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The American Journal of Emergency... Sep 2023Succinylcholine and rocuronium are the most commonly utilized neuromuscular blocker agents (NMBAs) for rapid sequence intubation (RSI) in the emergency department (ED)....
BACKGROUND
Succinylcholine and rocuronium are the most commonly utilized neuromuscular blocker agents (NMBAs) for rapid sequence intubation (RSI) in the emergency department (ED). The duration of action of rocuronium is significantly longer (∼30 min) compared to succinylcholine (∼10 min) and previous studies have shown that patients receiving rocuronium are more likely to have longer time to sedation initiation following RSI. Furthermore, patients receiving rocuronium may be more likely to experience awareness with paralysis than those receiving succinylcholine. The primary goal for this study was to evaluate the association between NMBA use during RSI and post-intubation sedation and analgesia practices in the ED.
METHODS
This was a retrospective, multicenter cohort study including patients 18 years and older that received succinylcholine or rocuronium during RSI in the ED between September 1, 2020 and August 31, 2021. Patients were excluded if they were intubated prior to ED arrival, experienced an out-of-hospital or in ED cardiac arrest, or received sugammadex within 60 min of rocuronium administration. Patients were screened in reverse chronological order until the targeted sample size was achieved and all data was abstracted from the electronic health record. The primary outcome was the time to initiation of analgesia or sedation. Secondary outcomes included dose of sedatives or analgesia administered at 30- and 60 min, and medications administered for post-intubation sedation or analgesia.
FINDINGS
A total of 200 ED patients were included of which 100 received succinylcholine and 100 received rocuronium. There was no difference in the median time to initiation of analgesia or sedation between the succinylcholine and rocuronium groups (10 vs 8.5 min, p = 0.82) or in Kaplan-Meier cumulative probabilities (p = 0.17). At 60 min post-RSI, those receiving succinylcholine received significantly higher median doses of propofol (20 μg/kg/min vs. 10 μg/kg/min; p = 0.02) and fentanyl [100 μg vs. 84.2 μg; p = 0.02].
CONCLUSION
While no differences were observed in the time to initiation of post-intubation sedation or analgesia in ED patients receiving succinylcholine compared to rocuronium, differences in the intensity of post-intubation regimens was observed. Further investigation is needed to evaluate the adequacy of sedation following RSI in the ED.
Topics: Humans; Succinylcholine; Rocuronium; Neuromuscular Depolarizing Agents; Retrospective Studies; Cohort Studies; Androstanols; Neuromuscular Nondepolarizing Agents; Intubation, Intratracheal; Analgesia; Emergency Service, Hospital
PubMed: 37356339
DOI: 10.1016/j.ajem.2023.06.017 -
Biomolecules Jul 2023Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the...
Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERβ/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC.
Topics: Female; Humans; Succinic Acid; Heme; Estrogens; Endometrial Neoplasms; Receptors, Estrogen; Aminolevulinic Acid
PubMed: 37509133
DOI: 10.3390/biom13071097 -
Metabolic Engineering Sep 2023Cyanobacteria are attracting increasing attention as a photosynthetic chassis organism for diverse biochemical production, however, photoautotrophic production remains...
Cyanobacteria are attracting increasing attention as a photosynthetic chassis organism for diverse biochemical production, however, photoautotrophic production remains inefficient. Photomixotrophy, a method where sugar is used to supplement baseline autotrophic metabolism in photosynthetic hosts, is becoming increasingly popular for enhancing sustainable bioproduction with multiple input energy streams. In this study, the commercially relevant diacid, succinate, was produced photomixotrophically. Succinate is an important industrial chemical that can be used for the production of a wide array of products, from pharmaceuticals to biopolymers. In this system, the substrate, glucose, is transported by a proton symporter and the product, succinate, is hypothesized to be transported by another proton symporter, but in the opposite direction. Thus, low pH is required for the import of glucose and high pH is required for the export of succinate. Succinate production was initiated in a pH 7 medium containing bicarbonate. Glucose was efficiently imported at around neutral pH. Utilization of bicarbonate by CO fixation raised the pH of the medium. As succinate, a diacid, was produced, the pH of the medium dropped. By repeating this cycle with additional pH adjustment, those contradictory requirements for transport were overcome. pH affects a variety of biological factors and by cycling from high pH to neutral pH processes such as CO fixation rates and CO solubility can vary. In this study the engineered strains produced succinate during fluctuating pH conditions, achieving a titer of 5.0 g L after 10 days under shake flask conditions. These results demonstrate the potential for photomixotrophic production as a viable option for the large-scale production of succinate.
Topics: Succinic Acid; Carbon Dioxide; Protons; Bicarbonates; Metabolic Engineering; Succinates; Glucose; Hydrogen-Ion Concentration; Symporters
PubMed: 37499856
DOI: 10.1016/j.ymben.2023.07.008 -
JCI Insight Sep 2023Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly...
Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α-mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.
Topics: Humans; Animals; Mice; Succinic Acid; Lung Injury; Succinates; Respiratory Distress Syndrome; Epithelial Cells; Hypoxia; Inflammation; Lung
PubMed: 37737265
DOI: 10.1172/jci.insight.166860 -
Water Research Nov 2023Previous research suggested that two major groups of polyphosphate-accumulating organisms (PAOs), i.e., Ca. Accumulibacter and Tetrasphaera, play cooperative roles in...
Previous research suggested that two major groups of polyphosphate-accumulating organisms (PAOs), i.e., Ca. Accumulibacter and Tetrasphaera, play cooperative roles in enhanced biological phosphorus removal (EBPR). The fermentation of complex organic compounds by Tetrasphaera provides carbon sources for Ca. Accumulibacter. However, the viability of the fermentation products (e.g., lactate, succinate, alanine) as carbon sources for Ca. Accumulibacter and their potential effects on the metabolism of Ca. Accumulibacter were largely unknown. This work for the first time investigated the capability and metabolic details of Ca. Accumulibacter cognatus clade IIC strain SCUT-2 (enriched in a lab-scale reactor with a relative abundance of 42.8%) in using these fermentation products for EBPR. The enrichment culture was able to assimilate lactate and succinate with the anaerobic P release to carbon uptake ratios of 0.28 and 0.36 P mol/C mol, respectively. In the co-presence of acetate, the uptake of lactate was strongly inhibited, since two substrates shared the same transporter as suggested by the carbon uptake bioenergetic analysis. When acetate and succinate were fed at the same time, Ca. Accumulibacter assimilated two carbon sources simultaneously. Proton motive force (PMF) was the key driving force (up to 90%) for the uptake of lactate and succinate by Ca. Accumulibacter. Apart from the efflux of proton in symport with phosphate via the inorganic phosphate transport system, translocation of proton via the activity of fumarate reductase contributed to the generation of PMF, which agreed with the fact that PHV was a major component of PHA when lactate and succinate were used as carbon sources, involving the succinate-propionate pathway. Metabolic models for the usage of lactate and succinate by Ca. Accumulibacter for EBPR were built based on the combined physiological, biochemical, metagenomic, and metatranscriptomic analyses. Alanine was shown as an invalid carbon source for Ca. Accumulibacter. Instead, it significantly and adversely affected Ca. Accumulibacter-mediated EBPR. Phosphate release was observed without alanine uptake. Significant inhibitions on the aerobic phosphate uptake was also evident. Overall, this study suggested that there might not be a simply synergic relationship between Ca. Accumulibacter and Tetrasphaera. Their interactions would largely be determined by the kind of fermentation products released by the latter.
Topics: Phosphorus; Fermentation; Protons; Bioreactors; Betaproteobacteria; Polyphosphates; Lactates; Alanine; Succinates; Carbon; Acetates
PubMed: 37839225
DOI: 10.1016/j.watres.2023.120713 -
Frontiers in Immunology 2024Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy... (Review)
Review
Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Signal Transduction; Inflammation; Succinates
PubMed: 38487538
DOI: 10.3389/fimmu.2024.1352165 -
The Journal of Physiology Aug 2023An understanding of the metabolic determinants of postexercise appetite regulation would facilitate development of adjunctive therapeutics to suppress compensatory... (Randomized Controlled Trial)
Randomized Controlled Trial
An understanding of the metabolic determinants of postexercise appetite regulation would facilitate development of adjunctive therapeutics to suppress compensatory eating behaviours and improve the efficacy of exercise as a weight-loss treatment. Metabolic responses to acute exercise are, however, dependent on pre-exercise nutritional practices, including carbohydrate intake. We therefore aimed to determine the interactive effects of dietary carbohydrate and exercise on plasma hormonal and metabolite responses and explore mediators of exercise-induced changes in appetite regulation across nutritional states. In this randomized crossover study, participants completed four 120 min visits: (i) control (water) followed by rest; (ii) control followed by exercise (30 min at ∼75% of maximal oxygen uptake); (iii) carbohydrate (75 g maltodextrin) followed by rest; and (iv) carbohydrate followed by exercise. An ad libitum meal was provided at the end of each 120 min visit, with blood sample collection and appetite assessment performed at predefined intervals. We found that dietary carbohydrate and exercise exerted independent effects on the hormones glucagon-like peptide 1 (carbohydrate, 16.8 pmol/L; exercise, 7.4 pmol/L), ghrelin (carbohydrate, -48.8 pmol/L; exercise: -22.7 pmol/L) and glucagon (carbohydrate, 9.8 ng/L; exercise, 8.2 ng/L) that were linked to the generation of distinct plasma H nuclear magnetic resonance metabolic phenotypes. These metabolic responses were associated with changes in appetite and energy intake, and plasma acetate and succinate were subsequently identified as potential novel mediators of exercise-induced appetite and energy intake responses. In summary, dietary carbohydrate and exercise independently influence gastrointestinal hormones associated with appetite regulation. Future work is warranted to probe the mechanistic importance of plasma acetate and succinate in postexercise appetite regulation. KEY POINTS: Carbohydrate and exercise independently influence key appetite-regulating hormones. Temporal changes in postexercise appetite are linked to acetate, lactate and peptide YY. Postexercise energy intake is associated with glucagon-like peptide 1 and succinate levels.
Topics: Male; Appetite; Appetite Regulation; Cross-Over Studies; Dietary Carbohydrates; Energy Intake; Exercise; Ghrelin; Glucagon-Like Peptide 1; Insulin; Peptide YY; Succinates; Humans
PubMed: 37269207
DOI: 10.1113/JP284294 -
Skeletal Muscle Sep 2023Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy without an effective treatment, caused by mutations in the DMD gene, leading to the absence of...
BACKGROUND
Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy without an effective treatment, caused by mutations in the DMD gene, leading to the absence of dystrophin. DMD results in muscle weakness, loss of ambulation, and death at an early age. Metabolomics studies in mdx mice, the most used model for DMD, reveal changes in metabolites associated with muscle degeneration and aging. In DMD, the tongue muscles exhibit unique behavior, initially showing partial protection against inflammation but later experiencing fibrosis and loss of muscle fibers. Certain metabolites and proteins, like TNF-α and TGF-β, are potential biomarkers for dystrophic muscle characterization.
METHODS
To investigate disease progression and aging, we utilized young (1 month old) and old (21-25 months old) mdx and wild-type tongue muscles. Metabolite changes were analyzed using 1H nuclear magnetic resonance, while TNF-α and TGF-β were assessed using Western blotting to examine inflammation and fibrosis. Morphometric analysis was conducted to assess the extent of myofiber damage between groups.
RESULTS
The histological analysis of the mid-belly tongue showed no differences between groups. No differences were found between the concentrations of metabolites from wild-type or mdx whole tongues of the same age. The metabolites alanine, methionine, and 3-methylhistidine were higher, and taurine and glycerol were lower in young tongues in both wild type and mdx (p < 0.001). The metabolites glycine (p < 0.001) and glutamic acid (p = 0.0018) were different only in the mdx groups, being higher in young mdx mice. Acetic acid, phosphocreatine, isoleucine, succinic acid, creatine, and the proteins TNF-α and TGF-β had no difference in the analysis between groups (p > 0.05).
CONCLUSIONS
Surprisingly, histological, metabolite, and protein analysis reveal that the tongue of old mdx remains partially spared from the severe myonecrosis observed in other muscles. The metabolites alanine, methionine, 3-methylhistidine, taurine, and glycerol may be effective for specific assessments, although their use for disease progression monitoring should be cautious due to age-related changes in the tongue muscle. Acetic acid, phosphocreatine, isoleucine, succinate, creatine, TNF-α, and TGF-β do not vary with aging and remain constant in spared muscles, suggesting their potential as specific biomarkers for DMD progression independent of aging.
Topics: Mice; Animals; Muscular Dystrophy, Duchenne; Tumor Necrosis Factor-alpha; Creatine; Mice, Inbred mdx; Phosphocreatine; Glycerol; Isoleucine; Muscle Fibers, Skeletal; Methionine; Racemethionine; Acetic Acid; Alanine; Disease Progression
PubMed: 37705069
DOI: 10.1186/s13395-023-00325-z -
The Journal of Hand Surgery, European... Dec 2023Madelung deformity remains a fascinating yet unresolved challenge. There is an increasing awareness for early diagnosis by healthcare providers with improvement in... (Review)
Review
Madelung deformity remains a fascinating yet unresolved challenge. There is an increasing awareness for early diagnosis by healthcare providers with improvement in diagnostic modalities, however, the exact mechanisms for the development of the deformity have still to be clarified. While some corrective procedures have been described to effectively address an established deformity, the existing literature lacks clear and evidence-based treatment guidelines on how to proceed in daily practice. This review article aims to summarize the current best evidence on this topic, including particular areas of controversy and areas with need for future research.
Topics: Humans; Growth Disorders; Osteochondrodysplasias; Osteotomy; Dioctyl Sulfosuccinic Acid; Radius
PubMed: 37572317
DOI: 10.1177/17531934231191208 -
Journal of Virology Oct 2023Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral...
Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.
Topics: Humans; Active Transport, Cell Nucleus; Antiviral Agents; Influenza, Human; Nuclear Proteins; Virus Replication; Succinates; Exportin 1 Protein
PubMed: 37823646
DOI: 10.1128/jvi.01325-23