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Free Radical Biology & Medicine Jul 2024Cardiovascular diseases (CVDs) are the leading cause of death globally, resulting in a major health burden. Thus, an urgent need exists for exploring effective... (Review)
Review
Cardiovascular diseases (CVDs) are the leading cause of death globally, resulting in a major health burden. Thus, an urgent need exists for exploring effective therapeutic targets to block progression of CVDs and improve patient prognoses. Immune and inflammatory responses are involved in the development of atherosclerosis, ischemic myocardial damage responses and repair, calcification, and stenosis of the aortic valve. These responses can involve both large and small blood vessels throughout the body, leading to increased blood pressure and end-organ damage. While exploring potential avenues for therapeutic intervention in CVDs, researchers have begun to focus on immune metabolism, where metabolic changes that occur in immune cells in response to exogenous or endogenous stimuli can influence immune cell effector responses and local immune signaling. Itaconate, an intermediate metabolite of the tricarboxylic acid (TCA) cycle, is related to pathophysiological processes, including cellular metabolism, oxidative stress, and inflammatory immune responses. The expression of immune response gene 1 (IRG1) is upregulated in activated macrophages, and this gene encodes an enzyme that catalyzes the production of itaconate from the TCA cycle intermediate, cis-aconitate. Itaconate and its derivatives have exerted cardioprotective effects through immune modulation in various disease models, such as ischemic heart disease, valvular heart disease, vascular disease, heart transplantation, and chemotherapy drug-induced cardiotoxicity, implying their therapeutic potential in CVDs. In this review, we delve into the associated signaling pathways through which itaconate exerts immunomodulatory effects, summarize its specific roles in CVDs, and explore emerging immunological therapeutic strategies for managing CVDs.
Topics: Humans; Succinates; Animals; Cardiovascular Diseases; Citric Acid Cycle; Oxidative Stress; Signal Transduction; Carboxy-Lyases
PubMed: 38604314
DOI: 10.1016/j.freeradbiomed.2024.04.218 -
Nature Communications Mar 2024Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC...
Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.
Topics: Humans; Myeloid-Derived Suppressor Cells; Glutamine; Hematologic Neoplasms; Adenosine Triphosphate; Doxorubicin; Succinates
PubMed: 38555305
DOI: 10.1038/s41467-024-47096-9 -
Cell Metabolism Mar 2024The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional...
The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional role for itaconate in malaria.Plasmodium Chabaudi induces itaconate in dendritic cells (DCs), leading to programmed death-ligand 1 (PD-L1) induction. This suppresses CD8 T cells, important for host defense against malaria, thereby promoting parasitemia.
Topics: Humans; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Dietary Supplements; Malaria; Succinates
PubMed: 38447526
DOI: 10.1016/j.cmet.2024.02.005 -
Nature Communications May 2024Elevated intracellular sodium Na adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic...
Elevated intracellular sodium Na adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Na decreases Gibb's free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH, which are all reversed on lowering Na to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Na elevation. Elevated Na plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.
Topics: Animals; Rats; Mitochondria, Heart; Sodium; Male; Myocardium; Hypoxia-Inducible Factor 1, alpha Subunit; Heart Failure; Adenosine Triphosphate; Citric Acid Cycle; Rats, Sprague-Dawley; Organophosphorus Compounds; Sodium-Calcium Exchanger; Ubiquinone; Sodium-Potassium-Exchanging ATPase; Oxidation-Reduction; Succinic Acid
PubMed: 38769288
DOI: 10.1038/s41467-024-48474-z -
Cell Chemical Biology Apr 2024Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride...
Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the FF-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.
Topics: Humans; Mycobacterium tuberculosis; Succinate Dehydrogenase; Antitubercular Agents; Tuberculosis; Adenosine Triphosphate; Enzyme Inhibitors; Succinates
PubMed: 38151019
DOI: 10.1016/j.chembiol.2023.12.002 -
Cell Communication and Signaling : CCS Jan 2024Renal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing...
BACKGROUND
Renal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis.
METHODS
Male C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms.
RESULTS
Succinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3β/β-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells.
CONCLUSIONS
The causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3β/β-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.
Topics: Male; Mice; Animals; beta Catenin; Succinic Acid; Liposomes; Clodronic Acid; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Renal Insufficiency, Chronic; Fibrosis; Macrophages
PubMed: 38291510
DOI: 10.1186/s12964-024-01481-5 -
Journal of Advanced Research Oct 2023Currently, revealing how to prevent and control hyperuricemia has become an essential public health issue. Sulforaphane hasawiderangeofapplications in the management of...
INTRODUCTION
Currently, revealing how to prevent and control hyperuricemia has become an essential public health issue. Sulforaphane hasawiderangeofapplications in the management of hyperuricemia.
OBJECTIVE
The study objective was to verify the uric acid-lowering effects and the regulation of the gut-kidney axis mediated by sulforaphane and identify host-microbial co-metabolites in hyperuricemia.
METHODS
A hyperuricemia model was established by administering feedstuffs with 4% potassium oxonate and 20% yeast. Forty male Sprague-Dawley rats were randomly divided into the normal control, hyperuricemia, allopurinol, and sulforaphane groups. Animals were treated by oral gavage for six consecutive weeks, and then phenotypic parameters, metabolomic profiling, and metagenomicsequencing were performed.
RESULTS
Sulforaphane could lower uric acid by decreasing urate synthesis and increasing renal urate excretion in hyperuricemic rats (P<0.05). We identified succinic acid and oxoglutaric acid as critical host-gut microbiome co-metabolites. Moreover, sulforaphane improved the diversity of microbial ecosystems and functions, as well as metabolic control of the kidney. Notably, sulforaphane exerted its renoprotective effect through epigenetic modification of Nrf2 and interaction between gut microbiota and epigenetic modification in hyperuricemic rats.
CONCLUSION
We revealed that sulforaphane could ameliorate the progression of hyperuricemia by reprogramming the gut microbiome and metabolome. Our findings may provide a good means for efficiently preventing and treating hyperuricemia.
Topics: Rats; Male; Animals; Hyperuricemia; Uric Acid; Gastrointestinal Microbiome; Ecosystem; Rats, Sprague-Dawley; Metabolome
PubMed: 36371056
DOI: 10.1016/j.jare.2022.11.003 -
The Journal of Biological Chemistry Jan 2024The prevailing notion that reduced cofactors NADH and FADH transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates... (Review)
Review
The prevailing notion that reduced cofactors NADH and FADH transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates ambiguities regarding respiratory Complex II (CII). CII is the only membrane-bound enzyme in the tricarboxylic acid cycle and is part of the electron transfer system of the mitochondrial inner membrane feeding electrons into the coenzyme Q-junction. The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces the covalently bound prosthetic group FAD to FADH in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the electron transfer system depict FADH in the mitochondrial matrix as a substrate to be oxidized by CII. This leads to the false conclusion that FADH from the β-oxidation cycle in fatty acid oxidation feeds electrons into CII. In reality, dehydrogenases of fatty acid oxidation channel electrons to the Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational resources call for quality control, to secure scientific standards in current communications of bioenergetics, and ultimately support adequate clinical applications. This review aims to raise awareness of the inherent ambiguity crisis, complementing efforts to address the well-acknowledged issues of credibility and reproducibility.
Topics: Electron Transport; Electrons; Fatty Acids; Flavin-Adenine Dinucleotide; Oxidation-Reduction; Reproducibility of Results; Succinate Dehydrogenase; Citric Acid Cycle; Mitochondria; Ubiquinone; Succinic Acid; Electron Transport Complex II; Energy Metabolism
PubMed: 38118236
DOI: 10.1016/j.jbc.2023.105470 -
The American Journal of Emergency... Oct 2023
Topics: Humans; Succinylcholine; Eye; Face
PubMed: 37573237
DOI: 10.1016/j.ajem.2023.08.009 -
Journal of Cellular and Molecular... Apr 2024Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research...
Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1β. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.
Topics: Animals; Mice; Cisplatin; NF-E2-Related Factor 2; Reactive Oxygen Species; Antioxidants; Ferroptosis; Apoptosis; Hearing Loss; Anti-Inflammatory Agents; Succinates
PubMed: 38506087
DOI: 10.1111/jcmm.18207