The role of gene fusions in the evolution of metabolic pathways: the histidine biosynthesis case

Identification of the NSCLC subtype at an early stage is still quite sophisticated. Metabolomics analysis of tissue and plasma of NSCLC patients may indicate new, and yet unknown, metabolic pathways active in the NSCLC. Our research characterized the metabolomics profile of tissue and plasma of patients with early and advanced NSCLC stage. Samples were subjected to thorough metabolomics analyses using liquid chromatography-mass spectrometry (LC-MS) technique. Tissue and/or plasma samples from 137 NSCLC patients were analyzed. Based on the early stage tissue analysis, more than 200 metabolites differentiating adenocarcinoma (ADC) and squamous cell lung carcinoma (SCC) subtypes as well as normal tissue, were identified. Most of the identified metabolites were amino acids, fatty acids, carnitines, lysoglycerophospholipids, sphingomyelins, plasmalogens and glycerophospholipids. Moreover, metabolites related to N-acyl ethanolamine (NAE) biosynthesis, namely glycerophospho (N-acyl) ethanolamines (GP-NAE), which discriminated early-stage SCC from ADC, have also been identified. On the other hand, the analysis of plasma of chronic obstructive pulmonary disease (COPD) and NSCLC patients allowed exclusion of the metabolites related to the inflammatory state in lungs and the identification of compounds (lysoglycerophospholipids, glycerophospholipids and sphingomyelins) truly characteristic to cancer. Our results, among already known, showed novel, thus far not described, metabolites discriminating NSCLC subtypes, especially in the early stage of cancer. Moreover, the presented results also indicated the activity of new metabolic pathways in NSCLC. Further investigations on the role of NAE biosynthesis pathways in the early stage of NSCLC may reveal new prognostic and diagnostic targets.

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The Role of Cell Metabolism in Innate Immune Memory

Journal of Innate Immunity ◽

10.1159/000512280 ◽

2020 ◽

pp. 1-9

Author(s):

Anaisa Valido Ferreira ◽

Jorge Domiguéz-Andrés ◽

Mihai Gheorghe Netea

Keyword(s):

Metabolic Pathways ◽

Tricarboxylic Acid Cycle ◽

Cell Metabolism ◽

Innate Immune ◽

Immune Memory ◽

Functional Changes ◽

Trained Immunity ◽

Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

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Mitochondrial Sirtuins in Reproduction

Antioxidants ◽

10.3390/antiox10071047 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1047

Author(s):

Giovanna Di Emidio ◽

Stefano Falone ◽

Paolo Giovanni Artini ◽

Fernanda Amicarelli ◽

Anna Maria D’Alessandro ◽

...

Keyword(s):

Stress Responses ◽

Metabolic Pathways ◽

Redox Balance ◽

Antioxidant Defenses ◽

Metabolic Abnormalities ◽

Female Reproduction ◽

Mitochondrial Dysfunctions ◽

Early Embryos ◽

The Relationship

Mitochondria act as hubs of numerous metabolic pathways. Mitochondrial dysfunctions contribute to altering the redox balance and predispose to aging and metabolic alterations. The sirtuin family is composed of seven members and three of them, SIRT3-5, are housed in mitochondria. They catalyze NAD+-dependent deacylation and the ADP-ribosylation of mitochondrial proteins, thereby modulating gene expression and activities of enzymes involved in oxidative metabolism and stress responses. In this context, mitochondrial sirtuins (mtSIRTs) act in synergistic or antagonistic manners to protect from aging and aging-related metabolic abnormalities. In this review, we focus on the role of mtSIRTs in the biological competence of reproductive cells, organs, and embryos. Most studies are focused on SIRT3 in female reproduction, providing evidence that SIRT3 improves the competence of oocytes in humans and animal models. Moreover, SIRT3 protects oocytes, early embryos, and ovaries against stress conditions. The relationship between derangement of SIRT3 signaling and the imbalance of ROS and antioxidant defenses in testes has also been demonstrated. Very little is known about SIRT4 and SIRT5 functions in the reproductive system. The final goal of this work is to understand whether sirtuin-based signaling may be taken into account as potential targets for therapeutic applications in female and male infertility.

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The Pleiotropic Function of Human Sirtuins as Modulators of Metabolic Pathways and Viral Infections

Cells ◽

10.3390/cells10020460 ◽

2021 ◽

Vol 10 (2) ◽

pp. 460

Author(s):

Mohammed Hamed Alqarni ◽

Ahmed Ibrahim Foudah ◽

Magdy Mohamed Muharram ◽

Nikolaos E. Labrou

Keyword(s):

Metabolic Pathways ◽

Histone Deacetylases ◽

Viral Infections ◽

Cell Physiology ◽

Functional Roles ◽

Regulatory Processes ◽

Complex Functions ◽

Natural Polyphenol ◽

Antiviral Targets

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent histone deacetylases that incorporate complex functions in the mechanisms of cell physiology. Mammals have seven distinct members of the SIRT family (SIRT1-7), which play an important role in a well-maintained network of metabolic pathways that control and adapt the cell to the environment, energy availability and cellular stress. Until recently, very few studies investigated the role of SIRTs in modulating viral infection and progeny. Recent studies have demonstrated that SIRT1 and SIRT2 are promising antiviral targets because of their specific connection to numerous metabolic and regulatory processes affected during infection. In the present review, we summarize some of the recent progress in SIRTs biochemistry and their emerging function as antiviral targets. We also discuss the potential of natural polyphenol-based SIRT modulators to control their functional roles in several diseases including viral infections.

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Placental 13C-DHA metabolism and relationship with maternal BMI, glycemia and birthweight

Molecular Medicine ◽

10.1186/s10020-021-00344-w ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Oliver C. Watkins ◽

Preben Selvam ◽

Reshma Appukuttan Pillai ◽

Victoria K. B. Cracknell-Hazra ◽

Hannah E. J. Yong ◽

...

Keyword(s):

Mass Spectrometry ◽

Liquid Chromatography ◽

Lipid Metabolism ◽

Metabolic Pathways ◽

Liquid Chromatography Mass Spectrometry ◽

Fasting Glycemia ◽

Glucose Treatment ◽

Maternal Bmi

Abstract Background Fetal docosahexaenoic acid (DHA) supply relies on preferential transplacental transfer, which is regulated by placental DHA lipid metabolism. Maternal hyperglycemia and obesity associate with higher birthweight and fetal DHA insufficiency but the role of placental DHA metabolism is unclear. Methods Explants from 17 term placenta were incubated with 13C-labeled DHA for 48 h, at 5 or 10 mmol/L glucose treatment, and the production of 17 individual newly synthesized 13C-DHA labeled lipids quantified by liquid chromatography mass spectrometry. Results Maternal BMI positively associated with 13C-DHA-labeled diacylglycerols, triacylglycerols, lysophospholipids, phosphatidylcholine and phosphatidylethanolamine plasmalogens, while maternal fasting glycemia positively associated with five 13C-DHA triacylglycerols. In turn, 13C-DHA-labeled phospholipids and triacylglycerols positively associated with birthweight centile. In-vitro glucose treatment increased most 13C-DHA-lipids, but decreased 13C-DHA phosphatidylethanolamine plasmalogens. However, with increasing maternal BMI, the magnitude of the glucose treatment induced increase in 13C-DHA phosphatidylcholine and 13C-DHA lysophospholipids was curtailed, with further decline in 13C-DHA phosphatidylethanolamine plasmalogens. Conversely, with increasing birthweight centile glucose treatment induced increases in 13C-DHA triacylglycerols were exaggerated, while glucose treatment induced decreases in 13C-DHA phosphatidylethanolamine plasmalogens were diminished. Conclusions Maternal BMI and glycemia increased the production of different placental DHA lipids implying impact on different metabolic pathways. Glucose-induced elevation in placental DHA metabolism is moderated with higher maternal BMI. In turn, findings of associations between many DHA lipids with birthweight suggest that BMI and glycemia promote fetal growth partly through changes in placental DHA metabolism.

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PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

Cancers ◽

10.3390/cancers13020164 ◽

2021 ◽

Vol 13 (2) ◽

pp. 164

Author(s):

Federica Costa ◽

Valentina Marchica ◽

Paola Storti ◽

Fabio Malavasi ◽

Nicola Giuliani

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Survival ◽

Immune Suppression ◽

Metabolic Pathways ◽

Therapeutic Strategy ◽

Myeloma Cell ◽

Immune Microenvironment ◽

Potential Use

The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

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Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

British Journal of Cancer ◽

10.1038/s41416-019-0666-4 ◽

2019 ◽

Vol 122 (1) ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Adrian L. Harris

Keyword(s):

Metabolic Pathways ◽

Trial Design ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Critical Role ◽

Therapeutic Approaches ◽

Preclinical Models ◽

Wide Range ◽

Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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Role of dendritic cell metabolic reprogramming in tumor immune evasion

International Immunology ◽

10.1093/intimm/dxaa036 ◽

2020 ◽

Vol 32 (7) ◽

pp. 485-491 ◽

Cited By ~ 2

Author(s):

Michael P Plebanek ◽

Michael Sturdivant ◽

Nicholas C DeVito ◽

Brent A Hanks

Keyword(s):

Dendritic Cell ◽

Metabolic Pathways ◽

Checkpoint Inhibitor ◽

Therapeutic Strategies ◽

Metabolic Reprogramming ◽

Combination Immunotherapy ◽

Tumor Immune Evasion ◽

Effector T Cell ◽

Cell Responses

Abstract The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.

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Smith–Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399411001827 ◽

2011 ◽

Vol 13 ◽

Cited By ~ 25

Author(s):

Sarah H. Elsea ◽

Stephen R. Williams

Keyword(s):

Metabolic Pathways ◽

Gene Dosage ◽

Therapeutic Strategies ◽

Molecular Evidence ◽

Diagnostic Strategies ◽

Functional Studies ◽

Molecular Features ◽

Altered Gene ◽

Behavioural Management

Smith–Magenis syndrome (SMS) is a complex neurobehavioural disorder characterised by intellectual disability, self-injurious behaviours, sleep disturbance, obesity, and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. Functional studies based on the hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. Here, we review the clinical and molecular features of SMS and explore more recent studies supporting possible therapeutic strategies for behavioural management.

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In Silico Evolution of Early Metabolism

Artificial Life ◽

10.1162/artl_a_00021 ◽

2011 ◽

Vol 17 (2) ◽

pp. 87-108 ◽

Cited By ~ 8

Author(s):

Alexander Ullrich ◽

Markus Rohrschneider ◽

Gerik Scheuermann ◽

Peter F. Stadler ◽

Christoph Flamm

Keyword(s):

Metabolic Pathways ◽

Genetic System ◽

Simulation Tool ◽

Metabolic Evolution ◽

Metabolic System ◽

Evolution Of Metabolic Pathways ◽

Core Set ◽

Catalytically Active ◽

Almost Open ◽

In Silico Evolution

We developed a simulation tool for investigating the evolution of early metabolism, allowing us to speculate on the formation of metabolic pathways from catalyzed chemical reactions and on the development of their characteristic properties. Our model consists of a protocellular entity with a simple RNA-based genetic system and an evolving metabolism of catalytically active ribozymes that manipulate a rich underlying chemistry. Ensuring an almost open-ended and fairly realistic simulation is crucial for understanding the first steps in metabolic evolution. We show here how our simulation tool can be helpful in arguing for or against hypotheses on the evolution of metabolic pathways. We demonstrate that seemingly mutually exclusive hypotheses may well be compatible when we take into account that different processes dominate different phases in the evolution of a metabolic system. Our results suggest that forward evolution shapes metabolic network in the very early steps of evolution. In later and more complex stages, enzyme recruitment supersedes forward evolution, keeping a core set of pathways from the early phase.

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