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Signal Transduction and Targeted Therapy Jan 2023Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate...
Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.
Topics: Animals; Rats; Succinic Acid; Osteogenesis; Urolithiasis; Kidney Calculi; Succinates
PubMed: 36681678
DOI: 10.1038/s41392-023-01311-z -
Circulation Research Dec 2023
Topics: Succinic Acid; Succinates; Heart
PubMed: 38112098
DOI: 10.1161/CIRCRESAHA.123.323651 -
Nature Immunology May 2019Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a...
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
Topics: Adipose Tissue; Animals; Cells, Cultured; Cytokines; Gene Expression Profiling; Humans; Inflammation; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Receptors, G-Protein-Coupled; Succinic Acid; THP-1 Cells
PubMed: 30962591
DOI: 10.1038/s41590-019-0372-7 -
Proceedings of the National Academy of... Jun 2023Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells...
Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.
Topics: Humans; Dysbiosis; Mucous Membrane; Inflammation; Paneth Cells; Succinates; Succinic Acid
PubMed: 37307458
DOI: 10.1073/pnas.2219431120 -
Current Opinion in Organ Transplantation Oct 2022This review describes the role of mitochondria in ischemia-reperfusion-injury (IRI). (Review)
Review
PURPOSE OF REVIEW
This review describes the role of mitochondria in ischemia-reperfusion-injury (IRI).
RECENT FINDINGS
Mitochondria are the power-house of our cells and play a key role for the success of organ transplantation. With their respiratory chain, mitochondria are the main energy producers, to fuel metabolic processes, control cellular signalling and provide electrochemical integrity. The mitochondrial metabolism is however severely disturbed when ischemia occurs. Cellular energy depletes rapidly and various metabolites, including Succinate accumulate. At reperfusion, reactive oxygen species are immediately released from complex-I and initiate the IRI-cascade of inflammation. Prior to the development of novel therapies, the underlying mechanisms should be explored to target the best possible mitochondrial compound. A clinically relevant treatment should recharge energy and reduce Succinate accumulation before organ implantation. While many interventions focus instead on a specific molecule, which may inhibit downstream IRI-inflammation, mitochondrial protection can be directly achieved through hypothermic oxygenated perfusion (HOPE) before transplantation.
SUMMARY
Mitochondria are attractive targets for novel molecules to limit IRI-associated inflammation. Although dynamic preservation techniques could serve as delivery tool for new therapeutic interventions, their own inherent mechanism should not only be studied, but considered as key treatment to reduce mitochondrial injury, as seen with the HOPE-approach.
Topics: Humans; Inflammation; Ischemia; Mitochondria; Reperfusion Injury; Succinic Acid
PubMed: 35950880
DOI: 10.1097/MOT.0000000000001015 -
American Journal of Health-system... Jan 2022
Topics: Humans; Protein Kinase Inhibitors; Succinates; Succinic Acid
PubMed: 34964824
DOI: 10.1093/ajhp/zxab395 -
Proceedings of the National Academy of... May 2023Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely...
Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.
Topics: Cell Line, Tumor; Epithelial Cells; Epithelial-Mesenchymal Transition; Neoplasms; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Succinates; Succinic Acid; Humans
PubMed: 37155842
DOI: 10.1073/pnas.2214942120 -
Cancer Letters Apr 2017Succinate is an important intermediate of the tricarboxylic acid (TCA) cycle. In mitochondria, it plays a crucial role in generating adenosine triphosphate. Succinate... (Review)
Review
Succinate is an important intermediate of the tricarboxylic acid (TCA) cycle. In mitochondria, it plays a crucial role in generating adenosine triphosphate. Succinate metabolism is also intertwined with the metabolism of other metabolites and with the "GABA shunt" of the glutamine pathway. Recently, it has become increasingly apparent that the roles of succinate extend into the realms of immunity and cancer. Succinate is a key modulator of the hypoxic response, an important player in tumorigenesis; succinate is also involved in protein succinylation, a novel posttranslational modification pathway. This expanding repertoire of succinate functions suggests that it has broad roles in cellular contexts. Mutations in enzymes such as succinate dehydrogenase (SDH) that participate in succinate-related pathways lead to various pathologies, including tumor formation and innate inflammatory processes. Succinate can have both pro- or anti-tumor effectiveness. Therefore, investigation of succinate as an inflammatory signal may increase our understanding of the cancer-immunity cycle involved in both inflammatory diseases and cancer. Here, we briefly review the emerging roles of succinate, extending beyond metabolism, into anti-cancer immunity. This expansion of succinate roles suggests that it may represent a novel class of regulators in inflammation, which act as key signals in human cancers.
Topics: Citric Acid Cycle; Humans; Inflammation; Neoplasms; Succinic Acid
PubMed: 28109906
DOI: 10.1016/j.canlet.2017.01.019 -
Current Opinion in Biotechnology Apr 2021Macrophages are the prominent innate immune cells to combat infection and then restore tissue homeostasis after clearance of pathogens. Intracellular metabolic... (Review)
Review
Macrophages are the prominent innate immune cells to combat infection and then restore tissue homeostasis after clearance of pathogens. Intracellular metabolic reprogramming is required for macrophage activation and function, as such adaptations confer macrophages with sufficient energy and metabolites to support biosynthesis and diverse functions. During the last 10 years, knowledge in this field has been greatly extended by outstanding advances demonstrating that several metabolic intermediates possess the ability to directly control macrophage activation and effector functions by various mechanisms. Of note, citrate and succinate contribute to the inflammatory activation of macrophages while tricarboxylic acid cycle-derived metabolite itaconate has a variety of immunomodulatory effects. Such progress not only encourages a further exploration into the emerging new area immunometabolism, but also provides potential therapeutic targets to control unwanted inflammation due to infection.
Topics: Citric Acid Cycle; Humans; Inflammation; Macrophage Activation; Macrophages; Succinic Acid
PubMed: 33610128
DOI: 10.1016/j.copbio.2021.01.020 -
Khirurgiia 2021The ischemia-reperfusion syndrome complicates the course of a number of emergency conditions in various fields of clinical medicine, determines the course, prognosis and... (Review)
Review
The ischemia-reperfusion syndrome complicates the course of a number of emergency conditions in various fields of clinical medicine, determines the course, prognosis and outcome of the disease. This review examines various aspects of the etiology, pathogenesis, and clinical manifestations of this syndrome. Particular attention is paid to its prevention and treatment. It is indicated that most of the studies devoted to this problem are of an experimental nature. The use of preparations based on succinic acid in the clinic is seen as the most promising direction in solving this issue.
Topics: Humans; Ischemia; Reperfusion; Reperfusion Injury; Succinic Acid
PubMed: 34480458
DOI: 10.17116/hirurgia202109171