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1.
The Emerging Role of l-Glutamine in Cardiovascular Health and Disease.
Durante, W
Nutrients. 2019;(9)
Abstract
Emerging evidence indicates that l-glutamine (Gln) plays a fundamental role in cardiovascular physiology and pathology. By serving as a substrate for the synthesis of DNA, ATP, proteins, and lipids, Gln drives critical processes in vascular cells, including proliferation, migration, apoptosis, senescence, and extracellular matrix deposition. Furthermore, Gln exerts potent antioxidant and anti-inflammatory effects in the circulation by inducing the expression of heme oxygenase-1, heat shock proteins, and glutathione. Gln also promotes cardiovascular health by serving as an l-arginine precursor to optimize nitric oxide synthesis. Importantly, Gln mitigates numerous risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, glucose intolerance, obesity, and diabetes. Many studies demonstrate that Gln supplementation protects against cardiometabolic disease, ischemia-reperfusion injury, sickle cell disease, cardiac injury by inimical stimuli, and may be beneficial in patients with heart failure. However, excessive shunting of Gln to the Krebs cycle can precipitate aberrant angiogenic responses and the development of pulmonary arterial hypertension. In these instances, therapeutic targeting of the enzymes involved in glutaminolysis such as glutaminase-1, Gln synthetase, glutamate dehydrogenase, and amino acid transaminase has shown promise in preclinical models. Future translation studies employing Gln delivery approaches and/or glutaminolysis inhibitors will determine the success of targeting Gln in cardiovascular disease.
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2.
Glutamine in Burn Injury.
Wischmeyer, PE
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2019;(5):681-687
Abstract
Burn injury is the most devastating of survivable injuries and is a worldwide public health crisis. Burn injury is among the most severe metabolic stresses a patient can sustain. A major burn leads to an inflammatory response and catabolism that, when compounded by burn wound nutrient losses, can lead to severe nutrition losses and deficiencies. These losses can impair immune function and wound healing and place burn patients at high risk for organ injury and mortality. Experimental data indicate glutamine (GLN) is well positioned mechanistically, perhaps above and beyond in any other intensive care unit setting, to improve outcome in burn-injured patients. Initial clinical trial data have also shown a consistent signal of reduced mortality and reduced hospital length of stay in burn-injured subjects, without signals of clinical risk. A number of GLN clinical trials demonstrate significant reductions of gram-negative bacteremia in burn injury, perhaps via maintenance of the gut barrier or gut immune function. Current societal recommendations continue to suggest the use of GLN in burn injury. The promising clinical data in burn-injured patients, with no signals of harm, have warranted study of GLN in the definitive RE-ENERGIZE trial, which is now ongoing.
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3.
Influence of Growth Hormone and Glutamine on Intestinal Stem Cells: A Narrative Review.
Chen, Y, Tsai, YH, Tseng, BJ, Tseng, SH
Nutrients. 2019;(8)
Abstract
Growth hormone (GH) and glutamine (Gln) stimulate the growth of the intestinal mucosa. GH activates the proliferation of intestinal stem cells (ISCs), enhances the formation of crypt organoids, increases ISC stemness markers in the intestinal organoids, and drives the differentiation of ISCs into Paneth cells and enterocytes. Gln enhances the proliferation of ISCs and increases crypt organoid formation; however, it mainly acts on the post-proliferation activity of ISCs to maintain the stability of crypt organoids and the intestinal mucosa, as well as to stimulate the differentiation of ISCs into goblet cells and possibly Paneth cells and enteroendocrine cells. Since GH and Gln have differential effects on ISCs. Their use in combination may have synergistic effects on ISCs. In this review, we summarize the evidence of the actions of GH and/or Gln on crypt cells and ISCs in the literature. Overall, most studies demonstrated that GH and Gln in combination exerted synergistic effects to activate the proliferation of crypt cells and ISCs and enhance crypt organoid formation and mucosal growth. This treatment influenced the proliferation of ISCs to a similar degree as GH treatment alone and the differentiation of ISCs to a similar degree as Gln treatment alone.
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4.
Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations.
El Ansari, R, McIntyre, A, Craze, ML, Ellis, IO, Rakha, EA, Green, AR
Histopathology. 2018;(2):183-190
Abstract
Cancer cells must alter their metabolism in order to satisfy the demands of necessary energy and cellular building blocks. These metabolic alterations are mediated by many oncogenic changes that affect cellular signalling pathways, which result in sustained cell growth and proliferation. Recently, metabolomics has received great attention in the field of cancer research, and as the essential metabolic pathways that drive tumour growth and progression are determined the possibilities of new targets for therapeutic intervention are opened. More specifically, as breast cancer is a heterogeneous disease, there is growing evidence that differences in metabolic changes exist between molecular subtypes. In this review, the most recent findings in breast cancer cell metabolism are discussed, with particular emphasis on glutamine and its transporters, which is considered one of the key amino acids fuelling cancer growth. Furthermore, the metabolic differences between the molecular subtypes of breast cancer are examined, highlighting the clinical utility for breast cancer diagnosis and treatment.
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5.
Amino Acid Transporters and Glutamine Metabolism in Breast Cancer.
Cha, YJ, Kim, ES, Koo, JS
International journal of molecular sciences. 2018;(3)
Abstract
Amino acid transporters are membrane transport proteins, most of which are members of the solute carrier families. Amino acids are essential for the survival of all types of cells, including tumor cells, which have an increased demand for nutrients to facilitate proliferation and cancer progression. Breast cancer is the most common malignancy in women worldwide and is still associated with high mortality rates, despite improved treatment strategies. Recent studies have demonstrated that the amino acid metabolic pathway is altered in breast cancer and that amino acid transporters affect tumor growth and progression. In breast cancer, glutamine is one of the key nutrients, and glutamine metabolism is closely related to the amino acid transporters. In this review, we focus on amino acid transporters and their roles in breast cancer. We also highlight the different subsets of upregulated amino acid transporters in breast cancer and discuss their potential applications as treatment targets, cancer imaging tracers, and drug delivery components. Glutamine metabolism as well as its regulation and therapeutic implication in breast cancer are also discussed.
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6.
Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine.
Morris, CR, Hamilton-Reeves, J, Martindale, RG, Sarav, M, Ochoa Gautier, JB
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2017;(1_suppl):30S-47S
Abstract
Nonessential amino acids are synthesized de novo and therefore not diet dependent. In contrast, essential amino acids must be obtained through nutrition since they cannot be synthesized internally. Several nonessential amino acids may become essential under conditions of stress and catabolic states when the capacity of endogenous amino acid synthesis is exceeded. Arginine and glutamine are 2 such conditionally essential amino acids and are the focus of this review. Low arginine bioavailability plays a pivotal role in the pathogenesis of a growing number of varied diseases, including sickle cell disease, thalassemia, malaria, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, certain cancers, and trauma, among others. Catabolism of arginine by arginase enzymes is the most common cause of an acquired arginine deficiency syndrome, frequently contributing to endothelial dysfunction and/or T-cell dysfunction, depending on the clinical scenario and disease state. Glutamine, an arginine precursor, is one of the most abundant amino acids in the body and, like arginine, becomes deficient in several conditions of stress, including critical illness, trauma, infection, cancer, and gastrointestinal disorders. At-risk populations are discussed together with therapeutic options that target these specific acquired amino acid deficiencies.
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7.
Drug-induced amino acid deprivation as strategy for cancer therapy.
Fung, MKL, Chan, GC
Journal of hematology & oncology. 2017;(1):144
Abstract
Cancer is caused by uncontrollable growth of neoplastic cells, leading to invasion of adjacent and distant tissues resulting in death. Cancer cells have specific nutrient(s) auxotrophy and have a much higher nutrient demand compared to normal tissues. Therefore, different metabolic inhibitors or nutrient-depleting enzymes have been tested for their anti-cancer activities. We review recent available laboratory and clinical data on using various specific amino acid metabolic pathways inhibitors in treating cancers. Our focus is on glutamine, asparagine, and arginine starvation. These three amino acids are chosen due to their better scientific evidence compared to other related approaches in cancer treatment. Amino acid-specific depleting enzymes have been adopted in different standard chemotherapy protocols. Glutamine starvation by glutaminase inhibitior, transporter inhibitor, or glutamine depletion has shown to have significant anti-cancer effect in pre-clinical studies. Currently, glutaminase inhibitor is under clinical trial for testing anti-cancer efficacy. Clinical data suggests that asparagine depletion is effective in treating hematologic malignancies even as a single agent. On the other hand, arginine depletion has lower toxicity profile and can effectively reduce the level of pro-cancer biochemicals in patients as shown by ours and others' data. This supports the clinical use of arginine depletion as anti-cancer therapy but its exact efficacy in various cancers requires further investigation. However, clinical application of these enzymes is usually hindered by common problems including allergy to these foreign proteins, off-target cytotoxicity, short half-life and rapidly emerging chemoresistance. There have been efforts to overcome these problems by modifying the drugs in different ways to circumvent these hindrance such as (1) isolate human native enzymes to reduce allergy, (2) isolate enzyme isoforms with higher specificities and efficiencies, (3) pegylate the enzymes to reduce allergy and prolong the half-lives, and (4) design drug combinations protocols to enhance the efficacy of chemotherapy by drug synergy and minimizing resistance. These improvements can potentially lead to the development of more effective anti-cancer treatment with less adverse effects and higher therapeutic efficacy.
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8.
Metabolic Imaging of Glutamine in Cancer.
Zhu, L, Ploessl, K, Zhou, R, Mankoff, D, Kung, HF
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;(4):533-537
Abstract
Glucose and glutamine are the most abundant nutrients for producing energy and building blocks in normal and tumor cells. Increased glycolysis in tumors, the Warburg Effect, is the basis for 18F-FDG PET imaging. Cancer cells can also be genetically reprogrammed to use glutamine. 5-11C-(2S)-glutamine and 18F-(2S,4R)4-fluoroglutamine may be useful complementary tools to measure changes in tumor metabolism. In glioma patients, the tracer 18F-(2S,4R)4-fluoroglutamine showed tumor-to-background contrast different from that of 18F-FDG and differences in uptake in glioma patients with clinical progression of disease versus stable disease (tumor-to-brain ratio > 3.7 in clinically active glioma tumors, minimal or no specific uptake in clinically stable tumors). These preliminary results suggest that 18F-(2S,4R)4-fluoroglutamine PET may be a new tool for probing in vivo metabolism of glutamine in cancer patients and for guiding glutamine-targeted therapeutics. Further studies of uptake mechanism, and comparison of kinetics for 18F-(2S,4R)4-fluoroglutamine versus the 11C-labeled native glutamine, will be important and enlightening.
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9.
Metabolic rewiring in melanoma.
Ratnikov, BI, Scott, DA, Osterman, AL, Smith, JW, Ronai, ZA
Oncogene. 2017;(2):147-157
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Abstract
Oncogene-driven metabolic rewiring is an adaptation to low nutrient and oxygen conditions in the tumor microenvironment that enables cancer cells of diverse origin to hyperproliferate. Aerobic glycolysis and enhanced reliance on glutamine utilization are prime examples of such rewiring. However, tissue of origin as well as specific genetic and epigenetic changes determines gene expression profiles underlying these metabolic alterations in specific cancers. In melanoma, activation of the mitogen-activated protein kinase (MAPK) pathway driven by mutant BRAF or NRAS is a primary cause of malignant transformation. Activity of the MAPK pathway, as well as other factors, such as HIF1α, Myc and MITF, are among those that control the balance between non-oxidative and oxidative branches of central carbon metabolism. Here, we discuss the nature of metabolic alterations that underlie melanoma development and affect its response to therapy.
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10.
Glutamine Metabolism in Cancer: Understanding the Heterogeneity.
Cluntun, AA, Lukey, MJ, Cerione, RA, Locasale, JW
Trends in cancer. 2017;(3):169-180
Abstract
Reliance on glutamine has long been considered a hallmark of cancer cell metabolism. However, some recent studies have challenged this notion in vivo, prompting a need for further clarifications on the role of glutamine metabolism in cancer. We find that there is ample evidence of an essential role for glutamine in tumors and that a variety of factors, including tissue type, the underlying cancer genetics, the tumor microenvironment and other variables such as diet and host physiology collectively influence the role of glutamine in cancer. Thus the requirements for glutamine in cancer are overall highly heterogeneous. In this review, we discuss the implications both for basic science and for targeting glutamine metabolism in cancer therapy.