Coenzyme A (CoA) serves as a vital cofactor in numerous enzymatic reactions involved in energy production, lipid metabolism, and synthesis of essential molecules. Dysregulation of CoA‐dependent ...metabolic pathways can contribute to chronic diseases, such as inflammatory diseases, obesity, diabetes, cancer, and cardiovascular disorders. Additionally, CoA influences immune cell activation by modulating the metabolism of these cells, thereby affecting their proliferation, differentiation, and effector functions. Targeting CoA metabolism presents a promising avenue for therapeutic intervention, as it can potentially restore metabolic balance, mitigate chronic inflammation, and enhance immune cell function. This might ultimately improve the management and outcomes for these diseases. This review will more specifically focus on the contribution of pathways regulating the availability of the CoA precursor Vitamin B5/pantothenate in vivo and modulating the development of Th17‐mediated inflammation, CD8‐dependent anti‐tumor immunity but also tissue repair processes in chronic inflammatory or degenerative diseases.
Graphical : Appropriate levels of CoA and AcCoA in tissues undergoing chronic inflammatory, infectious, tumoral, or degenerative diseases regulate tissue repair and maintenance of functional infiltrating lymphocytes. Enzymes controlling vitamin B5 (vanin = VNN) and CoA (pantothenate kinase = PANK) synthesis participate to this homeostasis.
Pantetheinase is an ubiquitous enzyme which hydrolyses D-pantetheine into cysteamine and pantothenate (vitamin B5) on the dissimilative pathway of CoA. Pantetheinase isoforms are encoded by the Vnn ...(vanin) genes and Vnn1 is the predominant tissue isoform in mice and humans. In the present article, we review the results showing the regulation of Vnn1 expression during developmental, repair and inflammatory situations and the impact of a Vnn1 deficiency in mouse models of pathologies. We document the involvement of the Vnn1 pantetheinase in situations of increased tissue needs and propose that Vnn1 through recycling of pantothenate and release of cysteamine in tissues participates in the adaptive response of the tissue to stress.
Metabolic landscapes in sarcomas Miallot, Richard; Galland, Franck; Millet, Virginie ...
Journal of hematology and oncology,
07/2021, Volume:
14, Issue:
1
Journal Article
Peer reviewed
Open access
Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological ...definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.
Embryonic implantation comprises a dynamic and complicated series of events, which takes place only when the maternal uterine endometrium is in a receptive state. Blastocysts reaching the uterus ...communicate with the uterine endometrium to implant within a narrow time window. Interplay among various signalling molecules and transcription factors under the control of ovarian hormones is necessary for successful establishment of pregnancy. However, the molecular mechanisms that allow embryonic implantation in the receptive endometrium are still largely unknown. Here, we show that Sry-related HMG box gene-17 (Sox17) heterozygous mutant female mice exhibit subfertility due to implantation failure. Sox17 was expressed in the oviduct, uterine luminal epithelium, and blood vessels. Sox17 heterozygosity caused no appreciable defects in ovulation, fertilisation, blastocyst formation, and gross morphology of the oviduct and uterus. Another group F Sox transcription factor, Sox7, was also expressed in the uterine luminal and glandular epithelium relatively weakly. Despite uterine Sox7 expression, a significant reduction in the number of implantation sites was observed in Sox17 heterozygous mutant females due to haploinsufficiency. Our findings revealed a novel role of Sox17 in uterine receptivity to embryo implantation.
Objective
Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine ...or by inactivating ATP‐binding cassette transporter A1 (ABCA1) ameliorates murine SSc.
Methods
First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo. SSc was induced in BALB/c mice by daily intradermal injection of HOCl. Mice were simultaneously treated daily with pantethine by oral gavage.
Results
In vitro, pantethine inhibited MP shedding from tumor necrosis factor–stimulated ECs and abrogated MP‐induced oxidative and nitrosative stresses in ECs and fibroblasts. Ex vivo, pantethine also restored redox homeostasis in fibroblasts from mice with SSc. In vivo, mice with SSc displayed skin and lung fibrosis associated with increased levels of circulating MPs and markers of oxidative and endothelial stress, which were normalized by administration of pantethine or inactivation of ABCA1.
Conclusion
Pantethine is a well‐tolerated molecule that represents a potential treatment of human SSc.
•The Vnn1 pantetheinase is expressed in liver and secreted in serum.•The vnn1 gene is a target of PPARα regulation.•The level of serum Vnn1 production reflects PPARα activation in liver.
The ...membrane-bound Vanin-1 pantetheinase regulates tissue adaptation to stress. We investigated Vnn1 expression and its regulation in liver. Vnn1 is expressed by centrolobular hepatocytes. Using novel tools, we identify a soluble form of Vnn1 in mouse and human serum and show the contribution of a cysteine to its catalytic activity. We show that liver contributes to Vanin-1 secretion in serum and that PPARalpha is a limiting factor in serum Vnn1 production. Functional PPRE sites are identified in the Vnn1 promoter. These results indicate that serum Vnn1 might be a reliable reporter of PPARalpha activity in liver.
In liver, cysteamine in all probability represents a "low-capacity, high-affinity" scavenger of ROS. The available body of evidence suggests that reduced cysteamine and oxidized cystamine exist in ...equilibrium and that this ratio acts as an active redox sensor within the cell much like GSH. During normal liver homeostasis cysteamine's antioxidant properties are evident. Highly metabolic and/or pro-oxidative conditions, such as in mice treated with peroxisome proliferators, shift this equilibrium to favor the oxidized form. Under these conditions, cystamine is likely able to inactivate proteins involved in energy biogenesis through cysteaminylation of critical Cys residues as has been shown in vitro. This would allow cystamine to function as a "metabolic brake" to prevent the formation of additional ROS. In vivo, subcellular localization, pH, reducing capacity, FMO status and metabolic rate are all probable factors in determining the cysteamine:cystamine ratio. The availability of free cysteamine is also regulated by hydrolysis of pantetheine by pantetheinase. This cleavage results in the formation of pantothenic acid, a precursor to Coenzyme A which is prominently involved with lipid metabolism and energy production by the β -oxidation pathway and TCA cycle, respectively. Expression of pantetheinase is controlled by the Vnn1 gene and is upregulated in response to free fatty acids, PPAR activation or oxidative stress. The use of Vnn1 knockout mice has provided clear evidence that Vnn1 modulates redox and immune pathways In vivo, both of which appear at least partially due to a loss of cysteamine/cystamine. Immunologically, Vnn1 expression may influence cell signaling indirectly through maintenance of disulfide bonds or directly by interaction of pantetheinase on the cell surface. Cysteamine treatment has been used clinically as an antidote to APAP poisoning and in animal models against hepatotoxicants including APAP, galactosamine and CCl4. Protection in animal models occurs even when administered up to 12 hours following intoxication, suggesting that protection is the result of effects that occur downstream of bioactivation and covalent binding of reactive metabolites to target cellular macromolecules. Currently, the downstream influences of Vnn1 expression and cysteamine at endogenous concentrations remain largely unknown. Vnn1 knockout mice represent a valuable tool available to researchers investigating these events. Future studies in the field are needed to elucidate the precise mechanisms by which pantetheinase and/or cysteamine impact immune cell recruitment, cell signaling and survival, though it is clear that these factors have far reaching implications in the fields of immunology and toxicology.
Invading bacteria are recognized, captured and killed by a specialized form of autophagy, called xenophagy. Recently, defects in xenophagy in Crohn's disease (CD) have been implicated in the ...pathogenesis of human chronic inflammatory diseases of uncertain etiology of the gastrointestinal tract. We show here that pathogenic adherent-invasive Escherichia coli (AIEC) isolated from CD patients are able to adhere and invade neutrophils, which represent the first line of defense against bacteria. Of particular interest, AIEC infection of neutrophil-like PLB-985 cells blocked autophagy at the autolysosomal step, which allowed intracellular survival of bacteria and exacerbated interleukin-8 (IL-8) production. Interestingly, this block in autophagy correlated with the induction of autophagic cell death. Likewise, stimulation of autophagy by nutrient starvation or rapamycin treatment reduced intracellular AIEC survival and IL-8 production. Finally, treatment with an inhibitor of autophagy decreased cell death of AIEC-infected neutrophil-like PLB-985 cells. In conclusion, excessive autophagy in AIEC infection triggered cell death of neutrophils.
Thymic dendritic cells (DC) and epithelial cells play a major role in central tolerance but their respective roles are still controversial. Epithelial cells have the unique ability to ectopically ...express peripheral tissue-restricted antigens conferring self-tolerance to tissues. Paradoxically, while negative selection seems to occur for some of these antigens, epithelial cells, contrary to DC, are poor negative selectors. Using a thymic epithelial cell line, we show the functional intercellular transfer of membrane material, including MHC molecules, occurring between epithelial cells. Using somatic and bone marrow chimeras, we show that this transfer occurs efficiently in vivo between epithelial cells and, in a polarized fashion, from epithelial to DC. This novel mode of transfer of MHC-associated, epithelial cell-derived self-antigens onto DC might participate to the process of negative selection in the thymic medulla.
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