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Phytomedicine : International Journal... Jan 2024Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome...
BACKGROUND
Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury.
PURPOSE
This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved.
METHODS/RESULTS
From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury.
CONCLUSION
These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Tubulin; Metabolic Reprogramming; Macrophages; Succinates; Cardiomyopathies; Sepsis; Succinic Acid; Lipopolysaccharides; Caffeic Acids
PubMed: 37951150
DOI: 10.1016/j.phymed.2023.155175 -
Frontiers in Immunology 2022Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by...
Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by succinate receptor 1 (Sucnr1) and then transferred to effector cells. It is worth exploring whether succinate is capable of facilitating the inflammatory response in atherosclerosis. In this study, we firstly found that arterial serum of Coronary Heart Disease (CHD) patients contained significantly higher succinate and interleukin (IL)-1β than Health control (HC) subjects, and succinate was positively correlated with IL-1β. As demonstrated by the study, succinate/hypoxia-inducible factor 1α (Hif)-1α/IL-1β signal axis existed and significantly facilitated the inflammatory program in human umbilical vein endothelial cells (HUVECs). Under the coculture, activated macrophages released succinate, which would be transferred to HUVECs Sucnr1 and then activate Hif-1α to produce a greater amount of IL-1β. Likewise, the aortic sinus's inflammatory phenotype was found to be more significant within Apoe mice that were injected with succinate. Furthermore, Sucnr1 inhibitor (NF-56-EJ40) could significantly interrupt succinate/IL-1β signal in HUVECs and macrophages. As revealed by this study, glycolytic metabolism following the release of succinate could be found in atherosclerotic pathology, and succinate would drive succinate/IL-1β signal dependent on Sucnr1 and then exacerbate inflammatory responses. Sucnr1 might be a novel target for cutting off the transduction of succinate signal to prevent the inflammation of atherosclerosis.
Topics: Animals; Atherosclerosis; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Mice; Signal Transduction; Succinic Acid
PubMed: 35273600
DOI: 10.3389/fimmu.2022.817572 -
European Journal of Pharmacology Feb 2023This study aimed to investigate the alterations of myocardial succinate and fumarate levels with or without succinate dehydrogenase (SDH) inhibitor dimethyl malonate...
Succinate level is increased and succinate dehydrogenase exerts forward and reverse catalytic activities in lipopolysaccharides-stimulated cardiac tissue: The protective role of dimethyl malonate.
This study aimed to investigate the alterations of myocardial succinate and fumarate levels with or without succinate dehydrogenase (SDH) inhibitor dimethyl malonate during 24 h of lipopolysaccharides (LPS) challenge, as well as the effects of dimethyl malonate on the impaired cardiac tissue. Myocardial succinate and fumarate levels were increased in the initial 9 h of LPS challenge. During this time, dimethyl malonate increased the succinate level, decreased the fumarate level, aggravated the cardiac dysfunction, reduced the oxidative stress, had little effect on interleukin-1β production, promoted interleukin-10 production and bothered the ATP production. Co-treatment with exogenous succinate significantly increased interleukin-1β production in this period. After 12 h of LPS challenge, myocardial the succinate level increased sharply, while the fumarate level gradually decreased. During 12-24 h of LPS challenge, dimethyl malonate effectively reduced the succinate level, increased the fumarate level, improved cardiac dysfunction, inhibited interleukin-1β production, and had little effect on oxidative stress, interleukin-10 production, and ATP production. LPS challenge also significantly increased the myocardial succinate receptor 1 expression and circulating succinate level. Inhibition of succinate receptor 1 significantly reduced the mRNA expression of interleukin-1β. In conclusion, the current study suggests that myocardial succinate accumulates during LPS challenge, and that SDH activity may be transformed (from forward to reversed) and involved in a line of stress response. Dimethyl malonate inhibits SDH and, depending on the time of treatment, reduces LPS-induced cardiac impairment. Furthermore, accumulated succinate exerts pro-inflammatory effects partly via succinate receptor 1 signaling.
Topics: Humans; Succinate Dehydrogenase; Lipopolysaccharides; Succinic Acid; Interleukin-1beta; Interleukin-10; Heart Diseases; Fumarates; Adenosine Triphosphate
PubMed: 36549501
DOI: 10.1016/j.ejphar.2022.175472 -
MBio Aug 2022Succinate is a major focal point in mycobacterial metabolism and respiration, serving as both an intermediate of the tricarboxylic acid (TCA) cycle and a direct electron...
Succinate is a major focal point in mycobacterial metabolism and respiration, serving as both an intermediate of the tricarboxylic acid (TCA) cycle and a direct electron donor for the respiratory chain. Mycobacterium tuberculosis encodes multiple enzymes predicted to be capable of catalyzing the oxidation of succinate to fumarate, including two different succinate dehydrogenases (Sdh1 and Sdh2) and a separate fumarate reductase (Frd) with possible bidirectional behavior. Previous attempts to investigate the essentiality of succinate oxidation in M. tuberculosis have relied on the use of single-gene deletion mutants, raising the possibility that the remaining enzymes could catalyze succinate oxidation in the absence of the other. To address this, we report on the use of mycobacterial CRISPR interference (CRISPRi) to construct single, double, and triple transcriptional knockdowns of , , and in M. tuberculosis. We show that the simultaneous knockdown of and is required to prevent succinate oxidation and overcome the functional redundancy within these enzymes. Succinate oxidation was demonstrated to be essential for the optimal growth of M. tuberculosis, with the combined knockdown of and significantly impairing the activity of the respiratory chain and preventing growth on a range of carbon sources. Moreover, impaired succinate oxidation was shown to influence the activity of cell wall-targeting antibiotics and bioenergetic inhibitors against M. tuberculosis. Together, these data provide fundamental insights into mycobacterial physiology, energy metabolism, and antimicrobial susceptibility. New drugs are urgently required to combat the tuberculosis epidemic that claims 1.5 million lives annually. Inhibitors of mycobacterial energy metabolism have shown significant promise clinically; however, further advancing this nascent target space requires a more fundamental understanding of the respiratory enzymes and pathways used by Mycobacterium tuberculosis. Succinate is a major focal point in mycobacterial metabolism and respiration; yet, the essentiality of succinate oxidation and the consequences of inhibiting this process are poorly defined. In this study, we demonstrate that impaired succinate oxidation prevents the optimal growth of M. tuberculosis on a range of carbon sources and significantly reduces the activity of the electron transport chain. Moreover, we show that impaired succinate oxidation both positively and negatively influences the activity of a variety of antituberculosis drugs. Combined, these findings provide fundamental insights into mycobacterial physiology and drug susceptibility that will be useful in the continued development of bioenergetic inhibitors.
Topics: Carbon; Humans; Mycobacterium tuberculosis; Succinate Dehydrogenase; Succinates; Succinic Acid; Tuberculosis
PubMed: 35856639
DOI: 10.1128/mbio.01672-22 -
Bioconjugate Chemistry Jul 2015Many synthetic strategies are available for preparing well-defined conjugates of peptides/proteins and polymers. Most reports on this topic involve coupling methoxy... (Review)
Review
Many synthetic strategies are available for preparing well-defined conjugates of peptides/proteins and polymers. Most reports on this topic involve coupling methoxy poly(ethylene glycol) to therapeutic proteins, a process referred to as PEGylation, to increase their circulation lifetime and reduce their immunogenicity. Unfortunately, the major dissuading dogma of PEGylation is that, in many cases, polymer modification leads to significant (or total) loss of activity/function. One approach that is gaining momentum to address this challenge is to release the native protein from the polymer with time in the body (releasable PEGylation). This contribution will present the state-of-the-art of this rapidly evolving field, with emphasis on the chemistry behind the release of the peptide/protein and the means for altering the rate of release in biological fluids. Linkers discussed include those based on the following: substituted maleic anhydride and succinates, disulfides, 1,6-benzyl-elimination, host-guest interactions, bicin, β-elimination, biodegradable polymers, E1cb elimination, β-alanine, photoimmolation, coordination chemistry, zymogen activation, proteolysis, and thioesters.
Topics: Animals; Benzyl Compounds; Glycine; Humans; Maleic Anhydrides; Models, Molecular; NADH, NADPH Oxidoreductases; Nitroreductases; Polyethylene Glycols; Polymers; Proteins; Succinic Acid; Sulfhydryl Compounds; beta-Alanine
PubMed: 25612877
DOI: 10.1021/bc500611k -
Bioresource Technology Jan 2022As a result of environmental concerns and the depletion of biomass assets, eco-friendly, renewable biomass-based chemical extraction has recently received significant... (Review)
Review
As a result of environmental concerns and the depletion of biomass assets, eco-friendly, renewable biomass-based chemical extraction has recently received significant attention. Bio-based chemicals can be prepared using different renewable feedstockbio-resources through microbial fermentation. Chemicals produced from renewable feedstockscan reduce ecological consequences from improper disposal and repurpose them into valuable products. Biodegradability, biocompatibility and non-toxicity, particularly in biomedical applications, have inspired researchers towards developing novel technologies that have social benefit. Among semi-synthetic and synthetic polymeric materials, utilization of natural bio-based monomeric materials can provide opportunities for sustainable development of novel non-toxic, biodegradable and biocompatible products. The purpose of this work is to give a summary of research into the generation of natural bio-based succinic acid (SA) monomer, the development of poly(butylene succinate) (PBS) as biodegradable polymer, PBS-based nanocomposites and their innovative uses.
Topics: Biomass; Fermentation; Polymers; Succinic Acid
PubMed: 34695587
DOI: 10.1016/j.biortech.2021.126156 -
International Journal of Molecular... Dec 2022Scientists have long established that fatty acids are the primary substrates for kidney mitochondria. However, to date we still do not know how long-chain and...
Scientists have long established that fatty acids are the primary substrates for kidney mitochondria. However, to date we still do not know how long-chain and middle-chain fatty acids are oxidized at the mitochondrial level. Our previous research has shown that mitochondria from the heart, brain, and kidney oxidize palmitoylcarnitine at a high rate only in the presence of succinate, glutamate, or pyruvate. In this paper, we report properties of the isolated kidney mitochondria and how malate and succinate affect the oxidation of C16 and C8 acylcarnitines. The isolated kidney mitochondria contain very few endogenous substrates and require malate to oxidize pyruvate, glutamate, and C16 or C8 acylcarnitines. We discovered that with 10 µM of C16 or C8 acylcarnitines, low concentrations of malate (0.2 mM) or succinate (0.5 mM) enhance the States 4 and 3 respiratory rates several times. The highest respiration rates were observed with C16 or C8 acylcarnitines and 5 mM succinate mixtures. Results show that kidney mitochondria, unlike the heart and brain mitochondria, lack the intrinsic inhibition of succinate dehydrogenase. Additionally, results show that the oxidation of fatty acid by the small respirasome's supercomplex generates a high level of CoQH2, and this makes SDH in the presence of succinate reverse the flow of electrons from CoQH2 to reduce fumarate to succinate. Finally, we report evidence that succinate dehydrogenase is a key mitochondrial enzyme that allows fast oxidation of fatty acids and turns the TCA cycle function from the catabolic to the anabolic and anaplerotic metabolic pathways.
Topics: Mice; Animals; Succinate Dehydrogenase; Malates; Mitochondria; Fatty Acids; Energy Metabolism; Oxidation-Reduction; Succinic Acid; Succinates; Pyruvic Acid; Glutamates; Kidney
PubMed: 36613826
DOI: 10.3390/ijms24010379 -
ACS Applied Materials & Interfaces Dec 2023We synthesized a series of [(l-Ala)--(l-Thr succinate)] (PATs), which are analogous to natural antifreezing glycoprotein with the structure of [l-Ala-l-Ala-l-Thr...
We synthesized a series of [(l-Ala)--(l-Thr succinate)] (PATs), which are analogous to natural antifreezing glycoprotein with the structure of [l-Ala-l-Ala-l-Thr disaccharide], by varying the composition and degree of succinylation while fixing their molecular weight () and Ala/Thr ratio at approximately 10-12 kDa and 2:1, respectively. We investigated their ice recrystallization inhibition (IRI), ice nucleation inhibition (INI), dynamic ice shaping (DIS), thermal hysteresis (TH), and protein cryopreservation activities. Both IRI and INI activities were greater for PATs with higher l-Ala content (PATs-3 and PATs-4) than those with lower l-Ala content (PATs-1 and PATs-2). DIS activity with faceted crystal growth was clearly observed in PATs-2 and PATs-4 with a high degree of succinylation. TH was small with <0.1 °C for all PATs and slightly greater for PATs with a high l-Ala content. Except for PATs-1, the protein (lactate dehydrogenase, LDH) stabilization activity was excellent for all PATs studied, maintaining LDH activity as high as that of fresh LDH even after 15 freeze-thaw cycles. To conclude, the cryo-active biomimetic PATs were synthesized by controlling the l-Ala content and degree of succinylation. Our results showed that PATs with an l-Ala content of 65-70% and degree of succinylation of 12-19% exhibited the cryo-activities of IRI, INI, and DIS, and particularly promising properties for the cryoprotection of LDH protein.
Topics: Ice; Succinic Acid; Threonine; Biomimetics; Cryoprotective Agents; Succinates
PubMed: 38060278
DOI: 10.1021/acsami.3c11260 -
Journal of Leukocyte Biology Jul 2019Cellular metabolism is a means of generating ATP to provide energy for key cellular functions. However, recent research shows that citric acid cycle intermediates target... (Review)
Review
Cellular metabolism is a means of generating ATP to provide energy for key cellular functions. However, recent research shows that citric acid cycle intermediates target vital cellular functions of the innate immune system. Succinate, itaconate, citrate, and fumarate have been shown to mediate or regulate important myeloid cell functions during infection and inflammation. This review covers the regulatory functions of citric acid cycle intermediates in myeloid cells and discusses potential translational applications, key mechanistic questions, and future research directions.
Topics: Animals; Citric Acid; Citric Acid Cycle; Fumarates; Humans; Leukocytes; Reactive Oxygen Species; Succinates; Succinic Acid
PubMed: 30791134
DOI: 10.1002/JLB.3MIR1118-415R -
Journal of Crohn's & Colitis Nov 2022Crohn's disease [CD] is associated with complex microbe-host interactions, involving changes in microbial communities, and gut barrier defects, leading to the...
BACKGROUND AND AIMS
Crohn's disease [CD] is associated with complex microbe-host interactions, involving changes in microbial communities, and gut barrier defects, leading to the translocation of microorganisms to surrounding adipose tissue [AT]. We evaluated the presence of beige AT depots in CD and questioned whether succinate and/or bacterial translocation promotes white-to-beige transition in adipocytes.
METHODS
Visceral [VAT] and subcutaneous [SAT] AT biopsies, serum and plasma were obtained from patients with active [n = 21] or inactive [n = 12] CD, and from healthy controls [n = 15]. Adipose-derived stem cells [ASCs] and AT macrophages [ATMs] were isolated from VAT biopsies.
RESULTS
Plasma succinate levels were significantly higher in patients with active CD than in controls and were intermediate in those with inactive disease. Plasma succinate correlated with the inflammatory marker high-sensitivity C-reactive protein. Expression of the succinate receptor SUCNR1 was higher in VAT, ASCs and ATMs from the active CD group than from the inactive or control groups. Succinate treatment of ASCs elevated the expression of several beige AT markers from controls and from patients with inactive disease, including uncoupling protein-1 [UCP1]. Notably, beige AT markers were prominent in ASCs from patients with active CD. Secretome profiling revealed that ASCs from patients with active disease secrete beige AT-related proteins, and co-culture assays showed that bacteria also trigger the white-to-beige switch of ASCs from patients with CD. Finally, AT depots from patients with CD exhibited a conversion from white to beige AT together with high UCP1 expression, which was corroborated by in situ thermal imaging analysis.
CONCLUSIONS
Succinate and bacteria trigger white-to-beige AT transition in CD. Understanding the role of beige AT in CD might aid in the development of therapeutic or diagnostic interventions.
Topics: Humans; Crohn Disease; Gastrointestinal Microbiome; Succinic Acid; Adipose Tissue; Adipose Tissue, White; Uncoupling Protein 1
PubMed: 35554517
DOI: 10.1093/ecco-jcc/jjac069