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1.
Host cell glutamine metabolism as a potential antiviral target.
Hirabara, SM, Gorjao, R, Levada-Pires, AC, Masi, LN, Hatanaka, E, Cury-Boaventura, MF, da Silva, EB, Santos-Oliveira, LCD, Sousa Diniz, VL, Serdan, TAD, et al
Clinical science (London, England : 1979). 2021;(2):305-325
Abstract
A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.
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Identification and analysis of 35 genes associated with vitamin D deficiency: A systematic review to identify genetic variants.
Sepulveda-Villegas, M, Elizondo-Montemayor, L, Trevino, V
The Journal of steroid biochemistry and molecular biology. 2020;:105516
Abstract
Vitamin D deficiency is a public health concern associated with, but not limited to, skeletal anomalies, chronic diseases, immune conditions, and cancer, among others. Hypovitaminosis D is mainly associated with environmental and lifestyle factors that affect sunlight exposure. However, genetic factors also influence 25-hydroxyvitamin D (25[OH]D) serum concentration. Although there is available information of genes with clear biological relevance or markers identified by Genome-Wide Association Studies, an overall view and screening tool to identify known genetic causes of altered serum levels of 25(OH)D is lacking. Moreover, there are no studies including the total genetic evidence associated with abnormal serum concentration of 25(OH)D. Therefore, we conducted a de-novo systematic literature review to propose a set of genes comprehensive of all genetic variants reported to be associated with deficiency of vitamin D. Abstracts retrieved from PubMed search were organized by gene and curated one-by-one using the PubTerm web tool. The genes identified were classified according to the type of genetic evidence associated with serum 25(OH)D levels and were also compared with the few commonly screened genes related to vitamin D status. This strategy allowed the identification of 35 genes associated with serum 25(OH)D concentrations, 27 (75%) of which are not commercially available and are not, therefore, analyzed in clinical practice for genetic counseling, nor are they sufficiently studied for research purposes. Functional analysis of the genes identified confirmed their role in vitamin D pathways and diseases. Thus, the list of genes is an important source to understand the genetic determinants of 25(OH)D levels. To further support our findings, we provide a map of the reported functional variants and SNPs not included in ClinVar, minor allelic frequencies, SNP effect sizes, associated diseases, and an integrated overview of the biological role of the genes. In conclusion, we identified a comprehensive candidate list of genes associated with serum 25(OH)D concentrations, most of which are not commercially available, but would prove of importance in clinical practice in screening for patients that should respond to supplementation because of alterations in absorption, patients that would have little benefit because alterations in the downstream metabolism of vitamin D, and to study non-responsiveness to supplementation with vitamin D.
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Targeting Cell Metabolism as Cancer Therapy.
Ngoi, NYL, Eu, JQ, Hirpara, J, Wang, L, Lim, JSJ, Lee, SC, Lim, YC, Pervaiz, S, Goh, BC, Wong, ALA
Antioxidants & redox signaling. 2020;(5):285-308
Abstract
Significance: Cancer cells exhibit altered metabolic pathways to keep up with biosynthetic and reduction-oxidation needs during tumor proliferation and metastasis. The common induction of metabolic pathways during cancer progression, regardless of cancer histio- or genotype, makes cancer metabolism an attractive target for therapeutic exploitation. Recent Advances: Emerging data suggest that these altered pathways may even result in resistance to anticancer therapies. Identifying specific metabolic dependencies that are unique to cancer cells has proved challenging in this field, limiting the therapeutic window for many candidate drug approaches. Critical Issues: Cancer cells display significant metabolic flexibility in nutrient-limited environments, hampering the longevity of suppressing cancer metabolism through any singular approach. Combinatorial "synthetic lethal" approaches may have a better chance for success and promising strategies are reviewed here. The dynamism of the immune system adds a level of complexity, as various immune populations in the tumor microenvironment often share metabolic pathways with cancer, with successive alterations during immune activation and quiescence. Decoding the reprogramming of metabolic pathways within cancer cells and stem cells, as well as examining metabolic symbiosis between components of the tumor microenvironment, would be essential to further meaningful drug development within the tumor's metabolic ecosystem. Future Directions: In this article, we examine evidence for the therapeutic potential of targeting metabolic alterations in cancer, and we discuss the drawbacks and successes that have stimulated this field.
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Glycomacropeptide Bioactivity and Health: A Review Highlighting Action Mechanisms and Signaling Pathways.
Córdova-Dávalos, LE, Jiménez, M, Salinas, E
Nutrients. 2019;(3)
Abstract
Food-derived bioactive peptides are reported as beneficial and safe for human health. Glycomacropeptide (GMP) is a milk-protein-derived peptide that, in addition to its nutritional value, retains many biological properties and has therapeutic effects in several inflammatory disorders. GMP was shown under in vitro and in vivo conditions to exert a number of activities that regulate the physiology of important body systems, namely the gastrointestinal, endocrine, and immune systems. This review represents a comprehensive compilation summarizing the current knowledge and updated information on the major biological properties associated with GMP. GMP bioactivity is addressed with special attention on mechanisms of action, signaling pathways involved, and structural characteristics implicated. In addition, the results of various studies dealing with the effects of GMP on models of inflammatory diseases are reviewed and discussed.
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Perspectives of Reprogramming Breast Cancer Metabolism.
Wang, YP, Lei, QY
Advances in experimental medicine and biology. 2017;:217-232
Abstract
Reprogramming of cellular metabolism is one of the hallmarks of breast cancer. Breast cancer cells remodel metabolic network to maintain their transformed state and survive in a harsh tumor microenvironment. Dysregulated metabolism further interacts with cellular signaling and epigenetics to promote breast cancer development. Meanwhile, breast cancer stem cells exhibit unique metabolic features, which are critical for therapeutic resistance and tumor recurrence. Besides, aberrant metabolism of breast cancer cells reshapes tumor microenvironment, such as promoting cancer vascularization and sabotaging tumor immunity, to accelerate tumor progression. These special metabolic traits not only open vulnerabilities of breast cancer by targeting essential metabolic pathways but also provide promising diagnostic and prognostic biomarkers to facilitate clinical investigations. Studies in the last few decades have significantly advanced our understanding of mechanisms underlying the reprogramming of breast cancer metabolism and metabolic regulation of breast cancer biology. Targeting tumor metabolism serves as a potentially effective therapeutic approach to suppress breast cancer.
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Review: Metabolic Control of Immune System Activation in Rheumatic Diseases.
Perl, A
Arthritis & rheumatology (Hoboken, N.J.). 2017;(12):2259-2270
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Abstract
Metabolic pathways mediate lineage specification within the immune system through the regulation of glucose utilization, a process that generates energy in the form of ATP and synthesis of amino acids, nucleotides, and lipids to enable cell growth, proliferation, and survival. CD4+ T cells, a proinflammatory cell subset, preferentially produce ATP through glycolysis, whereas cells with an antiinflammatory lineage, such as memory and regulatory T cells, favor mitochondrial ATP generation. In conditions of metabolic stress or a shortage of nutrients, cells rely on autophagy to secure amino acids and other substrates, while survival depends on the sparing of mitochondria and maintenance of a reducing environment. The pentose phosphate pathway acts as a key gatekeeper of inflammation by supplying ribose-5-phosphate for cell proliferation and NADPH for antioxidant defenses. Increased lysosomal catabolism, accumulation of branched amino acids, glutamine, kynurenine, and histidine, and depletion of glutathione and cysteine activate the mechanistic target of rapamycin (mTOR), an arbiter of lineage development within the innate and adaptive immune systems. Mapping the impact of susceptibility genes to metabolic pathways allows for better understanding and therapeutic targeting of disease-specific expansion of proinflammatory cells. Therapeutic approaches aimed at glutathione depletion and mTOR pathway activation appear to be safe and effective for treating lupus, while an opposing intervention may be of benefit in rheumatoid arthritis. Environmental sources of origin for metabolites within immune cells may include microbiota and plants. Thus, a better understanding of the pathways of immunometabolism could provide new insights into the pathogenesis and treatment of the rheumatic diseases.
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T lymphocyte regulation by mevalonate metabolism.
Thurnher, M, Gruenbacher, G
Science signaling. 2015;(370):re4
Abstract
Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like γδ T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells.
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Transcriptome from circulating cells suggests dysregulated pathways associated with long-term recurrent events following first-time myocardial infarction.
Suresh, R, Li, X, Chiriac, A, Goel, K, Terzic, A, Perez-Terzic, C, Nelson, TJ
Journal of molecular and cellular cardiology. 2014;:13-21
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Abstract
BACKGROUND Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for high-risk cardiovascular diseases. However, the feasibility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome. METHODS AND RESULTS Whole-genome expression microarray on blood samples from normal cardiac function controls (n=21) and first-time AMI patients (n=31) within 48-hours post-MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways. To determine molecular signatures at the time of AMI associated with long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially-expressed genes. Bioinformatic analysis of this differential gene-set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of genes involved in the developmental epithelial-to-mesenchymal transition pathway, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome. CONCLUSION Differentially regulated genes and modulated pathways were identified that were associated with recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients and warrants further study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes.
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Cytokinin signaling networks.
Hwang, I, Sheen, J, Müller, B
Annual review of plant biology. 2012;:353-80
Abstract
Despite long-standing observations on diverse cytokinin actions, the discovery path to cytokinin signaling mechanisms was tortuous. Unyielding to conventional genetic screens, experimental innovations were paramount in unraveling the core cytokinin signaling circuitry, which employs a large repertoire of genes with overlapping and specific functions. The canonical two-component transcription circuitry involves His kinases that perceive cytokinin and initiate signaling, as well as His-to-Asp phosphorelay proteins that transfer phosphoryl groups to response regulators, transcriptional activators, or repressors. Recent advances have revealed the complex physiological functions of cytokinins, including interactions with auxin and other signal transduction pathways. This review begins by outlining the historical path to cytokinin discovery and then elucidates the diverse cytokinin functions and key signaling components. Highlights focus on the integration of cytokinin signaling components into regulatory networks in specific contexts, ranging from molecular, cellular, and developmental regulations in the embryo, root apical meristem, shoot apical meristem, stem and root vasculature, and nodule organogenesis to organismal responses underlying immunity, stress tolerance, and senescence.