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1.
Glucose Metabolism in the Kidney: Neurohormonal Activation and Heart Failure Development.
Gronda, E, Jessup, M, Iacoviello, M, Palazzuoli, A, Napoli, C
Journal of the American Heart Association. 2020;(23):e018889
Abstract
The liver is not the exclusive site of glucose production in humans in the postabsorptive state. Robust data support that the kidney is capable of gluconeogenesis and studies have demonstrated that renal glucose production can increase systemic glucose production. The kidney has a role in maintaining glucose body balance, not only as an organ for gluconeogenesis but by using glucose as a metabolic substrate. The kidneys reabsorb filtered glucose through the sodium-glucose cotransporters sodium-glucose cotransporter (SGLT) 1 and SGLT2, which are localized on the brush border membrane of the early proximal tubule with immune detection of their expression in the tubularized Bowman capsule. In patients with diabetes mellitus, the renal maximum glucose reabsorptive capacity, and the threshold for glucose passage into the urine, are higher and contribute to the hyperglycemic state. The administration of SGLT2 inhibitors to patients with diabetes mellitus enhances sodium and glucose excretion, leading to a reduction of the glycosuria threshold and tubular maximal transport of glucose. The net effects of SGLT2 inhibition are to drive a reduction in plasma glucose levels, improving insulin secretion and sensitivity. The benefit of SGLT2 inhibitors goes beyond glycemic control, since inhibition of renal glucose reabsorption affects blood pressure and improves the hemodynamic profile and the tubule glomerular feedback. This action acts to rebalance the dense macula response by restoring adenosine production and restraining renin-angiotensin-aldosterone activation. By improving renal and cardiovascular function, we explain the impressive reduction in adverse outcomes associated with heart failure supporting the current clinical perspective.
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2.
The dark side of the spoon - glucose, ketones and COVID-19: a possible role for ketogenic diet?
Paoli, A, Gorini, S, Caprio, M
Journal of translational medicine. 2020;(1):441
Abstract
The novel coronavirus disease (COVID-19) is posing a serious challenge to the health-care systems worldwide, with an enormous impact on health conditions and loss of lives. Notably, obesity and its related comorbidities are strictly related with worse clinical outcomes of COVID-19 disease. Recently, there is a growing interest in the clinical use of ketogenic diets (KDs), particularly in the context of severe obesity with related metabolic complications. KDs have been proven effective for a rapid reduction of fat mass, preserving lean mass and providing an adequate nutritional status. In particular, the physiological increase in plasma levels of ketone bodies exerts important anti-inflammatory and immunomodulating effects, which may reveal as precious tools to prevent infection and potential adverse outcomes of COVID-19 disease. We discuss here the importance of KDs for a rapid reduction of several critical risk factors for COVID-19, such as obesity, type 2 diabetes and hypertension, based on the known effects of ketone bodies on inflammation, immunity, metabolic profile and cardiovascular function. We do believe that a rapid reduction of all modifiable risk factors, especially obesity with its metabolic complications, should be a pillar of public health policies and interventions, in view of future waves of SARS-CoV-2 infection.
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3.
Competitive glucose metabolism as a target to boost bladder cancer immunotherapy.
Afonso, J, Santos, LL, Longatto-Filho, A, Baltazar, F
Nature reviews. Urology. 2020;(2):77-106
Abstract
Bladder cancer - the tenth most frequent cancer worldwide - has a heterogeneous natural history and clinical behaviour. The predominant histological subtype, urothelial bladder carcinoma, is characterized by high recurrence rates, progression and both primary and acquired resistance to platinum-based therapy, which impose a considerable economic burden on health-care systems and have substantial effects on the quality of life and the overall outcomes of patients with bladder cancer. The incidence of urothelial tumours is increasing owing to population growth and ageing, so novel therapeutic options are vital. Based on work by The Cancer Genome Atlas project, which has identified targetable vulnerabilities in bladder cancer, immune checkpoint inhibitors (ICIs) have arisen as an effective alternative for managing advanced disease. However, although ICIs have shown durable responses in a subset of patients with bladder cancer, the overall response rate is only ~15-25%, which increases the demand for biomarkers of response and therapeutic strategies that can overcome resistance to ICIs. In ICI non-responders, cancer cells use effective mechanisms to evade immune cell antitumour activity; the overlapping Warburg effect machinery of cancer and immune cells is a putative determinant of the immunosuppressive phenotype in bladder cancer. This energetic interplay between tumour and immune cells leads to metabolic competition in the tumour ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. Thus, molecular hallmarks of cancer cell metabolism are potential therapeutic targets, not only to eliminate malignant cells but also to boost the efficacy of immunotherapy. In this sense, integrating the targeting of tumour metabolism into immunotherapy design seems a rational approach to improve the therapeutic efficacy of ICIs.
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4.
The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: Interplay with the complex tumor microenvironment and novel therapeutic strategies.
El Hassouni, B, Granchi, C, Vallés-Martí, A, Supadmanaba, IGP, Bononi, G, Tuccinardi, T, Funel, N, Jimenez, CR, Peters, GJ, Giovannetti, E, et al
Seminars in cancer biology. 2020;:238-248
Abstract
Cancer metastasis to distant organs is initiated by tumor cells that disseminate from primary heterogeneous tumors. The subsequent growth and survival of tumor metastases depend on different metabolic changes, which constitute one of the enigmatic properties of tumor cells. Aerobic glycolysis, 'the Warburg effect', contributes to tumor energy supply, by oxidizing glucose in a faster manner compared to oxidative phosphorylation, leading to an increased lactate production by lactate dehydrogenase A (LDH-A), which in turn affects the immune response. Surrounding stromal cells contribute to feedback mechanisms further prompting the acquisition of pro-invasive metabolic features. Hence, therapeutic strategies targeting the glycolytic pathway are intensively investigated, with a special interest on their anti-metastatic properties. Various small molecules, such as LDH-A inhibitors, have shown pre-clinical activity against different cancer types, and blocking LDH-A could also help in designing future complimentary therapies. Modulation of specific targets in cells with an altered glycolytic metabolism should indeed result in a milder and distinct toxicity profile, compared to conventional cytotoxic therapy, while a combination treatment with vitamin C leading to increasing reactive oxygen species levels, should further inhibit cancer cell survival and invasion. In this review we describe the impact of metabolic reprogramming in cancer metastasis, the contribution of lactate in this aberrant process and its effect on oncogenic processes. Furthermore, we discuss experimental compounds that target glycolytic metabolism, such as LDH-A inhibitors, and their potential to improve current and experimental therapeutics against metastatic tumors.
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5.
Metabolic host response and therapeutic approaches to influenza infection.
Keshavarz, M, Solaymani-Mohammadi, F, Namdari, H, Arjeini, Y, Mousavi, MJ, Rezaei, F
Cellular & molecular biology letters. 2020;:15
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Abstract
Based on available metabolomic studies, influenza infection affects a variety of cellular metabolic pathways to ensure an optimal environment for its replication and production of viral particles. Following infection, glucose uptake and aerobic glycolysis increase in infected cells continually, which results in higher glucose consumption. The pentose phosphate shunt, as another glucose-consuming pathway, is enhanced by influenza infection to help produce more nucleotides, especially ATP. Regarding lipid species, following infection, levels of triglycerides, phospholipids, and several lipid derivatives undergo perturbations, some of which are associated with inflammatory responses. Also, mitochondrial fatty acid β-oxidation decreases significantly simultaneously with an increase in biosynthesis of fatty acids and membrane lipids. Moreover, essential amino acids are demonstrated to decline in infected tissues due to the production of large amounts of viral and cellular proteins. Immune responses against influenza infection, on the other hand, could significantly affect metabolic pathways. Mainly, interferon (IFN) production following viral infection affects cell function via alteration in amino acid synthesis, membrane composition, and lipid metabolism. Understanding metabolic alterations required for influenza virus replication has revealed novel therapeutic methods based on targeted inhibition of these cellular metabolic pathways.
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6.
Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells.
Gerresheim, GK, Roeb, E, Michel, AM, Niepmann, M
Cells. 2019;(11)
Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the "Warburg Effect" and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
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7.
Proliferating tumor cells mimick glucose metabolism of mature human erythrocytes.
Ghashghaeinia, M, Köberle, M, Mrowietz, U, Bernhardt, I
Cell cycle (Georgetown, Tex.). 2019;(12):1316-1334
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Abstract
Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules. Proliferating tumor cells mimick mature human erythrocytes to glycolytically generate two ATP molecules. They deliberately avoid or switch off their respiration, i.e. tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) machinery and consequently dispense with the production of additional 36 ATP molecules from one glucose molecule. This phenomenon is named aerobic glycolysis or Warburg effect. The present review deals with the fate of a glucose molecule after entering a mature human erythrocyte or a proliferating tumor cell and describes why it is useful for a proliferating tumor cell to imitate a mature erythrocyte. Blood consisting of plasma and cellular components (99% of the cells are erythrocytes) may be regarded as a mobile organ, constantly exercising a direct interaction with other organs. Therefore, the use of drugs, which influences the biological activity of erythrocytes, has an immediate effect on the entire organism. Abbreviations: TCA: tricarboxylic acid cycle; OXPHOS oxidative phosphorylation; GSH: reduced state of glutathione; NFκB: Nuclear factor of kappa B; PKB (Akt): protein kinase B; NOS: nitric oxide synthase; IgG: immune globulin G; H2S: hydrogen sulfide; slanDCs: Human 6-sulfo LacNAc-expressing dendritic cells; IL-8: interleukin-8; LPS: lipopolysaccharide; ROS: reactive oxygen species; PPP: pentose phosphate pathway; NADPH nicotinamide adenine dinucleotide phosphate hydrogen; R5P: ribose-5-phophate; NAD: nicotinamide adenine dinucleotide; FAD: flavin adenine dinucleotide; O2●-: superoxide anion; G6P: glucose 6-phosphate; HbO2: Oxyhemoglobin; GAPDH glyceraldehyde-3-phosphate dehydrogenase; GAP: glyceraldehyde-3-phosphate; 1,3-BPG: 1,3-bis-phosphoglycerate; 2,3-BPG: 2,3-bisphosphoglycerte; PGAM1: phosphoglycerate mutase 1; 3-PG: 3-phosphoglycerate; 2-PG: 2-phosphoglycerate; MIPP1: Multiple inositol polyphosphate phosphatase; mTORC1: mammalian target of rapamycin complex 1; Ru5P: ribulose 5-phosphate; ox-PPP: oxidative branch of pentose phosphate pathway; PGK: phosphoglycerate kinase; IFN-γ: interferon-γ; LDH: lactate dehydrogenase; STAT3: signal transducer and activator of transcription 3; Rheb: Ras homolog enriched in Brain; H2O2: hydrogen peroxide; ROOH lipid peroxide; SOD: superoxide dismutase; MRC: mitochondrial respiratory chain; MbFe2+-O2: methmyoglobin; RNR: ribonucleotide reductase; PRPP phosphoribosylpyrophosphate; PPi: pyrophosphate; GSSG oxidized state of glutathione; non-ox-PPP: non-oxidative branch of pentose phosphate pathway; RPI: ribose-5-phosphate isomerase; RPE: ribulose 5-phosphate 3-epimerase; X5P: xylulose 5-phosphate; TK: transketolase; TA: transaldolase; F6P: fructose-6-phosphate; AR2: aldose reductase 2; SD: sorbitol dehydrogenase; HK: hexokinase; MG: mehtylglyoxal; DHAP dihydroxyacetone phosphate; TILs: tumor-infiltrating lymphocytes; MCTs: monocarboxylate transporters; pHi: intracellular pH; Hif-1α: hypoxia-induced factor 1; NHE1: sodium/H+ (Na+/H+) antiporter 1; V-ATPase: vacuolar-type proton ATPase; CAIX carbonic anhydrase; CO2: carbon dioxide; HCO3-: bicarbonate; NBC: sodium/bicarbonate (Na+/HCO3-) symporter; pHe: extracellular pH; GLUT-1: glucose transporter 1; PGK-1: phosphoglycerate kinase 1.
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8.
Function and Dysfunction of Adipose Tissue.
Matafome, P, Seiça, R
Advances in neurobiology. 2017;:3-31
Abstract
Adipose tissue is an endocrine organ which is responsible for postprandial uptake of glucose and fatty acids, consequently producing a broad range of adipokines controlling several physiological functions like appetite, insulin sensitivity and secretion, immunity, coagulation, and vascular tone, among others. Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. Recent data suggest two main factors for adipose tissue dysfunction: accumulation of nonesterified fatty acids and their secondary products and hypoxia. Both of these factors are thought to be on the basis of low-grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. In turn, inflammation is involved in the inhibition of substrate uptake, alteration of the secretory profile, stimulation of angiogenesis, and recruitment of further inflammatory cells, which creates an inflammatory feedback in the tissue and is responsible for long-term establishment of insulin resistance.
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[Drugs affecting the incretin system and renal glucose transport: do they meet the expectations of modern therapy of type 2 diabetes?].
Gumieniczek, A
Postepy higieny i medycyny doswiadczalnej (Online). 2016;:425-34
Abstract
Agents introduced into therapy of type 2 diabetes in the last few years are still the subject of numerous clinical and experimental studies. Although many studies have been completed, we still do not know all aspects of these drugs' action, especially the long-term effects of their use. Most questionable is their impact on the processes of cell proliferation, on the cardiovascular and immune systems, on lipids and uric acid metabolism. A summary of the most important observations on the use of three groups of new drugs - analogs of glucagon-like peptide 1 (GLP-1), inhibitors of dipeptidyl peptidase IV (DPPIV) and inhibitors of sodium glucose cotransporters (SGLT1 and SGLT2) - has been made, based on a review of the literature over the past five years (2010-2014). The information included in the present review concerns the structure and activity relationship, therapeutic efficacy, side effects and the observed additional therapeutic effects, which can determine new standards in therapy of diabetes and also facilitate the development of better antidiabetic drugs.
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10.
Resistin: regulation of food intake, glucose homeostasis and lipid metabolism.
Nogueiras, R, Novelle, MG, Vazquez, MJ, Lopez, M, Dieguez, C
Endocrine development. 2010;:175-184
Abstract
Resistin has been identified as a hormone secreted by adipocytes that is under hormonal and nutritional control. This hormone has been suggested to be the link between obesity and type 2 diabetes. In rodents, resistin is mainly located and secreted from adipocytes, even though its expression was also found in several other tissues. However, in humans resistin is expressed primarily by macrophages and seems to be involved in the recruitment of other immune cells and the secretion of pro-inflammatory factors, although its role in insulin resistance cannot be ruled out. In addition to its role in glucose metabolism, resistin has been also involved in the control of hypothalamic and peripheral lipid metabolism and in the regulation of food intake. In this short review, we will summarize the most relevant findings of this hormone in rodents.