Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines

2017 ◽  
Vol 398 (3) ◽  
pp. 303-317 ◽  
Author(s):  
Vito Iacobazzi ◽  
Vittoria Infantino ◽  
Alessandra Castegna ◽  
Alessio Menga ◽  
Erika Mariana Palmieri ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Lipid Mediators ◽  
Metabolic Changes ◽  
Intracellular Signalling ◽  
Metabolic Reprogramming ◽  
Bacterial Endotoxin ◽  
Mitochondrial Carriers ◽  
Signalling Molecules ◽  
Number Of Genes ◽  
Membrane Change

Abstract Significant metabolic changes occur in the shift from resting to activated cellular status in inflammation. Thus, changes in expression of a large number of genes and extensive metabolic reprogramming gives rise to acquisition of new functions (e.g. production of cytokines, intermediates for biosynthesis, lipid mediators, PGE, ROS and NO). In this context, mitochondrial carriers, which catalyse the transport of solute across mitochondrial membrane, change their expression to transport mitochondrially produced molecules, among which citrate and succinate, to be used as intracellular signalling molecules in inflammation. This review summarises the mitochondrial carriers studied so far that are, directly or indirectly, involved in inflammation.

scholarly journals 5-Lipoxygenase Pathway, Dendritic Cells, and Adaptive Immunity

2004 ◽  
Vol 2004 (2) ◽  
pp. 99-105 ◽  
Author(s):  
Harizi Hedi ◽  
Gualde Norbert
Keyword(s):  
Dendritic Cells ◽  
Adaptive Immunity ◽  
Inflammatory Cells ◽  
Lipid Mediators ◽  
G Protein Coupled Receptors ◽  
Lipoxygenase Pathway ◽  
Innate And Adaptive Immunity ◽  
Paracrine Signalling ◽  
Signalling Molecules ◽  
G Protein Coupled

5-lipoxygenase (5-LO) pathway is the major source of potent proinflammatory leukotrienes (LTs) issued from the metabolism of arachidonic acid (AA), and best known for their roles in the pathogenesis of asthma. These lipid mediators are mainly released from myeloid cells and may act as physiological autocrine and paracrine signalling molecules, and play a central role in regulating the interaction between innate and adaptive immunity. The biological actions of LTs including their immunoregulatory and proinflammatory effects are mediated through extracellular specific G-protein-coupled receptors. Despite their role in inflammatory cells, such as neutrophils and macrophages, LTs may have important effects on dendritic cells (DC)-mediated adaptive immunity. Several lines of evidence show that DC not only are important source of LTs, but also become targets of their actions by producing other lipid mediators and proinflammatory molecules. This review focuses on advances in 5-LO pathway biology, the production of LTs from DC and their role on various cells of immune system and in adaptive immunity.

Targeting intracellular mediators of pattern-recognition receptor signalling to adjuvant vaccination

2007 ◽  
Vol 35 (6) ◽  
pp. 1501-1503 ◽  
Author(s):  
J. Wales ◽  
E. Andreakos ◽  
M. Feldmann ◽  
B. Foxwell
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Systemic Toxicity ◽  
Pattern Recognition Receptor ◽  
Intracellular Signalling ◽  
Present Review ◽  
Signalling Molecules ◽  
Receptor Signalling ◽  
Intracellular Mediators ◽  
Recognition Receptor

PRR (pattern-recognition receptor) signalling is involved early in the immune response and therefore would be attractive to target during vaccination. The use of PRR ligands has shown some success; however, toxicity and non-specificity are issues with this strategy. The targeting of PRR intracellular signalling networks would allow for greater specificity and reduced systemic toxicity. The present review examines the successes seen with overexpression or repression of PRR signalling molecules.

scholarly journals HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
David Wu ◽  
Ru-Ting Huang ◽  
Robert B Hamanaka ◽  
Matt Krause ◽  
Myung-Jin Oh ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Glycolytic Enzyme ◽  
Metabolic Changes ◽  
Metabolic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
Respiratory Capacity ◽  
Disturbed Flow ◽  
Bioenergetic Analysis ◽  
Mitochondrial Respiratory

Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1α (HIF-1α), downstream of NAD(P)H oxidase-4 (NOX4)-derived reactive oxygen species (ROS). HIF-1α increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1α, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow-induced metabolic reprogramming and inflammation in ECs.

scholarly journals NAD+ surfaces again

2004 ◽  
Vol 382 (3) ◽  
Author(s):  
Mathias ZIEGLER ◽  
Marc NIERE
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Immune Cells ◽  
Degradation Product ◽  
Intracellular Signalling ◽  
Potential Significance ◽  
Signalling Molecules ◽  
Regulatory Processes ◽  
Biochemical Journal ◽  
Extracellular Side

NAD+ and its metabolites serve important functions in intracellular signalling. NAD+-mediated regulatory processes also take place on the cell surface, particularly of immune cells. In this issue of the Biochemical Journal, Gerth et al. have demonstrated a new mechanism of Ca2+ uptake into monocytes which is triggered by NAD+ or its degradation product, ADP-ribose. These observations point to a hitherto unknown Ca2+-influx mechanism and underscore the potential significance of NAD+ and ADP-ribose as signalling molecules on the extracellular side of the plasma membrane.

scholarly journals Regulation of intracellular signalling by the terminal membrane proteins of members of the Gammaherpesvirinae

2006 ◽  
Vol 87 (5) ◽  
pp. 1047-1074 ◽  
Author(s):  
Melanie M. Brinkmann ◽  
Thomas F. Schulz
Keyword(s):  
Membrane Proteins ◽  
Tyrosine Kinases ◽  
Cellular Transformation ◽  
Lytic Replication ◽  
Janus Kinase ◽  
Intracellular Signalling ◽  
Receptor Protein ◽  
Tumour Necrosis Factor Receptor ◽  
Signalling Molecules ◽  
Barr Virus

The human γ 1-herpesvirus Epstein–Barr virus (EBV) and the γ 2-herpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV), rhesus rhadinovirus (RRV), herpesvirus saimiri (HVS) and herpesvirus ateles (HVA) all contain genes located adjacent to the terminal-repeat region of their genomes, encoding membrane proteins involved in signal transduction. Designated ‘terminal membrane proteins' (TMPs) because of their localization in the viral genome, they interact with a variety of cellular signalling molecules, such as non-receptor protein tyrosine kinases, tumour-necrosis factor receptor-associated factors, Ras and Janus kinase (JAK), thereby initiating further downstream signalling cascades, such as the MAPK, PI3K/Akt, NF-κB and JAK/STAT pathways. In the case of TMPs expressed during latent persistence of EBV and HVS (LMP1, LMP2A, Stp and Tip), their modulation of intracellular signalling pathways has been linked to the provision of survival signals to latently infected cells and, hence, a contribution to occasional cellular transformation. In contrast, activation of similar pathways by TMPs of KSHV (K1 and K15) and RRV (R1), expressed during lytic replication, may extend the lifespan of virus-producing cells, alter their migration and/or modulate antiviral immune responses. Whether R1 and K1 contribute to the oncogenic properties of KSHV and RRV has not been established satisfactorily, despite their transforming qualities in experimental settings.

Linking proximal and downstream signalling events in hepatic ischaemia/reperfusion injury

2006 ◽  
Vol 34 (5) ◽  
pp. 957-959 ◽  
Author(s):  
G. Jeyabalan ◽  
A. Tsung ◽  
T.R. Billiar
Keyword(s):  
Reperfusion Injury ◽  
Immune Surveillance ◽  
High Mobility ◽  
Intracellular Signalling ◽  
Ischaemia Reperfusion Injury ◽  
Signalling Molecules ◽  
Ischaemia Reperfusion ◽  
The Many ◽  
Molecular Patterns

Hepatic I/R (ischaemia/reperfusion) injury occurs in a variety of clinical settings including transplantation, elective liver resections and trauma. One of the challenges in studying the pathophysiology of I/R injury is the fact that the liver plays a central role in a variety of metabolic pathways in addition to governing aspects of immune surveillance and tolerance. The pathways activated in response to insults as varied as toxins, microbial and endogenous ligands and I/R may share common elements. The multiple intracellular signalling cascades involved in this process and the initiating events are still under investigation. Recent work on the role of TLRs (Toll-like receptors) in I/R injury has elucidated some of the more proximal signalling events in the pathway. In addition to the well-established role of signalling molecules such as NO (nitric oxide) in mediating damage or protection following hepatic I/R, more recent studies have focused on the participation of endogenous danger signals or DAMPs (damage-associated molecular patterns) such as HMGB1 (high-mobility group box 1). The complex interplay between HMGB1, TLRs and the many intracellular signalling molecules and pathways is illustrative of how our understanding of hepatic I/R injury is continually evolving.

Effect of D-mannose on Philadelphia chromosome-positive leukemia cells

2021 ◽  
pp. 1-10
Author(s):  
Seiichi Okabe ◽  
Yuko Tanaka ◽  
Akihiko Gotoh
Keyword(s):  
Kinase Inhibitors ◽  
Combined Treatment ◽  
Philadelphia Chromosome ◽  
Body Weight Loss ◽  
K562 Cells ◽  
Metabolic Changes ◽  
Metabolic Reprogramming ◽  
Leukemia Cells ◽  
Severe Toxicity ◽  
Abl Tyrosine Kinase

BACKGROUND: Although Abelson (ABL) tyrosine kinase inhibitors (TKIs) have demonstrated potency against chronic myeloid leukemia (CML), resistance to ABL TKIs can develop in CML patients after discontinuation of therapy. OBJECTIVE: Glucose metabolism may be altered in CML cells because glucose is a key metabolite used by tumor cells. We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. METHODS: We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. RESULTS: Treatment with D-mannose for 72 h inhibited the growth of K562 cells. Combined treatment using ABL TKIs and D-mannose induced a significantly higher level of cytotoxicity in Philadelphia chromosome (Ph)-positive leukemia cells than in control cells. In the mouse model, severe toxicity was observed as evidenced by body weight loss in the ponatinib and D-mannose combination treatment groups. CONCLUSION: Our results indicate that metabolic reprogramming may be a useful strategy against Ph-positive leukemia cells. However, caution should be exercised during clinical applications.

scholarly journals Defining a metabolic landscape of tumours: genome meets metabolism

2019 ◽  
Vol 122 (2) ◽  
pp. 136-149 ◽  
Author(s):  
Chandan Seth Nanda ◽  
Sharavan Vishaan Venkateswaran ◽  
Neill Patani ◽  
Mariia Yuneva
Keyword(s):  
Complex Disease ◽  
Metabolic Diseases ◽  
Cellular Transformation ◽  
Metabolic Changes ◽  
Metabolic Reprogramming ◽  
Metabolic Dysregulation ◽  
Oncogenic Mutations ◽  
Essential Question ◽  
Metabolic Heterogeneity ◽  
Tumour Initiation

AbstractCancer is a complex disease of multiple alterations occuring at the epigenomic, genomic, transcriptomic, proteomic and/or metabolic levels. The contribution of genetic mutations in cancer initiation, progression and evolution is well understood. However, although metabolic changes in cancer have long been acknowledged and considered a plausible therapeutic target, the crosstalk between genetic and metabolic alterations throughout cancer types is not clearly defined. In this review, we summarise the present understanding of the interactions between genetic drivers of cellular transformation and cancer-associated metabolic changes, and how these interactions contribute to metabolic heterogeneity of tumours. We discuss the essential question of whether changes in metabolism are a cause or a consequence in the formation of cancer. We highlight two modes of how metabolism contributes to tumour formation. One is when metabolic reprogramming occurs downstream of oncogenic mutations in signalling pathways and supports tumorigenesis. The other is where metabolic reprogramming initiates transformation being either downstream of mutations in oncometabolite genes or induced by chronic wounding, inflammation, oxygen stress or metabolic diseases. Finally, we focus on the factors that can contribute to metabolic heterogeneity in tumours, including genetic heterogeneity, immunomodulatory factors and tissue architecture. We believe that an in-depth understanding of cancer metabolic reprogramming, and the role of metabolic dysregulation in tumour initiation and progression, can help identify cellular vulnerabilities that can be exploited for therapeutic use.

scholarly journals Intracellular signalling molecules as immunohistochemical markers of normal and neoplastic human leucocytes in routine biopsy samples

2004 ◽  
Vol 124 (4) ◽  
pp. 519-533 ◽  
Author(s):  
Michela Pozzobon ◽  
Teresa Marafioti ◽  
Martin-Leo Hansmann ◽  
Yasodha Natkunam ◽  
David Y. Mason
Keyword(s):  
Intracellular Signalling ◽  
Signalling Molecules ◽  
Immunohistochemical Markers ◽  
Routine Biopsy

scholarly journals Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3318
Author(s):  
Marina Serra ◽  
Amedeo Columbano ◽  
Andrea Perra ◽  
Marta Anna Kowalik
Keyword(s):  
Hepatocellular Carcinoma ◽  
Animal Models ◽  
Metabolic Profile ◽  
Cancer Metabolism ◽  
Therapeutic Strategies ◽  
Metabolic Changes ◽  
Metabolic Reprogramming ◽  
Rodent Models ◽  
Hallmarks Of Cancer ◽  
The Core

Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC.

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