Indoleamine-2,3-Dioxygenase as a Perioperative Marker of the Immune System

Indoleamine-2,3-dioxygenase (IDO) is the “rate-limiting” enzyme in the kynurenine (Kyn) pathway of the tryptophan (Trp) catabolism. By its immune-modulatory effect, IDO initiates changes to the physiologically balanced immune state and plays a key role in the pathogenesis of various diseases, as well as in the perioperative setting during surgery. In autoimmune processes, highly malignant cancers such as glioblastoma or organ transplantation, IDO’s involvement has been studied extensively. However, in severe systemic infections, as present in sepsis, it is not yet completely understood. Hereafter, in this narrative review, we present the current knowledge of IDO’s implication on such complex immune-related processes. Moreover, we address the role of IDO as a predictive biomarker as well as a therapeutic target for immune-mediated diseases. Finally, we discuss IDO in the setting of surgical trauma-induced stress and highlight its promising use as a biomarker in the pre-operative setting for all disciplines involved in the decision-making process and treatment of patients undergoing surgery.

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The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall

Cardiovascular Research ◽

10.1093/cvr/cvz067 ◽

2019 ◽

Vol 115 (9) ◽

pp. 1408-1415 ◽

Cited By ~ 8

Author(s):

Daniel F J Ketelhuth

Keyword(s):

Current Knowledge ◽

Large Body ◽

Vascular Wall ◽

Kynurenine Pathway ◽

Atherosclerotic Cardiovascular Disease ◽

Artery Wall ◽

Indoleamine 2,3 Dioxygenase ◽

Rate Limiting ◽

Accumulation Of Lipids

AbstractCoronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.

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Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽

10.3390/cancers13040909 ◽

2021 ◽

Vol 13 (4) ◽

pp. 909

Author(s):

Krzysztof Kotowski ◽

Jakub Rosik ◽

Filip Machaj ◽

Stanisław Supplitt ◽

Daniel Wiczew ◽

...

Keyword(s):

Current Knowledge ◽

Treatment Options ◽

Protein Structures ◽

New Drugs ◽

Proliferating Cells ◽

Cancer Tissues ◽

The Impact ◽

Rate Limiting ◽

Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

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GTP metabolic reprogramming by IMPDH2: unlocking cancer cells’ fuelling mechanism

The Journal of Biochemistry ◽

10.1093/jb/mvaa085 ◽

2020 ◽

Vol 168 (4) ◽

pp. 319-328 ◽

Cited By ~ 1

Author(s):

Satoshi Kofuji ◽

Atsuo T Sasaki

Keyword(s):

De Novo ◽

Current Knowledge ◽

Metabolic Reprogramming ◽

Inosine Monophosphate Dehydrogenase ◽

Metabolic Demand ◽

Adaptive Mechanisms ◽

Key Aspects ◽

Polymerase I ◽

Rate Limiting

Abstract Growing cells increase multiple biosynthetic processes in response to the high metabolic demands needed to sustain proliferation. The even higher metabolic requirements in the setting of cancer provoke proportionately greater biosynthesis. Underappreciated key aspects of this increased metabolic demand are guanine nucleotides and adaptive mechanisms to regulate their concentration. Using the malignant brain tumour, glioblastoma, as a model, we have demonstrated that one of the rate-limiting enzymes for guanosine triphosphate (GTP) synthesis, inosine monophosphate dehydrogenase-2 (IMPDH2), is increased and IMPDH2 expression is necessary for the activation of de novo GTP biosynthesis. Moreover, increased IMPDH2 enhances RNA polymerase I and III transcription directly linking GTP metabolism to both anabolic capacity as well as nucleolar enlargement historically observed as associated with cancer. In this review, we will review in detail the basis of these new discoveries and, more generally, summarize the current knowledge on the role of GTP metabolism in cancer.

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Evidence for a Potential Role of Metallothioneins in Inflammatory Bowel Diseases

Mediators of Inflammation ◽

10.1155/2009/729172 ◽

2009 ◽

Vol 2009 ◽

pp. 1-9 ◽

Cited By ~ 23

Author(s):

Anouk Waeytens ◽

Martine De Vos ◽

Debby Laukens

Keyword(s):

Inflammatory Bowel Diseases ◽

Potential Role ◽

Current Knowledge ◽

Zinc Homeostasis ◽

Central Position ◽

Small Proteins ◽

Immune Mediated ◽

Bowel Diseases ◽

Inflammatory Bowel

Inflammatory bowel diseases (IBDs) are a group of chronic, relapsing, immune-mediated disorders of the intestine, including Crohn's disease and ulcerative colitis. Recent studies underscore the importance of the damaged epithelial barrier and the dysregulated innate immune system in their pathogenesis. Metallothioneins (MTs) are a family of small proteins with a high and conserved cysteine content that are rapidly upregulated in response to an inflammatory stimulus. Herein, we review the current knowledge regarding the expression and potential role of MTs in IBD. MTs exert a central position in zinc homeostasis, modulate the activation of the transcription factor nuclear factor (NF)-B, and serve as antioxidants. In addition, MTs could be involved in IBD through their antiapoptotic effects or through specific immunomodulating extracellular effects. Reports on MT expression in IBD are contradictory but clearly demonstrate a deviant MT expression supporting the idea that these aberrations in IBD require further clarification.

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The role of miR-101 in esophageal and gastric cancer

Personalized Medicine ◽

10.2217/pme-2021-0024 ◽

2021 ◽

Author(s):

Athanasios Syllaios ◽

Stratigoula Sakellariou ◽

Nikolaos Garmpis ◽

Eleni Sarlani ◽

Christos Damaskos ◽

...

Keyword(s):

Gastric Cancer ◽

Crucial Role ◽

Cancer Biology ◽

Current Knowledge ◽

Predictive Biomarker ◽

Exact Role ◽

Esophagogastric Cancer ◽

Cell Progression ◽

Cancer Types

miR-101 is downregulated in various types of cancer, leading to the notion that miR-101 acts as a suppressor in cancer cell progression. The comprehensive mechanisms underlying the effects of miR-101 and the exact role of miR-101 dysregulations in esophagogastric tumors have not been fully elucidated. This review aims to summarize all current knowledge on the association between miR-101 expression and esophagogastric malignancies and to clarify the pathogenetic pathways and the possible prognostic and therapeutic role of miR-101 in those cancer types. miR-101 seems to play crucial role in esophageal and gastric cancer biology and tumorigenesis. It could also be a promising novel diagnostic and therapeutic target, as well as it may serve as a significant predictive biomarker in esophagogastric cancer.

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Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607152113 ◽

2016 ◽

Vol 113 (44) ◽

pp. E6806-E6812 ◽

Cited By ~ 101

Author(s):

Yang Ou ◽

Shang-Jui Wang ◽

Dawei Li ◽

Bo Chu ◽

Wei Gu

Keyword(s):

Cell Death ◽

Metabolic Pathways ◽

Cell Metabolism ◽

Specific Inhibitor ◽

Polyamine Metabolism ◽

Cycle Arrest ◽

Induced Stress ◽

Rate Limiting ◽

Insight Into

Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N1-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9–mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.

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Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections

Thrombosis and Haemostasis ◽

10.1160/th09-05-0323 ◽

2009 ◽

Vol 102 (12) ◽

pp. 1103-1109 ◽

Cited By ~ 49

Author(s):

Julia Eitel ◽

Karolin Meixenberger ◽

Norbert Suttorp ◽

Bastian Opitz

Keyword(s):

Endothelial Cells ◽

Current Knowledge ◽

Adaptive Immune Response ◽

Vascular Diseases ◽

Innate Immune ◽

Toll Like Receptors ◽

Surface Molecules ◽

Adaptive Immune ◽

Systemic Infections

SummaryBacteraemia and viraemia are characterised by pathogens entering the bloodstream. Endothelial cells are among the first cells coming into contact with the microbes and also some endogenous molecules which are released by tissue damage. As part of the innate immune system, endothelial cells respond to these contacts by producing inflammatory mediators and expressing surface molecules. The initial sensing of microbial and endogenous danger-associated molecules is mediated by so-called pattern recognition receptors (PRRs). PRRs can be classified in different protein families such as the Toll-like receptors, the NODlike receptors and the RIG-I-like receptors. By activating inflammatory gene transcription and posttranslational processing, PRRs control the immediate innate immune reaction and also the subsequent adaptive immune response. Here we describe the current knowledge of extra-and intracellular PRRs in endothelial cells and their potential role in sepsis and vascular diseases.

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Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases

Mediators of Inflammation ◽

10.1155/2013/391984 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 33

Author(s):

Yuki Murakami ◽

Masato Hoshi ◽

Yukio Imamura ◽

Yuko Arioka ◽

Yasuko Yamamoto ◽

...

Keyword(s):

Infectious Diseases ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Type I Interferons ◽

Regulatory Function ◽

Type I ◽

Indoleamine 2,3 Dioxygenase ◽

Tryptophan Metabolites

Indoleamine 2,3-dioxygenase 1 (IDO1), the L-tryptophan-degrading enzyme, plays a key role in the immunomodulatory effects on several types of immune cells. Originally known for its regulatory function during pregnancy and chronic inflammation in tumorigenesis, the activity of IDO1 seems to modify the inflammatory state of infectious diseases. The pathophysiologic activity of L-tryptophan metabolites, kynurenines, is well recognized. Therefore, an understanding of the regulation of IDO1 and the subsequent biochemical reactions is essential for the design of therapeutic strategies in certain immune diseases. In this paper, current knowledge about the role of IDO1 and its metabolites during various infectious diseases is presented. Particularly, the regulation of type I interferons (IFNs) production via IDO1 in virus infection is discussed. This paper offers insights into new therapeutic strategies in the modulation of viral infection and several immune-related disorders.

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PROLIDASE: A Review from Discovery to its Role in Health and Disease

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.723003 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ireti Eni-Aganga ◽

Zeljka Miletic Lanaghan ◽

Muthukumar Balasubramaniam ◽

Chandravanu Dash ◽

Jui Pandhare

Keyword(s):

Wound Healing ◽

Current Knowledge ◽

Matrix Remodeling ◽

Physiological Processes ◽

Rate Limiting Step ◽

Comprehensive Information ◽

Health And Disease ◽

Rate Limiting ◽

Peptidase D

Prolidase (peptidase D), encoded by the PEPD gene, is a ubiquitously expressed cytosolic metalloproteinase, the only enzyme capable of cleaving imidodipeptides containing C-terminal proline or hydroxyproline. Prolidase catalyzes the rate-limiting step during collagen recycling and is essential in protein metabolism, collagen turnover, and matrix remodeling. Prolidase, therefore plays a crucial role in several physiological processes such as wound healing, inflammation, angiogenesis, cell proliferation, and carcinogenesis. Accordingly, mutations leading to loss of prolidase catalytic activity result in prolidase deficiency a rare autosomal recessive metabolic disorder characterized by defective wound healing. In addition, alterations in prolidase enzyme activity have been documented in numerous pathological conditions, making prolidase a useful biochemical marker to measure disease severity. Furthermore, recent studies underscore the importance of a non-enzymatic role of prolidase in cell regulation and infectious disease. This review aims to provide comprehensive information on prolidase, from its discovery to its role in health and disease, while addressing the current knowledge gaps.

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Mesophyll conductance: the leaf corridors for photosynthesis

Biochemical Society Transactions ◽

10.1042/bst20190312 ◽

2020 ◽

Vol 48 (2) ◽

pp. 429-439 ◽

Cited By ~ 3

Author(s):

Jorge Gago ◽

Danilo M. Daloso ◽

Marc Carriquí ◽

Miquel Nadal ◽

Melanie Morales ◽

...

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Main Role ◽

Mesophyll Conductance ◽

Future Studies ◽

Cell Structures ◽

Leaf Tissues ◽

Change Framework ◽

Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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