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Nature Metabolism Oct 2023T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in...
T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8 T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8 T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.
Topics: CD8-Positive T-Lymphocytes; Glutarates; Biochemical Phenomena
PubMed: 37605057
DOI: 10.1038/s42255-023-00855-2 -
Circulation Research Dec 2023
Topics: Succinic Acid; Succinates; Heart
PubMed: 38112098
DOI: 10.1161/CIRCRESAHA.123.323651 -
Current Opinion in Nephrology and... Sep 2023Kidney stone disease is caused by supersaturation of urine with certain metabolites and minerals. The urine composition of stone formers has been measured to prevent... (Review)
Review
PURPOSE OF REVIEW
Kidney stone disease is caused by supersaturation of urine with certain metabolites and minerals. The urine composition of stone formers has been measured to prevent stone recurrence, specifically calcium, uric acid, oxalate, ammonia, citrate. However, these minerals and metabolites have proven to be unreliable in predicting stone recurrence. Metabolomics using high throughput technologies in well defined patient cohorts can identify metabolites that may provide insight into the pathogenesis of stones as well as offer possibilities in therapeutics.
RECENT FINDINGS
Techniques including 1H-NMR, and liquid chromatography paired with tandem mass spectroscopy have identified multiple possible metabolites involved in stone formation. Compared to formers of calcium oxalate stones, healthy controls had higher levels of hippuric acid as well as metabolites involved in caffeine metabolism. Both the gut and urine microbiome may contribute to the altered metabolome of stone formers.
SUMMARY
Although metabolomics has offered several potential metabolites that may be protective against or promote stone formation, the mechanisms behind these metabolomic profiles and their clinical significance requires further investigation.
Topics: Humans; Calcium Oxalate; Kidney Calculi; Calcium; Oxalates; Metabolomics
PubMed: 37530089
DOI: 10.1097/MNH.0000000000000903 -
Cell Reports Sep 2023The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens...
The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made in understanding the metabolic changes that occur during macrophage activation, little is known about how these metabolic changes affect the cGAS-STING axis. In this study, we identify that 4-octyl itaconate (4-OI), a derivative of itaconate, inhibits the activation of cGAS-STING. Furthermore, we show that 4-OI inhibits cGAS-STING-related antiviral immune responses and autoimmune inflammation. However, we find that endogenous itaconate does not affect cGAS-STING activation, indicating that 4-OI and itaconate function differently. Mechanistically, we find that 4-OI directly alkylates STING at Cys91, blocking STING palmitoylation and oligomerization. The alkylation of STING by 4-OI represents another type of post-translational modifications (PTMs) of STING. Our findings reveal a mechanism by which cGAS-STING function is regulated through 4-OI alkylation and provide insights into the crosstalk between different kinds of PTMs.
Topics: Lipoylation; Nucleotidyltransferases; Succinates
PubMed: 37624697
DOI: 10.1016/j.celrep.2023.113040 -
Current Opinion in Immunology Oct 2023Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages... (Review)
Review
Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages rewire their energy metabolism to execute their immune programs. Intensive research in the field of immunometabolism highlights cell-intrinsic immunometabolites such as succinate and itaconate as immunomodulatory signals. A role for cell-extrinsic stimuli now emerges with evidence for signals that shape macrophages' metabolism in a tissue-specific manner. In this review, we will cover macrophage immunometabolism in the gut, a complex metabolic and immunologically active tissue. During homeostasis, gut macrophages are constantly exposed to pro-inflammatory ligands from the microbiota, and in contrast, are balanced by microbiota-derived anti-inflammatory metabolites. Given their extensive metabolic changes during activation, spatial analyses of the tissue will allow the characterization of metabolic niches of macrophage in the gut. Identifying metabolic perturbations of macrophage subsets during chronic inflammation and infection can direct future tissue-specific metabolotherapies.
Topics: Humans; Macrophages; Energy Metabolism; Succinic Acid; Immunity; Inflammation
PubMed: 37473458
DOI: 10.1016/j.coi.2023.102369 -
Current Opinion in Biotechnology Oct 20232-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers... (Review)
Review
2-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers have been described to accumulate in diverse cancer and immune cells and can influence cell fate and function. While D-2HG was originally considered as an 'oncometabolite' that aberrantly builds up in certain cancers, it is becoming clear that it also physiologically accumulates in immune cells and regulates immune function. Conversely, L-2HG is considered as an 'immunometabolite' due to its induction and regulatory function in T cells, but it can also be induced in certain cancers. Here, the authors review the effects of both 2HG enantiomers on immune cells within the tumor microenvironment.
Topics: Humans; Neoplasms; Glutarates; Ketoglutaric Acids; Stereoisomerism; Mutation; Tumor Microenvironment
PubMed: 37515937
DOI: 10.1016/j.copbio.2023.102976 -
Inflammation Aug 2023With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic... (Review)
Review
With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.
Topics: Succinates; Macrophages; Adjuvants, Immunologic; Immunologic Factors
PubMed: 37142886
DOI: 10.1007/s10753-023-01819-0 -
La Tunisie Medicale Jul 2023The pre-analytical step of cytobacteriological examination of urine (CBEU) is one of the most critical in microbiology.
INTRODUCTION
The pre-analytical step of cytobacteriological examination of urine (CBEU) is one of the most critical in microbiology.
AIM
To analyze quantitatively and qualitatively the pre-analytical non-conformities related to the CBEU in order to propose reliable corrective measures.
METHOD
This was a 76-month retrospective study from March 2016 to June 2022. The study included all CBEU referred to our laboratory. The conformity of the requests was evaluated according to the requirements of the medical microbiology standard (REMIC). It concerned the CBEU request, the urine sample and its packaging.
RESULT
We collected 66631 CBEU requests. The urine was not conform in 1646 (2.47%) cases. The majority of non-conformities came from the emergency department (n= 653; 39.67%). The predominant non-conformities were (i) deteriorated sample (53.53%; n=878), (ii) delayed transport (28.55%; n=469) and (iii) damaged equipment (4.62%; n= 76).
CONCLUSION
In our study, pre-analytical non-conformities of CBEU were frequent and affected all steps of the pre-analytical process. They had a direct clinical and economic impact on the patient. Continuous improvement of the pre-analytical phase of the CBEU is necessary in our institution.
Topics: Humans; Retrospective Studies; Urinalysis; Dioctyl Sulfosuccinic Acid; Emergency Service, Hospital; Hospitals, University
PubMed: 38445422
DOI: No ID Found -
Trends in Endocrinology and Metabolism:... Mar 2024Metabolic byproducts have conventionally been disregarded as waste products without functions. In this opinion article, we bring to light the multifaceted role of... (Review)
Review
Metabolic byproducts have conventionally been disregarded as waste products without functions. In this opinion article, we bring to light the multifaceted role of methylmalonic acid (MMA), a byproduct of the propionate metabolism pathway mostly commonly known as a clinical biomarker of vitamin B12 deficiency. MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway, the gut microbiota, and aggressive cancers. Here, we describe the diverse metabolic and signaling functions of MMA and discuss the consequences of increased MMA levels, such as during the aging process, for several age-related human pathologies.
Topics: Humans; Vitamin B 12; Methylmalonic Acid; Propionates; Vitamin B 12 Deficiency; Aging
PubMed: 38030482
DOI: 10.1016/j.tem.2023.11.001