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Redox Biology Apr 2024Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more...
Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr atherogenic mice transplanted with Acod1 bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1 mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.
Topics: Humans; Animals; Mice; Plaque, Atherosclerotic; Atherosclerosis; Succinates; Macrophages
PubMed: 38309122
DOI: 10.1016/j.redox.2024.103054 -
Pharmacological Research Aug 2023Succinate is a vital signaling metabolite produced by the host and gut microbiota. Succinate has been shown to regulate host metabolic homeostasis and inhibit...
Succinate is a vital signaling metabolite produced by the host and gut microbiota. Succinate has been shown to regulate host metabolic homeostasis and inhibit obesity-associated inflammation in macrophages by engaging its cognate receptor, SUCNR1. However, the contribution of the succinate-SUCNR1 axis to intestinal barrier dysfunction in obesity remains unclear. In the present study, we explored the effects of succinate-SUCNR1 signaling on high-fat diet (HFD)-induced intestinal barrier dysfunction. Using a SUCNR1-deficient mouse model under HFD feeding conditions, we identified the effects of succinate-SUCNR1 axis on obesity-associated intestinal barrier impairment. Our results showed that HFD administration decreased goblet cell numbers and mucus production, promoted intestinal pro-inflammatory responses, induced gut microbiota composition imbalance, increased intestinal permeability, and caused mucosal barrier dysfunction. Dietary succinate supplementation was sufficient to activate a type 2 immune response, trigger the differentiation of barrier-promoting goblet cells, suppress intestinal inflammation, restore HFD-induced mucosal barrier impairment and intestinal dysbiosis, and eventually exert anti-obesity effects. However, SUNNR1-deficient mice failed to improve the intestinal barrier function and metabolic phenotype in HFD mice. Our data indicate the protective role of the succinate-SUCNR1 axis in HFD-induced intestinal barrier dysfunction.
Topics: Mice; Animals; Succinic Acid; Diet, High-Fat; Obesity; Signal Transduction; Inflammation; Intestinal Diseases; Gastrointestinal Diseases; Mice, Inbred C57BL
PubMed: 37482326
DOI: 10.1016/j.phrs.2023.106865 -
Science Advances Jun 2023P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it...
P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.
Topics: Humans; Succinic Acid; Transcription Factors; Cyclooxygenase 2; Pyridinolcarbamate; Carcinogenesis; Cell Transformation, Neoplastic; Succinates; Adenocarcinoma of Lung; Molecular Chaperones; HSP90 Heat-Shock Proteins; Lung Neoplasms
PubMed: 37390202
DOI: 10.1126/sciadv.ade0387 -
Journal of Translational Medicine Nov 2023Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of...
BACKGROUND
Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.
METHODS
The expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats. The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.
RESULTS
We demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats. Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.
CONCLUSIONS
Taken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.
Topics: Humans; Rats; Animals; Dimethyl Fumarate; NF-E2-Related Factor 2; Drug Repositioning; Epilepsy; Seizures; Status Epilepticus; Disease Models, Animal
PubMed: 37940957
DOI: 10.1186/s12967-023-04695-2 -
JCI Insight Oct 2023Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of...
Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury - potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate - and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.
Topics: Humans; Neutrophils; Succinates; Macrophages; Inflammation
PubMed: 37707952
DOI: 10.1172/jci.insight.169208 -
Microbiology Resource Announcements Oct 2023We report draft genome sequences for 15 non-conventional Saccharomycotina yeast strains obtained from public culture repositories. Included in our collection are eight...
We report draft genome sequences for 15 non-conventional Saccharomycotina yeast strains obtained from public culture repositories. Included in our collection are eight strains of with broad tolerance to dicarboxylic acids. The genome sequences of these strains will enable comparative genomics of acid-tolerant phenotypes and strain engineering of non-conventional hosts.
PubMed: 37747226
DOI: 10.1128/MRA.00337-23 -
Frontiers in Endocrinology 2023Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their... (Review)
Review
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.
Topics: Humans; Pheochromocytoma; Citric Acid Cycle; Ketoglutaric Acids; Paraganglioma; Adrenal Gland Neoplasms; Mutation; Succinates; Succinic Acid; Signal Transduction; Fumarates; Dioxygenases; Tumor Microenvironment
PubMed: 37867526
DOI: 10.3389/fendo.2023.1274239 -
Journal of Translational Medicine Jan 2024Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal...
Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11.
Topics: Humans; Mice; Animals; Enhancer of Zeste Homolog 2 Protein; Calcium Oxalate; Histones; Epigenesis, Genetic; Ferroptosis; Kidney; Diabetic Nephropathies; Kidney Calculi; RNA; SOXC Transcription Factors; Amino Acid Transport System y+
PubMed: 38169402
DOI: 10.1186/s12967-023-04793-1 -
Nutrients Nov 2023Pooled data from published reports on infants with clinically diagnosed vitamin B12 (B12) deficiency were analyzed with the purpose of describing the presentation,... (Review)
Review
Pooled data from published reports on infants with clinically diagnosed vitamin B12 (B12) deficiency were analyzed with the purpose of describing the presentation, diagnostic approaches, and risk factors for the condition to inform prevention strategies. An electronic (PubMed database) and manual literature search following the PRISMA approach was conducted (preregistration with the Open Science Framework, accessed on 15 February 2023). Data were described and analyzed using correlation analyses, Chi-square tests, ANOVAs, and regression analyses, and 102 publications (292 cases) were analyzed. The mean age at first symptoms (anemia, various neurological symptoms) was four months; the mean time to diagnosis was 2.6 months. Maternal B12 at diagnosis, exclusive breastfeeding, and a maternal diet low in B12 predicted infant B12, methylmalonic acid, and total homocysteine. Infant B12 deficiency is still not easily diagnosed. Methylmalonic acid and total homocysteine are useful diagnostic parameters in addition to B12 levels. Since maternal B12 status predicts infant B12 status, it would probably be advantageous to target women in early pregnancy or even preconceptionally to prevent infant B12 deficiency, rather than to rely on newborn screening that often does not reliably identify high-risk children.
Topics: Infant; Infant, Newborn; Pregnancy; Child; Humans; Female; Methylmalonic Acid; Vitamin B 12 Deficiency; Vitamin B 12; Breast Feeding; Homocysteine
PubMed: 38068819
DOI: 10.3390/nu15234960 -
RSC Advances May 2024Succinic (SUA), glutaric (GLA), pimelic (PA), suberic (SUBA), adipic (ADA), azelaic (AZA), and sebacic acids (SA) make up the majority of medium-chain dicarboxylic acids... (Review)
Review
Succinic (SUA), glutaric (GLA), pimelic (PA), suberic (SUBA), adipic (ADA), azelaic (AZA), and sebacic acids (SA) make up the majority of medium-chain dicarboxylic acids (MCDAs) with chain lengths of C4-C10, and are widely utilised in the chemical, food, textile, pesticide, pharmaceutical, and liquid crystal sectors. The MCDAs' two carboxyl groups provide them with an incredibly broad variety of applications. The focus of significant scientific research now is on the increasingly varied pharmacological effects of MCDAs. However, only a few studies have compared the biological characteristics of MCDAs in the contemporary pharmaceutical and cosmetic sectors and thoroughly examined the most recent research and marketing initiatives for MCDAs. This review's objective is to offer a thorough analysis of academic works on MCDAs, to assess the usefulness of these substances' chemical-pharmacological properties for use in the contemporary pharmaceutical and cosmetic industries, and to investigate the direction of their possible applications in these two disciplines. In addition, this review investigates how these compounds are metabolised in the human body.
PubMed: 38808239
DOI: 10.1039/d4ra02598a