiliation(s)
- Trevor W Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Richard O Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
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18
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Pawlowski T, Malyszczak K, Pawlak D, Inglot M, Zalewska M, Grzywacz A, Radkowski M, Laskus T, Janocha-Litwin J, Frydecka D. HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV). Cells 2023; 12:cells12060970. [PMID: 36980311 PMCID: PMC10046909 DOI: 10.3390/cells12060970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. MATERIALS AND METHODS The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. RESULTS Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, LG/LG, and S/LG) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. CONCLUSIONS Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.
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Affiliation(s)
- Tomasz Pawlowski
- Department of Psychiatry, Wrocław Medical University, 50-367 Wrocław, Poland
| | | | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, 15-089 Białystok, Poland
| | - Małgorzata Inglot
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiency, Wroclaw Medical University, 50-367 Wrocław, Poland
| | - Małgorzata Zalewska
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiency, Wroclaw Medical University, 50-367 Wrocław, Poland
| | - Anna Grzywacz
- Independent Laboratory of Health Promotion, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Dorota Frydecka
- Department of Psychiatry, Wrocław Medical University, 50-367 Wrocław, Poland
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19
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Linking nervous and immune systems in psychiatric illness: A meta-analysis of the kynurenine pathway. Brain Res 2023; 1800:148190. [PMID: 36463958 DOI: 10.1016/j.brainres.2022.148190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022]
Abstract
Tryptophan is an essential amino acid absorbed by the gut depending on a homoeostatic microbiome. Up to 95% of unbound tryptophan is converted into tryptophan catabolites (TRYCATs) through the kynurenine system. Recent studies identified conflicting associations between altered levels of TRYCATs and genetic polymorphisms in major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). This meta-analysis aimed to understand how tryptophan catabolic pathways are altered in MDD, SCZ, and BD. When compared to healthy controls, participants with MDD had moderately lower levels of tryptophan associated with a moderate increase of kynurenine/tryptophan ratios and no differences in kynurenine. While significant differences were found in SCZ for any of the TRYCATs, studies on kynurenic acid found opposing directions of effect sizes depending on the sample source. Unique changes in levels of TRYCATs were also observed in BD. Dynamic changes in levels of cytokines and other immune/inflammatory elements modulate the transcription and activity of kynurenine system enzymes, which lastly seems to be impacting glutamatergic neurotransmission via N-methyl-D-aspartate and α-7 nicotine receptors.
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20
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Chen J, Li J, Qiao H, Hu R, Li C. Disruption of IDO signaling pathway alleviates chronic unpredictable mild stress-induced depression-like behaviors and tumor progression in mice with breast cancer. Cytokine 2023; 162:156115. [PMID: 36599202 DOI: 10.1016/j.cyto.2022.156115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/30/2022] [Accepted: 12/19/2022] [Indexed: 01/04/2023]
Abstract
Women with breast cancer (BC) are often combined with psychological disorder such as depression and anxiety. Depression is associated or correlated with increased toxicity and severity of physical symptoms. However, the mechanism of BC progression related to the regulation of emotion-related circuitry remains to be further explored. The study aims to investigate indoleamine 2,3-dioxygenase (IDO) pathway mechanism underlying stress-induced progression of BC. BC cell line 4T1 was subcutaneously inoculated into BALB/c mice, and they then received daily chronic unpredictable mild stressors (CUMS) for 12 weeks. Depression-like behavior tests were conducted, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and novelty suppressed feeding test (NSF). The levels of 5-Hydroxytryptamine (5-HT) and inflammatory factors, IL-6, CXCL1, IL-10 and IL-4 were measured by enzyme linked immunosorbent assay (ELISA) of mouse serum. Immunohistochemical staining was performed to detect Ki67- or FOXP3-positive tumor cells. The status of IDO signaling pathway was assessed by immunoblotting analysis. CUMS induced depression-like behaviors, decreased the level of 5-HT, promoted tumor progression, enhanced the immunohistochemical staining of Ki-67, and promoted the activation of IDO signaling pathway in BC mice. The IDO signaling pathway was disrupted in mice by lentiviral transduction of shRAN-IDO. Lentivirus-mediated IDO knockdown attenuated CUMS-induced depression-like behaviors, increased the level of 5-HT, inhibited tumor progression, and reduced the immunohistochemical staining of Ki-67 in BC mice. The present study suggests that disruption of IDO signaling pathway alleviates CUMS-induced depression-like behaviors and inhibits tumor progression in BC mice.
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Affiliation(s)
- Jun Chen
- Department of Acupuncture and Massage, Shaanxi University of Chinese Medicine, 1 Middle Section of Century Avenue, Qindu District, Xianyang 712046, China
| | - Jing Li
- Department of Chinese Medicine, The Sixth Medical Center of PLA Hospital, 6 Fucheng Road, Haidian District, Beijing 100048, China.
| | - Haifa Qiao
- Department of Acupuncture and Massage, Shaanxi University of Chinese Medicine, 1 Middle Section of Century Avenue, Qindu District, Xianyang 712046, China
| | - Rong Hu
- Department of Chinese Medicine, The Sixth Medical Center of PLA Hospital, 6 Fucheng Road, Haidian District, Beijing 100048, China
| | - Chaoqun Li
- Department of Chinese Medicine, The Sixth Medical Center of PLA Hospital, 6 Fucheng Road, Haidian District, Beijing 100048, China
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21
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The exploitation of enzyme-based cancer immunotherapy. Hum Cell 2023; 36:98-120. [PMID: 36334180 DOI: 10.1007/s13577-022-00821-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022]
Abstract
Cancer immunotherapy utilizes the immune system and its wide-ranging components to deliver anti-tumor responses. In immune escape mechanisms, tumor microenvironment-associated soluble factors and cell surface-bound molecules are mainly accountable for the dysfunctional activity of tumor-specific CD8+ T cells, natural killer (NK) cells, tumor associated macrophages (TAMs) and stromal cells. The myeloid-derived suppressor cells (MDSCs) and Foxp3+ regulatory T cells (Tregs), are also key tumor-promoting immune cells. These potent immunosuppressive networks avert tumor rejection at various stages, affecting immunotherapies' outcomes. Numerous clinical trials have elucidated that disruption of immunosuppression could be achieved via checkpoint inhibitors. Another approach utilizes enzymes that can restore the body's potential to counter cancer by triggering the immune system inhibited by the tumor microenvironment. These immunotherapeutic enzymes can catalyze an immunostimulatory signal and modulate the tumor microenvironment via effector molecules. Herein, we have discussed the immuno-metabolic roles of various enzymes like ATP-dephosphorylating ectoenzymes, inducible Nitric Oxide Synthase, phenylamine, tryptophan, and arginine catabolizing enzymes in cancer immunotherapy. Understanding the detailed molecular mechanisms of the enzymes involved in modulating the tumor microenvironment may help find new opportunities for cancer therapeutics.
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22
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Chen H, Huang X, Zeng C, Sun D, Liu F, Zhang J, Liao Q, Luo S, Xu W, Xiao Y, Zeng D, Song M, Tian F. The role of indoleamine 2,3-dioxygenase 1 in early-onset post-stroke depression. Front Immunol 2023; 14:1125634. [PMID: 36911716 PMCID: PMC9998486 DOI: 10.3389/fimmu.2023.1125634] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/13/2023] [Indexed: 03/14/2023] Open
Abstract
Background The immune-inflammatory response has been widely considered to be involved in the pathogenesis of post-stroke depression (PSD), but there is ambiguity about the mechanism underlying such association. Methods According to Diagnostic and Statistical Manual of Mental Disorders (5th edition), depressive symptoms were assessed at 2 weeks after stroke onset. 15 single nucleotide polymorphisms (SNPs) in genes of indoleamine 2,3-dioxygenase (IDO, including IDO1 and IDO2) and its inducers (including pro-inflammatory cytokines interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-2 and IL-6) were genotyped using SNPscan™ technology, and serum IDO1 levels were detected by double-antibody sandwich enzyme-linked immune-sorbent assay. Results Fifty-nine patients (31.72%) were diagnosed with depression at 2 weeks after stroke onset (early-onset PSD). The IDO1 rs9657182 T/T genotype was independently associated with early-onset PSD (adjusted odds ratio [OR] = 3.008, 95% confidence interval [CI] 1.157-7.822, p = 0.024) and the frequency of rs9657182 T allele was significantly higher in patients with PSD than that in patients with non-PSD (χ2 = 4.355, p = 0.037), but these results did not reach the Bonferroni significance threshold (p > 0.003). Serum IDO1 levels were also independently linked to early-onset PSD (adjusted OR = 1.071, 95% CI 1.002-1.145, p = 0.044) and patients with PSD had higher serum IDO1 levels than patients with non-PSD in the presence of the rs9657182 T allele but not homozygous C allele (t = -2.046, p = 0.043). Stroke patients with the TNF-α rs361525 G/G genotype had higher serum IDO1 levels compared to those with the G/A genotype (Z = -2.451, p = 0.014). Conclusions Our findings provided evidence that IDO1 gene polymorphisms and protein levels were involved in the development of early-onset PSD and TNF-α polymorphism was associated with IDO1 levels, supporting that IDO1 which underlie strongly regulation by cytokines may be a specific pathway for the involvement of immune-inflammatory mechanism in the pathophysiology of PSD.
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Affiliation(s)
- Hengshu Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Xia Huang
- Department of Critical Care Medicine, The First People's Hospital of Huaihua, Huaihua, China
| | - Chang Zeng
- Health Management Center, Xiangya Hospital, Central South University, Changsha, China
| | - Dongren Sun
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Fan Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Jingyuan Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Qiao Liao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Shihang Luo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Weiye Xu
- Department of Human Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yeqing Xiao
- Department of Neurology, Hengyang Central Hospital, Hengyang, China
| | - Danfeng Zeng
- Department of Neurology, Xiangtan Central Hospital, Xiangtan, China
| | - Mingyu Song
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Fafa Tian
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
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23
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Evrensel A. Microbiome-Induced Autoimmunity and Novel Therapeutic Intervention. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1411:71-90. [PMID: 36949306 DOI: 10.1007/978-981-19-7376-5_4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Microorganisms' flora, which colonize in many parts of our body, stand out as one of the most important components for a healthy life. This microbial organization called microbiome lives in integration with the body as a single and whole organ/system. Perhaps, the human first encounters the microbial activity it carries through the immune system. This encounter and interaction are vital for the development of immune system cells that protect the body against pathogenic organisms and infections throughout life. In recent years, it has been determined that some disruptions in the host-microbiome interaction play an important role in the physiopathology of autoimmune diseases. Although the details of this interaction have not been clarified yet, the focus is on leaky gut syndrome, dysbiosis, toll-like receptor ligands, and B cell dysfunction. Nutritional regulations, prebiotics, probiotics, fecal microbiota transplantation, bacterial engineering, and vaccination are being investigated as new therapeutic approaches in the treatment of problems in these areas. This article reviews recent research in this area.
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Affiliation(s)
- Alper Evrensel
- Department of Psychiatry, Uskudar University, Istanbul, Turkey
- NP Brain Hospital, Istanbul, Turkey
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24
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Stone TW, Clanchy FIL, Huang YS, Chiang NY, Darlington LG, Williams RO. An integrated cytokine and kynurenine network as the basis of neuroimmune communication. Front Neurosci 2022; 16:1002004. [PMID: 36507331 PMCID: PMC9729788 DOI: 10.3389/fnins.2022.1002004] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/31/2022] [Indexed: 11/25/2022] Open
Abstract
Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.
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Affiliation(s)
- Trevor W. Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom,*Correspondence: Trevor W. Stone,
| | - Felix I. L. Clanchy
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Yi-Shu Huang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Nien-Yi Chiang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - L. Gail Darlington
- Department of Internal Medicine, Ashtead Hospital, Ashtead, United Kingdom
| | - Richard O. Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
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25
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Identification of Canine Pyometra-Associated Metabolites Using Untargeted Metabolomics. Int J Mol Sci 2022; 23:ijms232214161. [PMID: 36430638 PMCID: PMC9697130 DOI: 10.3390/ijms232214161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/09/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022] Open
Abstract
Canine pyometra frequently occurs in middle-aged to older intact bitches, which seriously affects the life of dogs and brings an economic loss to their owners. Hence, finding a key metabolite is very important for the diagnosis and development of a new safe and effective therapy for the disease. In this study, dogs with pyometra were identified by blood examinations, laboratory analyses and diagnostic imaging, and fifteen endometrium tissues of sick dogs with pyometra and fifteen controls were collected and their metabolites were identified utilizing a UHPLC-qTOF-MS-based untargeted metabolomics approach. The results indicated that the elevated inflammatory cells were observed in dogs with pyometra, suggesting that sick dogs suffered systemic inflammation. In the untargeted metabolic profile, 705 ion features in the positive polarity mode and 414 ion features in the negative polarity mode were obtained in endometrium tissues of sick dogs with pyometra, with a total of 275 differential metabolites (173 in positive and 102 in negative polarity modes). Moreover, the multivariate statistical analyses such as PCA and PLS-DA also showed that the metabolites were significantly different between the two groups. Then, these differential metabolites were subjected to pathway analysis using Metaboanalyst 4.0, and Galactose metabolism, cAMP signaling pathway and Glycerophospholipid metabolism were enriched, proving some insights into the metabolic changes during pyometra. Moreover, the receiver operating characteristic curves further confirmed kynurenic acid was expected to be a candidate biomarker of canine pyometra. In conclusion, this study provided a new idea for exploring early diagnosis methods and a safe and effective therapy for canine pyometra.
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26
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Meng R, Fu Y, Zhang Y, Mou Y, Liu G, Fan H. Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice. Front Immunol 2022; 13:1032280. [PMID: 36439161 PMCID: PMC9691980 DOI: 10.3389/fimmu.2022.1032280] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2023] Open
Abstract
The cestode Echinococcus multilocularis larva infection causes lethal zoonotic alveolar echinococcosis (AE), a disease posing a great threat to the public health worldwide. This persistent hepatic tumor-like disease in AE patients has been largely attributed to aberrant T cell responses, of which Th1 responses are impeded, whilst Th2 and regulatory T cell responses are elevated, creating an immune tolerogenic microenvironment in the liver. However, the immune tolerance mechanisms are not fully understood. Dendritic cells (DCs) are key cellular components in facilitating immune tolerance in chronic diseases, including AE. Here, we demonstrate that indoleamine 2,3-dioxygenase 1-deficient (IDO1-/-) mice display less severe AE as compared to wild-type (WT) mice during the infection. Mechanistically, IDO1 prevents optimal T cells responses by programming DCs into a tolerogenic state. Specifically, IDO1 prevents the maturation and migration potential of DCs, as shown by the significantly enhanced expression of the antigen-presenting molecule (MHC II), costimulatory molecules (CD80 and CD86), and chemokine receptors (CXCR4 and CCR7) in infected IDO1-/- mice as compared to infected wild-type mice. More importantly, the tolerogenic phenotype of DCs is partly reverted in IDO1-/- mice, as indicated by enhanced activation, proliferation, and differentiation of both CD4+ and CD8+ - T cells upon infection with Echinococcus multilocularis, in comparison with WT mice. Interestingly, in absence of IDO1, CD4+ T cells are prone to differentiate to effector memory cells (CD44+CD62L-); in contrast, CD8+ T cells are highly biased to the central memory phenotype (CD44+CD62L+). Overall, these data are the first to demonstrate the essential role of IDO1 signaling in inducing immunosuppression in mice infected with Echinococcus multilocularis.
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Affiliation(s)
- Ru Meng
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), The Research Key Laboratory for Echinococcosis of Qinghai Province, Qinghai University, Xining, China
- Academician Zhang Yong Innovation Center, Xining Animal Disease Control Center, Xining, China
| | - Yong Fu
- Qinghai Academy of Animal Sciences and Veterinary Medicine, Qinghai University, Xining, China
| | - Yaogang Zhang
- Qinghai University Affiliated Hospital, Qinghai University, Xining, China
| | - Yalin Mou
- Qinghai University Affiliated Hospital, Qinghai University, Xining, China
| | - Gongguan Liu
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Haining Fan
- Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), The Research Key Laboratory for Echinococcosis of Qinghai Province, Qinghai University, Xining, China
- Qinghai University Affiliated Hospital, Qinghai University, Xining, China
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27
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Gu P, Ling B, Ma W, Zhang J, Zhang W, Zeng Y, Liu Y, Chi J, Ruan X, Zheng X, Wei S, Gao M. Indoleamine 2,3-dioxygenase 2 immunohistochemical expression in medullary thyroid carcinoma: implications in prognosis and immunomodulatory effects. BMC Cancer 2022; 22:1116. [PMID: 36319978 PMCID: PMC9624013 DOI: 10.1186/s12885-022-10173-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The linkage between IDO2 expression and cancer progression is still unclear, particularly in medullary thyroid carcinoma (MTC). Our purpose is to unveil the potential correlations between IDO2 status, clinical-pathological parameters, patients' prognosis, and the possible immunomodulatory functions in MTC. METHODS Immunohistochemical expression levels of IDO2 were evaluated in the resected MTC surgical specimens and corresponding lymph nodes. CD4 + T cell infiltration was also evaluated by immunohistochemical analysis in the MTC tissues. The association of the IDO2 expression level with clinicopathologic characteristics, overall survival (OS)/recurrence-free survival (RFS), and CD4 + T cell infiltration were retrospectively investigated. RESULTS High expression of IDO2 is closely associated with more aggressive clinicopathological features, such as multifocality, ETE, a higher pT stage and especially a higher pN stage. Moreover, a significant difference in RFS was observed between the IDO2-high and IDO2-low groups. IDO2 expression of lymph node tissues was significantly related to the metastasis status. Furthermore, we found that IDO2 expression is negatively correlated with CD4 + T cell infiltrations in MTC tissues. CONCLUSION The expression level of IDO2 is associated with aggressive characteristics and is predictive of poor prognosis in patients with MTC. Also, an interesting observation is that IDO2 involvement in MTC showed a moderate sexual dimorphism, of which female patients tend to be more affected by IDO2 status. Moreover, our results showed the potential immunomodulatory functions of IDO2. The close relationship between IDO2 and CD4 + T cell infiltration in the MTC microenvironment, together with its potential prognostic implications, makes it possible for IDO2 to serve as an alternative drug target in cancer immunotherapy and as a new prognostic tool.
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Affiliation(s)
- Pengfei Gu
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Bin Ling
- grid.411918.40000 0004 1798 6427Cancer Precision Medicine Center, Tianjin Cancer Hospital Airport Hospital, Tianjin, China ,grid.411918.40000 0004 1798 6427Center For Precision Cancer Medicine & Translational Research, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Weike Ma
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Jinming Zhang
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Wei Zhang
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Yu Zeng
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Yu Liu
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Jiadong Chi
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Xianhui Ruan
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Xiangqian Zheng
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Songfeng Wei
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China
| | - Ming Gao
- grid.411918.40000 0004 1798 6427Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, 300060 Tianjin, China ,grid.417031.00000 0004 1799 2675Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, 300121 Tianjin, China ,grid.417031.00000 0004 1799 2675Tianjin Key Laboratory of General Surgery in construction, Tianjin Union Medical Center, 300121 Tianjin, China
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28
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Ogbechi J, Huang YS, Clanchy FIL, Pantazi E, Topping LM, Darlington LG, Williams RO, Stone TW. Modulation of immune cell function, IDO expression and kynurenine production by the quorum sensor 2-heptyl-3-hydroxy-4-quinolone (PQS). Front Immunol 2022; 13:1001956. [PMID: 36389710 PMCID: PMC9650388 DOI: 10.3389/fimmu.2022.1001956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/05/2022] [Indexed: 12/29/2023] Open
Abstract
Many invasive micro-organisms produce 'quorum sensor' molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS.
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Affiliation(s)
- Joy Ogbechi
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Yi-Shu Huang
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Felix I. L. Clanchy
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Eirini Pantazi
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Louise M. Topping
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | | | - Richard O. Williams
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
| | - Trevor W. Stone
- The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculo-skeletal Sciences (NDORMS), University of Oxford, Oxford, United Kingdom
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29
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McRitchie BR, Akkaya B. Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment. Front Immunol 2022; 13:940052. [PMID: 36248808 PMCID: PMC9562032 DOI: 10.3389/fimmu.2022.940052] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022] Open
Abstract
The concept of cancer immunotherapy has gained immense momentum over the recent years. The advancements in checkpoint blockade have led to a notable progress in treating a plethora of cancer types. However, these approaches also appear to have stalled due to factors such as individuals' genetic make-up, resistant tumor sub-types and immune related adverse events (irAE). While the major focus of immunotherapies has largely been alleviating the cell-intrinsic defects of CD8+ T cells in the tumor microenvironment (TME), amending the relationship between tumor specific CD4+ T cells and CD8+ T cells has started driving attention as well. A major roadblock to improve the cross-talk between CD4+ T cells and CD8+ T cells is the immune suppressive action of tumor infiltrating T regulatory (Treg) cells. Despite their indispensable in protecting tissues against autoimmune threats, Tregs have also been under scrutiny for helping tumors thrive. This review addresses how Tregs establish themselves at the TME and suppress anti-tumor immunity. Particularly, we delve into factors that promote Treg migration into tumor tissue and discuss the unique cellular and humoral composition of TME that aids survival, differentiation and function of intratumoral Tregs. Furthermore, we summarize the potential suppression mechanisms used by intratumoral Tregs and discuss ways to target those to ultimately guide new immunotherapies.
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Affiliation(s)
- Bayley R. McRitchie
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Billur Akkaya
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
- Department of Microbial Infection and Immunity, The College of Medicine, The Ohio State University, Columbus, OH, United States
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Davidson M, Rashidi N, Nurgali K, Apostolopoulos V. The Role of Tryptophan Metabolites in Neuropsychiatric Disorders. Int J Mol Sci 2022; 23:ijms23179968. [PMID: 36077360 PMCID: PMC9456464 DOI: 10.3390/ijms23179968] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/27/2022] [Accepted: 08/31/2022] [Indexed: 12/20/2022] Open
Abstract
In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various detrimental influences on patients. Tryptophan is an important amino acid that plays an indisputable role in several physiological processes, including neuronal function and immunity. Tryptophan’s metabolism process in the human body occurs using different pathways, including the kynurenine and serotonin pathways. Furthermore, other biologically active components, such as serotonin, melatonin, and niacin, are by-products of Tryptophan pathways. Current evidence suggests that a functional imbalance in the synthesis of Tryptophan metabolites causes the appearance of pathophysiologic mechanisms that leads to various neuropsychiatric diseases. This review summarizes the pharmacological influences of tryptophan and its metabolites on the development of neuropsychiatric disorders. In addition, tryptophan and its metabolites quantification following the neurotransmitters precursor are highlighted. Eventually, the efficiency of various biomarkers such as inflammatory, protein, electrophysiological, genetic, and proteomic biomarkers in the diagnosis/treatment of neuropsychiatric disorders was discussed to understand the biomarker application in the detection/treatment of various diseases.
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Affiliation(s)
- Majid Davidson
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
- Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
| | - Niloufar Rashidi
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
- Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
- Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
- Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
- Immunology Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
- Correspondence:
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Hassan A, Khan AH, Saleem F, Ahmad H, Khan KM. A patent review on pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013-2021). Expert Opin Ther Pat 2022; 32:969-1001. [PMID: 35993146 DOI: 10.1080/13543776.2022.2116312] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Oxadiazole is a unique class of heterocycle, possessing numerous important biomedical and therapeutic applications such as anti-bacterial, anti-cancer, anti-inflammatory, inhibitors for diverse enzymes, receptors modulators, and neuroprotective properties. The rapid development in the field of oxadiazole-containing structures is confirmed by the development of numerous clinical drugs such as doxazosin, nesapidil, pleconaril, fasiplon, ataluren, zibotentan, and prenoxdiazine as selected examples. AREAS COVERED This review provides a comprehensive overview of the range of biological applications of oxadiazole-containing drugs in a range of patents from 2013 to 2021. The information was collected from available data sources including SciFinder, Reaxys, MedLine, and Chemical Abstracts. EXPERT OPINION Oxadiazole is an established class of compounds with fascinating biological properties. The importance of oxadiazoles can be recognized by their enormous application in a wide spectrum of medicinal chemistry from anticancer, antibiotic, and antidiabetic to the use in agriculture and neuroprotection. For instance, the oxadiazole-based compounds have shown the ability to modulate a variety of receptors including the M4 receptor agonists, S1P1 receptor modulators, SSTR5 antagonists, orexin type-2 receptor agonists, liver X receptor agonists, and many more. This testifies to the special features associated with the oxadiazole scaffold making it a significant pharmacophore.
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Affiliation(s)
- Abbas Hassan
- Department of Chemistry, Quaid-i-Azam University, Islamabad-45320 Pakistan
| | - Abid Hussain Khan
- Department of Chemistry, Quaid-i-Azam University, Islamabad-45320 Pakistan
| | - Faiza Saleem
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75720, Pakistan
| | - Haseen Ahmad
- Department of Chemistry, Quaid-i-Azam University, Islamabad-45320 Pakistan
| | - Khalid Mohammed Khan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75720, Pakistan.,Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P. O. Box 31441, Dammam Saudi Arabia
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Kynurenine Pathway-An Underestimated Factor Modulating Innate Immunity in Sepsis-Induced Acute Kidney Injury? Cells 2022; 11:cells11162604. [PMID: 36010680 PMCID: PMC9406744 DOI: 10.3390/cells11162604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological mechanisms are not well understood. Sepsis has the ability to modulate the function of cells belonging to the innate immune system. Increased activity of indoleamine 2,3-dioxygenase 1 (IDO1) and production of kynurenines are the major metabolic pathways utilized by innate immunity cells to maintain immunological tolerance. The activation of the kynurenine pathway (KP) plays a dual role in sepsis—in the early stage, the induction of IDO1 elicits strong proinflammatory effects that may lead to tissue damage and septic shock. Afterwards, depletion of tryptophan and production of kynurenines contribute to the development of immunosuppression that may cause the inability to overpower opportunistic infections. The presented review provides available data on the various interdependencies between elements of innate immunity and sepsis-induced AKI (SAKI) with particular emphasis on the immunomodulatory significance of KP in the above processes. We believe that KP activation may be one of the crucial, though underestimated, components of a deregulated host response to infection during SAKI.
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Peng X, Zhao Z, Liu L, Bai L, Tong R, Yang H, Zhong L. Targeting Indoleamine Dioxygenase and Tryptophan Dioxygenase in Cancer Immunotherapy: Clinical Progress and Challenges. Drug Des Devel Ther 2022; 16:2639-2657. [PMID: 35965963 PMCID: PMC9374094 DOI: 10.2147/dddt.s373780] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/03/2022] [Indexed: 11/30/2022] Open
Abstract
Indoleamine 2.3-dioxygenases (IDO1/2) and tryptophan 2.3-dioxygenase (TDO) are the initial and rate-limiting enzymes in tryptophan metabolism, which play an essential role in mediating immunosuppression in tumor microenvironment. Accumulating evidence has indicated that both IDO1 and TDO are highly expressed in many malignant tumors, and their expression is generally associated with reduced tumor-infiltrating immune cells, increased regulatory T-cell infiltration, as well as cancer progression and poor prognosis for malignancies. A large number of IDO1 and TDO inhibitors have been screened or synthesized in the last two decades. Thus far, at least 12 antagonists targeting IDO1 and TDO have advanced to clinical trials. In this account, we conducted a comprehensive review of the development of IDO1 and TDO inhibitors in cancer immunotherapy, particularly their clinical research progress, and presented the current challenges and corresponding solutions.
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Affiliation(s)
- Xuerun Peng
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Zhipeng Zhao
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Liwen Liu
- Department of Obstetrics and Gynecology, Fengrun District People’s Hospital, Tangshan, Hebei, 063000, People’s Republic of China
| | - Lan Bai
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Rongsheng Tong
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Hao Yang
- POWERCHINA Chengdu Engineering Corporation Limited, Chengdu, Sichuan, 610072, People’s Republic of China
| | - Lei Zhong
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, People’s Republic of China
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Artichoke Leaf Extract-Mediated Neuroprotection against Effects of Aflatoxin in Male Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4421828. [PMID: 35909495 PMCID: PMC9325642 DOI: 10.1155/2022/4421828] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/10/2022] [Accepted: 06/27/2022] [Indexed: 02/07/2023]
Abstract
Attenuation of adverse effects of aflatoxin (AFB1) in brains of B1 rats by extracts of leaves of artichoke was studied. The active ingredients in extracts of leaves of artichoke, Cynara scolymus L., were determined by HPLC analysis. In the 42-day experiment, rats were exposed to either sterile water, 4% DMSO, 100 mg artichoke leaf extract/kg body mass, 72 μg aflatoxin B1/kg body mass, or AFB1 plus artichoke leaf extract. Neurotoxicity of AFB1 was determined by an increase in profile of lipids, augmentation of plasmatic glucose and concentrations of insulin, oxidative stress, increased activities of cholinergic enzymes, and a decrease in activities of several antioxidant enzymes and pathological changes in brain tissue. Extracts of artichoke leaf significantly reduced adverse effects caused by AFB1, rescuing most of the parameters to values similar to unexposed controls, which demonstrated that adverse, neurotoxic effects caused by aflatoxin B1 could be significantly reduced by simultaneous dietary supplementation with artichoke leaf extract, which itself is not toxic.
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Liu X, Deng R, Chen Y, Huang S, Lu J, Zheng L, Xiong G, Li S. Jian-Pi-Yi-Shen Formula Improves Adenine-Induced Chronic Kidney Disease via Regulating Tryptophan Metabolism and Aryl Hydrocarbon Receptor Signaling. Front Pharmacol 2022; 13:922707. [PMID: 35865941 PMCID: PMC9294467 DOI: 10.3389/fphar.2022.922707] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
Traditional Chinese medicine (TCM) is an important complementary and alternative branch of chronic kidney disease (CKD) therapy. Jian-Pi-Yi-Shen formula (JPYSF) is a TCM formula used for treating CKD with good efficacy. However, the underlying mechanisms of JPYSF in treating CKD remain to be elucidated. The purpose of the present study was to investigate the renoprotective effect and potential mechanism of JPYSF in treating CKD. CKD rat model was induced by feeding a diet containing 0.75% w/w adenine for 4 weeks. JPYSF was given by gavage every day, starting from the 3rd week of the adenine-containing diet and continuing for 4 weeks at the dose of 10.89 g/kg. Renal injury was evaluated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathology, and fibrotic markers expression. Serum levels of tryptophan metabolites were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Aryl hydrocarbon receptor (AHR) signaling was tested by Western blot analysis. The results found that JPYSF treatment significantly lowered Scr and BUN levels, improved renal pathological injury, and down-regulated fibrotic markers expression in CKD rats. Furthermore, JPYSF significantly reduced the levels of 10 tryptophan metabolites in the serum of CKD rats and restored the level of tryptophan. Additionally, the kidney expression of AHR signaling was enhanced in CKD rats and was further suppressed in JPYSF treated rats. These results suggested that JPYSF protected against adenine-induced CKD via modulating tryptophan metabolism and AHR activation.
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Affiliation(s)
- Xinhui Liu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
- *Correspondence: Xinhui Liu, ; Guoliang Xiong, ; Shunmin Li,
| | - Ruyu Deng
- Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, China
| | - Yulian Chen
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Shiying Huang
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jiandong Lu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Lin Zheng
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Guoliang Xiong
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
- *Correspondence: Xinhui Liu, ; Guoliang Xiong, ; Shunmin Li,
| | - Shunmin Li
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
- *Correspondence: Xinhui Liu, ; Guoliang Xiong, ; Shunmin Li,
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Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia. Biomedicines 2022; 10:biomedicines10061332. [PMID: 35740354 PMCID: PMC9220124 DOI: 10.3390/biomedicines10061332] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 05/29/2022] [Accepted: 06/02/2022] [Indexed: 11/17/2022] Open
Abstract
Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome’s evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes.
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Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases. Metabolites 2022; 12:metabo12060514. [PMID: 35736447 PMCID: PMC9227929 DOI: 10.3390/metabo12060514] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 02/01/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and therefore is its burden of disease as NALFD is a risk factor for cirrhosis and is associated with other metabolic conditions such as type II diabetes, obesity, dyslipidaemia and atherosclerosis. Linking these cardiometabolic diseases is a state of low-grade inflammation, with higher cytokines and c-reactive protein levels found in individuals with NAFLD, obesity and type II diabetes. A possible therapeutic target to decrease this state of low-grade inflammation is the metabolism of the essential amino-acid tryptophan. Its three main metabolic pathways (kynurenine pathway, indole pathway and serotonin/melatonin pathway) result in metabolites such as kynurenic acid, xanturenic acid, indole-3-propionic acid and serotonin/melatonin. The kynurenine pathway is regulated by indoleamine 2,3-dioxygenase (IDO), an enzyme that is upregulated by pro-inflammatory molecules such as INF, IL-6 and LPS. Higher activity of IDO is associated with increased inflammation and fibrosis in NAFLD, as well with increased glucose levels, obesity and atherosclerosis. On the other hand, increased concentrations of the indole pathway metabolites, regulated by the gut microbiome, seem to result in more favorable outcomes. This narrative review summarizes the interactions between tryptophan metabolism, the gut microbiome and the immune system as potential drivers of cardiometabolic diseases in NAFLD.
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Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol 2022; 13:877772. [PMID: 35693009 PMCID: PMC9174654 DOI: 10.3389/fneur.2022.877772] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/19/2022] [Indexed: 12/16/2022] Open
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, "brain fog" affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.
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Affiliation(s)
- Warren Tate
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Max Walker
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Eiren Sweetman
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
| | - Amber Helliwell
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Katie Peppercorn
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - Christina Edgar
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Anna Blair
- Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia
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Abstract
Advances in proteomic and metabolomic technologies have accelerated our understanding of multiple aspects of cancer biology across distinct tumour types. Here we review the current state-of-the-art in the use of proteomics and metabolomics in soft tissue sarcomas. We highlight the utility of these Omics-based methodologies to identify new drug targets, synthetic lethal interactions, candidate therapeutics and novel biomarkers to facilitate patient stratification. Due to the unbiased and global nature of these profiling methods to assess the levels of protein expression, post-translational modifications such as phosphorylation and glycosylation as well as key metabolites, many of these findings have broad applications not just in specific histotypes but across multiple STS subtypes. Specific examples of proteomic and metabolomic findings that have led to the development of early phase clinical trials of investigational agents will be discussed. While promising, the use of these technologies in the study of sarcoma is still limited, and there is a need for further research in this area. In particular, it would be important to integrate these approaches with other Omics strategies such as genomics and epigenomics as well as implement these tools alongside clinical trials in order to maximize the impact of these tools on our biological understanding and treatment of this group of rare diseases of unmet need.
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Affiliation(s)
- Madhumeeta Chadha
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK
| | - Paul H Huang
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK.
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Tryptophan, Kynurenine and Kynurenic Acid Concentrations in Milk and Serum of Dairy Cows with Prototheca Mastitis. Animals (Basel) 2021; 11:ani11123608. [PMID: 34944383 PMCID: PMC8698139 DOI: 10.3390/ani11123608] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 12/22/2022] Open
Abstract
The aim of this work was to investigate serum and milk levels of tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA), as well as the activity of indoleamine 2,3-dioxygenase (IDO) in cows with mastitis due to Prototheca algae. The study was prompted by previous research showing a link between the KYN pathway of TRP metabolism and bovine mastitis of bacterial etiology. The study was carried out over a 2-year period (2018-2019) and included quarter milk and serum samples collected from six dairy herds in Poland. The samples were obtained from healthy cows and cows with Prototheca mastitis of either clinical and subclinical manifestation, as determined upon direct measurement of the somatic cell count or indirectly by performing a California Mastitis Test on suspected quarters. Both TRP and KYN concentrations were significantly lower in milk of mastitic cows compared to healthy animals (0.8 vs. 8.72 µM, p = 0.001; 0.07 vs. 0.32 µM, p = 0.001, respectively). The difference in TRP and KYN concentrations in the sera of the two animal groups was much less pronounced (25.55 vs. 27.57 µM, 3.03 vs. 3.56 nM, respectively). The concentration of KYNA was almost at the same level in milk (1.73 vs. 1.70 nM) and in serum (80.47 vs. 75.48 nM) of both mastitic and healthy cows. The data showed that the level of TRP and its metabolites in serum was conspicuously higher compared to milk in all cows under the study. The activity of IDO was significantly higher in milk of cows with Prototheca mastitis compared to healthy animals (71.4 vs. 40.86, p < 0.05), while in serum it was pretty much the same (135.94 vs. 124.98, p > 0.05). The IDO activity differed significantly between serum and milk both for mastitic (135.94 vs. 71.4, p < 0.05) and healthy cows (124.98 vs. 40.86, p < 0.001). In conclusion, low values of TRP and KYN concentrations or elevated IDO activity in milk samples might be used as markers of mastitis due to infectious causes, including Prototheca spp.
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Recent advances in clinical trials targeting the kynurenine pathway. Pharmacol Ther 2021; 236:108055. [PMID: 34929198 DOI: 10.1016/j.pharmthera.2021.108055] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/15/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022]
Abstract
The kynurenine pathway (KP) is the major catabolic pathway for the essential amino acid tryptophan leading to the production of nicotinamide adenine dinucleotide. In inflammatory conditions, the activation of the KP leads to the production of several bioactive metabolites including kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid and quinolinic acid. These metabolites can have redox and immune suppressive activity, be neurotoxic or neuroprotective. While the activity of the pathway is tightly regulated under normal physiological condition, it can be upregulated by immunological activation and inflammation. The dysregulation of the KP has been implicated in wide range of neurological diseases and psychiatric disorders. In this review, we discuss the mechanisms involved in KP-mediated neurotoxicity and immune suppression, and its role in diseases of our expertise including cancer, chronic pain and multiple sclerosis. We also provide updates on the clinical trials evaluating the efficacy of KP inhibitors and/or analogues in each respective disease.
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Myint K, Jacobs K, Myint AM, Lam SK, Lim YAL, Boey CCM, Hoe SZ, Guillemin GJ. Psychological Stresses in Children Trigger Cytokine- and Kynurenine Metabolite-Mediated Abdominal Pain and Proinflammatory Changes. Front Immunol 2021; 12:702301. [PMID: 34539633 PMCID: PMC8442661 DOI: 10.3389/fimmu.2021.702301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
Recurrent abdominal pain (RAP) is a common medically unexplained symptom among children worldwide. However, the biological mechanisms behind the development of functional and behavioral symptoms and changes in blood markers have not been well explored. This study aimed to assess changes in the concentrations of inflammatory markers, including cytokines and tryptophan catabolites, in the serum of children with RAP compared to those with subclinical infections. Children with RAP but without organic diseases were included, and those with asymptomatic intestinal parasitic infections were used as a subclinical infection cohort. Blood samples were collected and used to measure the cytokine profile using Multiplex Immunoassay and tryptophan catabolites using high performance liquid chromatography. Children with RAP showed significantly higher concentrations of serum tumor necrotic factor-α, p<0.05, but lower concentrations of IL-10, p<0.001, IL-6, p<0.001 and brain-derived neurotrophic factors (BDNF) p<0.01. In addition, a significant increase in the metabolite of the kynurenine pathway, 3-hydroxyanthranilic acid (3-HAA) p<0.01, a significant decrease in the concentrations of anthranilic acid (AA) p<0.001, together with an increased ratio of serum 3-HAA to AA (3-HAA/AA) p<0.001, was found in this cohort. These findings indicate the significant activation of the immune system and presence of inflammation in children with RAP than those with subclinical parasitic infections. Moreover, children with RAP tested with the Strengths and Difficulties Questionnaire (SDQ), displayed high psychological problems though these SDQ scores were not statistically associated with measured cytokines and kynurenine metabolites. We however could hypothesize that the pro-inflammatory state together with concomitant low concentrations of BDNF in those children with RAP could play a role in psychological stress and experiencing medically unexplained symptoms.
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Affiliation(s)
- Kyaimon Myint
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kelly Jacobs
- Neuroinflammation Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Aye-Mu Myint
- Psychoneuroimmunology Research Group, European Collaborative Project, Munich, Germany
| | - Sau Kuen Lam
- Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Bandar Sungai Long, Malaysia
| | - Yvonne Ai-Lian Lim
- Department of Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - See Ziau Hoe
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Gilles J Guillemin
- Neuroinflammation Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
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Afia AB, Vila È, MacDowell KS, Ormazabal A, Leza JC, Haro JM, Artuch R, Ramos B, Garcia-Bueno B. Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology. J Neuroinflammation 2021; 18:198. [PMID: 34511126 PMCID: PMC8436477 DOI: 10.1186/s12974-021-02260-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 08/30/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). METHODS This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. RESULTS In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. CONCLUSIONS Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.
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Affiliation(s)
- Amira Ben Afia
- Laboratory of Genetics, Biodiversity and Bioresource Valorization, Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia
| | - Èlia Vila
- Psiquiatria Molecular, Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Barcelona, Spain
| | - Karina S MacDowell
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain
| | - Aida Ormazabal
- Clinical Chemistry Department, Institut de recerca Sant Joan de Déu and CIBERER-ISCIII, Passeig Sant Joan de Déu, 2. 08950, Esplugues de Llobregat, Barcelona, Spain
| | - Juan C Leza
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain.,Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain
| | - Josep M Haro
- Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain.,Parc Sanitari Sant Joan de Déu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Barcelona, Spain
| | - Rafael Artuch
- Clinical Chemistry Department, Institut de recerca Sant Joan de Déu and CIBERER-ISCIII, Passeig Sant Joan de Déu, 2. 08950, Esplugues de Llobregat, Barcelona, Spain
| | - Belén Ramos
- Psiquiatria Molecular, Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Dr. Antoni Pujadas, 42, 08830 Sant Boi de Llobregat, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain. .,Dept. de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain.
| | - Borja Garcia-Bueno
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Instituto Universitario de Investigación en Neuroquímica UCM, Avda. Complutense s/n, 28040, Madrid, Spain. .,Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (Biomedical Network Research Center of Mental Health), Ministry of Economy, Industry and Competitiveness Institute of Health Carlos III, Madrid, Spain.
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Li C, Zhao H. Tryptophan and Its Metabolites in Lung Cancer: Basic Functions and Clinical Significance. Front Oncol 2021; 11:707277. [PMID: 34422661 PMCID: PMC8377361 DOI: 10.3389/fonc.2021.707277] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 07/15/2021] [Indexed: 01/03/2023] Open
Abstract
Lung cancer is the most lethal malignancy worldwide. Recently, it has been recognized that metabolic reprogramming is a complex and multifaceted factor, contributing to the process of lung cancer. Tryptophan (Try) is an essential amino acid, and Try and its metabolites can regulate the progression of lung cancer. Here, we review the pleiotropic functions of the Try metabolic pathway, its metabolites, and key enzymes in the pathogenic process of lung cancer, including modulating the tumor environment, promoting immune suppression, and drug resistance. We summarize the recent advance in therapeutic drugs targeting the Try metabolism and kynurenine pathway and their clinical trials.
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Affiliation(s)
- Chenwei Li
- Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hui Zhao
- Department of Health Examination Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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45
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The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response. Mol Psychiatry 2021; 26:4085-4095. [PMID: 31732715 PMCID: PMC7225078 DOI: 10.1038/s41380-019-0589-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 10/21/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022]
Abstract
Dysfunction in a wide array of systems-including the immune, monoaminergic, and glutamatergic systems-is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18-65) received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes-including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)-were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.
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46
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Asghar K, Farooq A, Zulfiqar B, Loya A. Review of 10 years of research on breast cancer patients: Focus on indoleamine 2,3-dioxygenase. World J Clin Oncol 2021; 12:429-436. [PMID: 34189067 PMCID: PMC8223715 DOI: 10.5306/wjco.v12.i6.429] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/30/2020] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology. Immunosuppression regulates antitumour immune responses. An immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO) mediates tumour immune escape in various malignancies including breast cancer. IDO upregulation in breast cancer cells may lead to the recruitment of regulatory T (T-regs) cells into the tumour microenvironment, thus inhibiting local immune responses and promoting metastasis. Immunosuppression induced by myeloid derived suppressor cells activated in an IDO-dependent manner may enhance the possibility of immune evasion in breast cancer. IDO overexpression has independent prognostic significance in a subtype of breast cancer of emerging interest, basal-like breast carcinoma. IDO inhibitors as adjuvant therapeutic agents may have clinical implications in breast cancer. This review proposes future prospects of IDO not only as a therapeutic target but also as a valuable prognostic marker for breast cancer.
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Affiliation(s)
- Kashif Asghar
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
| | - Asim Farooq
- Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
| | - Bilal Zulfiqar
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia
| | - Asif Loya
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
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Effects of stress associated with academic examination on the kynurenine pathway profile in healthy students. PLoS One 2021; 16:e0252668. [PMID: 34081742 PMCID: PMC8174692 DOI: 10.1371/journal.pone.0252668] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 05/20/2021] [Indexed: 12/16/2022] Open
Abstract
The effects of stress on the neuroendocrine, central nervous and immune systems are extremely complex. The kynurenine pathway (KP) of the tryptophan metabolism is recognised as a cross-link between the neuroendocrine- and immune systems. However, the effects of acute stress from everyday life on KP activation have not yet been studied. This study aims to investigate changes in the levels of the KP neuroactive metabolites and cytokines in response to stress triggered by academic examinations. Ninety-two healthy first year medical students benevolently participated in the study. Parameters were measured pre- examination, which is considered to be a high-stress period, and post-examination, as a low-stress period. Stress induced by academic examinations significantly increases the perceived stress scores (p<0.001), serum cortisol levels (p<0.001) and brain-derived neurotrophic factor (BDNF) levels (p<0.01). It decreased IL-10 levels (p<0.05) but had no effect on IL-6 and TNF-alpha levels. Only the KP neuroactive metabolite, 3-hydroxykynurenine (3-HK) significantly increased (p<0.01) in the post-examination period. In addition, the stress scores positively correlated with the levels of cortisol (r2 = 0.297, p<0.01) at post examination. Acute stress triggered by academic examinations increases cortisol and BDNF production and suppresses the anti-inflammatory cytokine, IL-10, but did not increase significantly the levels of other pro-inflammatory cytokines, tryptophan, kynurenine and downstream KP metabolites. The concomitant increased levels of BDNF under the duress of acute examination stress appear to limit the levels pro-inflammatory markers, which may attenuate the action of cortisol and the neuroinflammatory branch of the KP.
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48
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Li P, Xu W, Liu F, Zhu H, Zhang L, Ding Z, Liang H, Song J. The emerging roles of IDO2 in cancer and its potential as a therapeutic target. Biomed Pharmacother 2021; 137:111295. [PMID: 33550042 DOI: 10.1016/j.biopha.2021.111295] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/10/2021] [Accepted: 01/18/2021] [Indexed: 01/03/2023] Open
Abstract
During the past decades, tryptophan metabolism disorder was discovered to play a vital and complex role in the development of cancer. Indoleamine 2,3-dioxygenase 2 (IDO2) is one of the initial and rate-limiting enzymes of the kynurenine pathway of tryptophan catabolism. Increasing evidence indicates that IDO2 is upregulated in some tumors and plays a role in the development of cancer. In spite of the growing body of research, few reviews focused on the role of IDO2 in cancer. Here, we review the emerging knowledge on the roles of IDO2 in cancer and its potential as a therapeutic target. Firstly, the main biological features and regulatory mechanisms are reviewed, after which we focus on the expression and roles of IDO2 in cancer. Finally, we discuss the potential of IDO2 as a therapeutic target for cancer treatment.
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Affiliation(s)
- Pengcheng Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weiqi Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - He Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Tang K, Wu YH, Song Y, Yu B. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J Hematol Oncol 2021; 14:68. [PMID: 33883013 PMCID: PMC8061021 DOI: 10.1186/s13045-021-01080-8] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/14/2021] [Indexed: 12/15/2022] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L-tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the "proteolysis targeting chimera" (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.
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Affiliation(s)
- Kai Tang
- School of Pharmaceutical Sciences and Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China
| | - Ya-Hong Wu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Yihui Song
- School of Pharmaceutical Sciences and Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China
| | - Bin Yu
- School of Pharmaceutical Sciences and Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China.
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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50
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Zhao Y, Tao F, Jiang J, Chen L, Du J, Cheng X, He Q, Zhong S, Chen W, Wu X, Ou R, Xu Y, Tang KF. Tryptophan 2, 3‑dioxygenase promotes proliferation, migration and invasion of ovarian cancer cells. Mol Med Rep 2021; 23:445. [PMID: 33846800 PMCID: PMC8060793 DOI: 10.3892/mmr.2021.12084] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 03/01/2021] [Indexed: 11/24/2022] Open
Abstract
Tryptophan 2,3-dioxygenase (TDO2) is a key rate-limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription-quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype-Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that RasV12-mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.
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Affiliation(s)
- Yuemei Zhao
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Fengxing Tao
- Department of Dermato‑Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Jiayu Jiang
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Lina Chen
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Jizao Du
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Xiaoxiao Cheng
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Qin He
- Department of Medical Ultrasonics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Shouhui Zhong
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Wei Chen
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Xiaoli Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Rongying Ou
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Yunsheng Xu
- Department of Dermato‑Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
| | - Kai-Fu Tang
- Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, P.R. China
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