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![| [1] Glycolysis, [2] tricarboxylic acid (TCA) cycle and oxidative phosphorylation, [3] fatty acid oxidation, [4] pentose phosphate pathway, [5] ornithine cycle, and [6] glutamine metabolism. This figure shows the main metabolic pathways in relation with nitric oxide (NO), hypoxia-inducible factor (HIF), and adenosine monophosphate-activated protein kinase (AMPK). NO is produced by NOS with l-arginine as the substrate while succinate, the intermediate of the TCA cycle stabilizes and activates HIF. Adenosine triphosphates (ATPs) are hydrolyzed to adenosine diphosphate (ADP), while some are converted to adenosine monophosphate (AMP) via adenylyl cyclase. The increase in AMP/ADP:ATP ratio as well as other extracellular metabolic stressors activate AMPK. The effect of these mediators on metabolic reprogramming is listed in Table 1. PFKFB3 converts fructose-6-phosphate to fructose-2,6-bisphosphate, which in turn activates phosphofructokinase-1 and promotes the rate of glycolysis. Citrate metabolism produces acetyl-CoA, which is converted to malonyl-CoAs for fatty acid synthesis. Arachidonic acid and its derived inflammatory prostaglandins are produced from the same pathway. Arginase regulates the ornithine cycle, which is involved in the production of polyamines, a prominent feature of metabolism in M2 macrophages.](profile/Claudio-Mauro/publication/318636324/figure/fig2/AS:518922618716160@1500732201999/1-Glycolysis-2-tricarboxylic-acid-TCA-cycle-and-oxidative-phosphorylation-3.png)
| [1] Glycolysis, [2] tricarboxylic acid (TCA) cycle and oxidative phosphorylation, [3] fatty acid oxidation, [4] pentose phosphate pathway, [5] ornithine cycle, and [6] glutamine metabolism. This figure shows the main metabolic pathways in relation with nitric oxide (NO), hypoxia-inducible factor (HIF), and adenosine monophosphate-activated protein kinase (AMPK). NO is produced by NOS with l-arginine as the substrate while succinate, the intermediate of the TCA cycle stabilizes and activates HIF. Adenosine triphosphates (ATPs) are hydrolyzed to adenosine diphosphate (ADP), while some are converted to adenosine monophosphate (AMP) via adenylyl cyclase. The increase in AMP/ADP:ATP ratio as well as other extracellular metabolic stressors activate AMPK. The effect of these mediators on metabolic reprogramming is listed in Table 1. PFKFB3 converts fructose-6-phosphate to fructose-2,6-bisphosphate, which in turn activates phosphofructokinase-1 and promotes the rate of glycolysis. Citrate metabolism produces acetyl-CoA, which is converted to malonyl-CoAs for fatty acid synthesis. Arachidonic acid and its derived inflammatory prostaglandins are produced from the same pathway. Arginase regulates the ornithine cycle, which is involved in the production of polyamines, a prominent feature of metabolism in M2 macrophages.
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![FiGURe 2 | [1] Glycolysis, [2] tricarboxylic acid (TCA) cycle and...](profile/Claudio-Mauro/publication/318636324/figure/fig2/AS:518922618716160@1500732201999/1-Glycolysis-2-tricarboxylic-acid-TCA-cycle-and-oxidative-phosphorylation-3_Q320.jpg)
Cellular metabolism has been known for its role in bioenergetics. In recent years, much light has been shed on the reprogrammable cellular metabolism underlying many vital cellular processes, such as cell activation, proliferation, and differentiation. Metabolic reprogramming in immune and endothelial cells (ECs) is being studied extensively. These...
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Context 1
... from its effect on glucose metabolism, AMPK activa- tion has been shown to increase FAO in human umbilical vein ECs (74). Specifically, palmitate oxidation is heightened from the activation of AMPK by bradykinin, suggesting that AMPK activation may mitigate lipotoxicity secondary to fatty acid accumulation in the initial stages of atherosclerosis (98) (Figure 2). [2] tricarboxylic acid (TCA) cycle and oxidative phosphorylation, [3] fatty acid oxidation, [4] pentose phosphate pathway, [5] ornithine cycle, and [6] glutamine metabolism. ...
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Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon,...
Citations
... In several models, including certain types of tumors [51][52][53], healthy brain [54], and lungs with pulmonary hypertension [55], NO-driven metabolic reprogramming towards aerobic glycolysis, or the Warburg effect, showed protective effects. Remarkably, this metabolic reprogramming is quite similar to that observed in the immune system and in endothelium [56]. In macrophages, the activation of the Warburg effect exerts anti-inflammatory effects [57]. ...
The search for a clinically affordable substitute of human blood for transfusion is still an unmet need of modern society. More than 50 years of research on acellular hemoglobin (Hb)-based oxygen carriers (HBOC) have not yet produced a single formulation able to carry oxygen to hemorrhage-challenged tissues without compromising the body’s functions. Of the several bottlenecks encountered, the high reactivity of acellular Hb with circulating nitric oxide (NO) is particularly arduous to overcome because of the NO-scavenging effect, which causes life-threatening side effects as vasoconstriction, inflammation, coagulopathies, and redox imbalance. The purpose of this manuscript is not to add a review of candidate HBOC formulations but to focus on the biochemical and physiological events that underly NO scavenging by acellular Hb. To this purpose, we examine the differential chemistry of the reaction of NO with erythrocyte and acellular Hb, the NO signaling paths in physiological and HBOC-challenged situations, and the protein engineering tools that are predicted to modulate the NO-scavenging effect. A better understanding of two mechanisms linked to the NO reactivity of acellular Hb, the nitrosylated Hb and the nitrite reductase hypotheses, may become essential to focus HBOC research toward clinical targets.
... The increase in knowledge about the relationship between metabolic diseases and the immune system and the development of techniques for metabolite analysis have boosted the recent advancement of this research area [17,18]. Among the numerous reports over the past two decades on lymphocyte metabolism, some highlights are: (a) the metabolic switch in effector and memory cells [19][20][21]; (b) the predominance of certain metabolic pathways in different subtypes of T lymphocytes (Th1, Th2, Th17, Treg) [22][23][24]; (c) the similarity between metabolism of activated inflammatory cells (Th1 and Th17 lymphocyte, M1 Macrophage and Neutrophils) and tumor cells [25][26][27][28]; (d) the changes involved with the production of antibodies [29,30]; and (e) specific pathways of metabolism as targets for the treatment of autoimmune diseases [31], viral infections [32,33], cancer [34]and other chronic diseases [33,35]. ...
Lymphocytes act as regulatory and effector cells in inflammation and infection situations. A metabolic switch towards glycolytic metabolism predominance occurs during T lymphocyte differentiation to inflammatory phenotypes (Th1 and Th17 cells). Maturation of T regulatory cells, however, may require activation of oxidative pathways. Metabolic transitions also occur in different maturation stages and activation of B lymphocytes. Under activation, B lymphocytes undergo cell growth and proliferation, associated with increased macromolecule synthesis. The B lymphocyte response to an antigen challenge requires an increased adenosine triphosphate (ATP) supply derived mainly through glycolytic metabolism. After stimulation, B lymphocytes increase glucose uptake, but they do not accumulate glycolytic intermediates, probably due to an increase in various metabolic pathway ‘end product’ formation. Activated B lymphocytes are associated with increased utilization of pyrimidines and purines for RNA synthesis and fatty acid oxidation. The generation of plasmablasts and plasma cells from B lymphocytes is crucial for antibody production. Antibody production and secretion require increased glucose consumption since 90% of consumed glucose is needed for antibody glycosylation. This review describes critical aspects of lymphocyte metabolism and functional interplay during activation. We discuss the primary fuels for the metabolism of lymphocytes and the particularities of T and B cell metabolism, including the differentiation of lymphocytes, stages of development of B cells, and the production of antibodies.
... Reduced breakdown of the dipeptides anserine and carnosine to beta-alanine favors anserine and carnosine antioxidant capacity. The observed decreases in arachidonic acid metabolism, which imply decreased inflammation [152], suggest no loss of antioxidant protection from the decrease in glutathione, arginine, and linoleic acid metabolism. ...
... The results of this study imply potential for hydration metabolomic profiles to be inversely associated with aging and risk for chronic diseases, including obesity, diabetes, atherosclerosis, and cancer [152]. The DunedinPACE index, a DNA methylation marker of the pace of aging, decreased significantly. ...
... Aestivation-related metabolism, including elevated BCAA and urea cycle metabolites, is associated with increased risk of insulin resistance, obesity, hypertension, dyslipidemia and coronary artery disease [84,85,87,90,159]. The Warburg metabolic profile is implicated in inflammation and the pathogenesis of cancer and atherosclerosis [152]. ...
Background/aims:
Cells adapt to chronic extracellular hypotonicity by altering metabolism. Corresponding effects of sustained hypotonic exposure at the whole-person level remain to be confirmed and characterized in clinical and population-based studies. This analysis aimed to 1) describe changes in urine and serum metabolomic profiles associated with four weeks of sustained > +1 L/d drinking water in healthy, normal weight, young men, 2) identify metabolic pathways potentially impacted by chronic hypotonicity, and 3) explore if effects of chronic hypotonicity differ by type of specimen and/or acute hydration condition.
Materials:
Untargeted metabolomic assays were completed for specimen stored from Week 1 and Week 6 of the Adapt Study for four men (20-25 years) who changed hydration classification during that period. Each week, first-morning urine was collected after overnight food and water restriction, and urine (t+60 min) and serum (t+90 min) were collected after a 750 mL bolus of drinking water. Metaboanalyst 5.0 was used to compare metabolomic profiles.
Results:
In association with four weeks of > + 1 L/d drinking water, urine osmolality decreased below 800 mOsm/kg H2O and saliva osmolality decreased below 100 mOsm/kg H2O. Between Week 1 and Week 6, 325 of 562 metabolic features in serum changed by 2-fold or more relative to creatinine. Based on hypergeometric test p-value <0.05 or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway impact factor >0.2, the sustained > + 1 L/d of drinking water was associated with concurrent changes in carbohydrate, protein, lipid, and micronutrient metabolism, a metabolomic pattern of carbohydrate oxidation via the tricarboxylic acid (TCA) cycle, instead of glycolysis to lactate, and a reduction of chronic disease risk factors in Week 6. Similar metabolic pathways appeared potentially impacted in urine, but the directions of impact differed by specimen type.
Conclusion:
In healthy, normal weight, young men with initial total water intake below 2 L/d, sustained > + 1 L/d drinking water was associated with profound changes in serum and urine metabolomic profile, which suggested normalization of an aestivation-like metabolic pattern and a switch away from a Warburg-like pattern. Further research is warranted to pursue whole-body effects of chronic hypotonicity that reflect cell-level effects and potential beneficial effects of drinking water on chronic disease risk.
... [11,12] Accumulating evidence indicates that almost 98% of glucose is metabolized into lactate, while little is oxidized by oxidative phosphorylation in angiogenic ECs. [13] In the pathogenesis of inflammation, enhanced glycolysis or reduced oxidative phosphorylation occurs in ECs; [14] and high levels of serum lactate, the final product of glycolysis, have been recognized as a critical biomarker for sepsis prognosis. [15] Furthermore, it results in a vicious cycle, whereby lactate-induced extracellular signal-regulated kinase 2 (ERK2) phosphorylation could promote ERK2 disassociation from vascular endothelialcadherin (VE-cadherin), thus destroying the vascular endothelial cadherin complex on the surface of ECs and leading to increased vascular permeability. ...
Background:
Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure. Endothelial cells (ECs) exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.
Methods:
Web of Science and PubMed were searched from inception to October 1, 2022. The search was limited to the English language only. Two reviewers independently identified studies related to EC metabolism in sepsis. The exclusion criteria were duplicate articles according to multiple search criteria.
Results:
Sixty articles were included, and most of them were cell and animal studies. These studies reported the role of glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism in EC homeostasis. including glycolysis, oxidative phosphorylation, fatty acid metabolism and amino acid metabolism. However, dysregulation of EC metabolism can contribute to sepsis progression.
Conclusion:
There are few clinical studies on EC metabolism in sepsis. Related research mainly focuses on basic research, but some scientific problems have also been clarified. Therefore, this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis.
... In recent years, much light has been shed on the reprogramming cellular metabolism affecting many vital cellular processes, such as cell activation, proliferation, and differentiation; 6 vessel sprouting; 7 and angiogenesis. One of the most notable metabolic reprogrammings is the Warburg effect (a phenomenon known as aerobic glycolysis), which is characterized by a metabolic switch favoring glycolysis over oxidative phosphorylation, 6 under conditions where oxygen is plentiful 8 and sufficient glucose is available. 9 ECs in the arteries are generally quiescent and exposed to normal/high levels of oxygen and nutrients. ...
It is generally believed that vascular endothelial cells (VECs) rely on glycolysis instead of the tricarboxylic acid (TCA) cycle under both normoxic and hypoxic conditions. However, the metabolic pattern of human umbilical vein endothelial cells (HUVECs) under extreme ischemia (hypoxia and nutrient deprivation) needs to be elucidated. We initiated a lethal ischemic model of HUVECs, performed proteomics and bioinformatics, and verified the metabolic pattern shift of HUVECs. Ischemic HUVECs displayed extensive aerobic respiration, including upregulation of the TCA cycle and mitochondrial respiratory chain in mitochondria and downregulation of glycolysis in cytoplasm. The TCA cycle was enhanced while the cell viability was decreased through the citrate synthase pathway when substrates of the TCA cycle (acetate and/or pyruvate) were added and vice versa when inhibitors of the TCA cycle (palmitoyl-CoA and/or avidin) were applied. The inconsistency of the TCA cycle level and cell viability suggested that the extensive TCA cycle can keep cells alive yet generate toxic substances that reduce cell viability. The data revealed that HUVECs depend on "ischemic TCA cycle" instead of glycolysis to keep cells alive under lethal ischemic conditions, but consideration must be given to relieve cell injury.
... In this case, arginine is required by macrophages with different polarization. Interestingly, endothelial cells as well as immune cells rely heavily on glycolysis and have lower levels of oxidative phosphorylation [172]. This metabolic strategy is known as the Warburg effect [173]. ...
Atherosclerosis is one of the key problems of modern medicine, which is due to the high prevalence of atherosclerotic cardiovascular diseases and their significant share in the structure of morbidity and mortality in many countries. Atherogenesis is a complex chain of events that proceeds over many years in the vascular wall with the participation of various cells. Endothelial cells are key participants in vascular function. They demonstrate involvement in the regulation of vascular hemodynamics, metabolism, and innate immunity, which act as leading links in the pathogenesis of atherosclerosis. These endothelial functions have close connections and deep evolutionary roots, a better understanding of which will improve the prospects of early diagnosis and effective treatment.
... Another interesting protein is the cytochrome c oxidase (COX) assembly factor COA3, which is involved in promoting a Warburg-like effect in cancer cells [53]. The Warburg-like effect has also been described as one of the changes that occur during metabolic reprogramming of immune cells [54]. ...
Damage-associated molecular patterns (DAMPs) play a critical role in dendritic cells (DCs) ability to trigger a specific and efficient adaptive immune response for different physiological and pathological scenarios. We have previously identified constitutive DAMPs (HMGB1 and Calreticulin) as well as new putative inducible DAMPs such as Haptoglobin (HP), from a therapeutically used heat shock-conditioned melanoma cell lysate (called TRIMEL). Remarkably, HP was shown to be the most abundant protein in the proteomic profile of heat shock-conditioned TRIMEL samples. However, its relative contribution to the observed DCs phenotype has not been fully elucidated. Human DCs were generated from monocytes isolated from PBMC of melanoma patients and healthy donors. DC lineage was induced with rhIL-4 and rhGM-CSF. After additional stimulation with HP, the proteome of these HP-stimulated cells was characterized. In addition, DCs were phenotypically characterized by flow cytometry for canonical maturation markers and cytokine production. Finally, in vitro transmigration capacity was assessed using Transwell plates. Our results showed that the stimulation with HP was associated with the presence of exclusive and higher relative abundance of specific immune-; energy production-; lipid biosynthesis-; and DAMPs-related proteins. Importantly, HP stimulation enhanced the expression of specific DC maturation markers and pro-inflammatory and Th1-associated cytokines, and an in vitro transmigration of primary human DCs. Taken together, these data suggest that HP can be considered as a new inducible DAMP with an important role in in vitro DC activation for cancer immunotherapy.
... This might be explained by the fact that cells that express low levels of surface bound IL-6R, including ECs, can still activate the pathway. This activation depends on the presence of soluble (s)IL-6R to drive IL-6 transsignaling, which is mediated via binding of IsIL-6R to IL-6/ glycoprotein 130 complexes on the cell surface (42)(43)(44). It is possible that there are insufficient levels of sIL-6R present in Tm sup to drive robust IL-6 pathway activation and therefore the effects obtained by blocking IL-6R are only limited. ...
... Although we did not explore the roles of IFNa and -g, our data indicates that these cytokines contribute to EC activation since both IFN response pathways were strongly upregulated by T m sup stimulation. In addition, other studies have shown that IFNg can induce EC responses including complement activation, apoptosis, proliferation and oxidative phosphorylation (18,(41)(42)(43)(44). Interestingly, all these responses were reversed when we treated ECs with iIKKb, suggesting an important role for IFNg in driving EC activation via NF-kB signaling. ...
Endothelial cells (ECs) are important contributors to inflammation in immune-mediated inflammatory diseases (IMIDs). In this study, we examined whether CD4+ memory T (Tm) cells can drive EC inflammatory responses. Human Tm cells produced ligands that induced inflammatory responses in human umbilical vein EC as exemplified by increased expression of inflammatory mediators including chemokines and adhesion molecules. NF-κB, a key regulator of EC activation, was induced by Tm cell ligands. We dissected the relative contribution of canonical and non-canonical NF-κB signaling to Tm induced EC responses using pharmacological small molecule inhibitors of IKKβ (iIKKβ) or NF-κB inducing kinase (iNIK). RNA sequencing revealed substantial overlap in IKKβ and NIK regulated genes (n=549) that were involved in inflammatory and immune responses, including cytokines (IL-1β, IL-6, GM-CSF) and chemokines (CXCL5, CXCL1). NIK regulated genes were more restricted, as 332 genes were uniquely affected by iNIK versus 749 genes by iIKKβ, the latter including genes involved in metabolism, proliferation and leukocyte adhesion (VCAM-1, ICAM-1). The functional importance of NIK and IKKβ in EC activation was confirmed by transendothelial migration assays with neutrophils, demonstrating stronger inhibitory effects of iIKKβ compared to iNIK. Importantly, iIKKβ – and to some extent iNIK - potentiated the effects of currently employed therapies for IMIDs, like JAK inhibitors and anti-IL-17 antibodies, on EC inflammatory responses. These data demonstrate that inhibition of NF-κB signaling results in modulation of Tm cell-induced EC responses and highlight the potential of small molecule NF-κB inhibitors as a novel treatment strategy to target EC inflammatory responses in IMIDs.
... Glycolysis generally occurs in an oxygen-deficient environment, providing the necessary ATP to tissues or cells. However, in an aerobic environment, a large amount of glycolysis occurs in tissues or cells that proliferate or metabolize faster, especially tumor cells, which is aerobic glycolysis or Warburg effects [26]. An important reason is that glycolysis produces DNA and other raw materials, and it also provides acidic microenvironment to meet proliferation, invasion or inflammatory cytokine production [12,27,28]. ...
Background
Up-regulation of aerobic glycolysis has been reported as a characterization of asthma and facilitates airway inflammation. We has been previously reported that short isoform thymic stromal lymphopoietin (sTSLP) could reduce inflammation in asthmatic airway epithelial cells. Here we wanted to investigate whether the inhibition of sTSLP on asthma is related to aerobic glycolysis.
Methods
Asthmatic model was established in challenging Male BALB/c mice and 16-HBE (human bronchial epithelial) cell line with house dust mite (HDM). Indicators of glycolysis were assessed to measure whether involve in sTSLP regulating airway epithelial cells inflammation in asthmatic model in vivo and in vitro.
Results
sTSLP decreased inflammation of asthmatic airway and aerobic glycolysis in mice. HDM or long isoform thymic stromal lymphopoietin (lTSLP) promoted HIF-1α expression and aerobic glycolysis by miR-223 to target and inhibit VHL (von Hippel-Lindau) expression 16-HBE. Inhibition of aerobic glycolysis restrained HDM- and lTSLP-induced inflammatory cytokines production. sTSLP along had almost no potential to alter aerobic glycolysis of 16-HBE. But sTSLP decreased LDHA (lactate dehydrogenase A) and LD (Lactic acid) levels in BALF, and HIF-1α and LDHA protein levels in airway epithelial cells of asthma mice model. lTSLP and sTSLP both induced formation of TSLPR and IL-7R receptor complex, and lTSLP obviously facilitated phosphorylation of JAK1, JAK2 and STAT5, while sTSLP induced a little phosphorylation of JAK1 and STAT5.
Conclusion
We identified a novel mechanism that lTSLP could promote inflammatory cytokines production by miR-223/VHL/HIF-1α pathway to upregulate aerobic glycolysis in airway epithelial cells in asthma. This pathway is suppressed by sTSLP through occupying binding site of lTSLP in TSLPR and IL-7R receptor complex.
... Upon activation, T cells increase in size and start to rapidly divide. To cover the increased amounts of energy, activated T cells upregulate aerobic glycolysis, which although inefficient, is a faster bioenergetic pathway compared to OXPHOS when there is a steady glucose supply [169]. Cell metabolism also plays a significant role in T cell differentiation. ...
Immune cells have emerged as powerful regulators of regenerative as well as pathological processes. The vast majority of regenerative immunoengineering efforts have focused on macrophages; however, growing evidence suggests that other cells of both the innate and adaptive immune system are as important for successful revascularization and tissue repair. Moreover, spatiotemporal regulation of immune cells and their signaling have a significant impact on the regeneration speed and the extent of functional recovery. In this review, we summarize the contribution of different types of immune cells to the healing process and discuss ways to manipulate and control immune cells in favor of vascularization and tissue regeneration. In addition to cell delivery and cell-free therapies using extracellular vesicles, we discuss in situ strategies and engineering approaches to attract specific types of immune cells and modulate their phenotypes. This field is making advances to uncover the extraordinary potential of immune cells and their secretome in the regulation of vascularization and tissue remodeling. Understanding the principles of immunoregulation will help us design advanced immunoengineering platforms to harness their power for tissue regeneration.
