Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics.
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ABSTRACT:
SUBMITTER: Stokes J
PROVIDER: S-EPMC8291971 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background Preclinical studies suggest that volatile anesthetics decrease infarct volume and improve the outcome of ischemic stroke. This study aims to determine their effect during noncardiac surgery on postoperative ischemic stroke incidence. Methods and Results This was a retrospective cohort study of surgical patients undergoing general anesthesia at 2 tertiary care centers in Boston, MA, between October 2005 and September 2017. Exclusion criteria comprised brain death, age <18 years, cardiac surgery, and missing covariate data. The exposure was defined as median age-adjusted minimum alveolar concentration of all intraoperative measurements of desflurane, sevoflurane, and isoflurane. The primary outcome was postoperative ischemic stroke within 30 days. Among 314 932 patients, 1957 (0.6%) experienced the primary outcome. Higher doses of volatile anesthetics had a protective effect on postoperative ischemic stroke incidence (adjusted odds ratio per 1 minimum alveolar concentration increase 0.49, 95% CI, 0.40-0.59, P<0.001). In Cox proportional hazards regression, the effect was observed for 17 postoperative days (postoperative day 1: hazard ratio (HR), 0.56; 95% CI, 0.48-0.65; versus day 17: HR, 0.85; 95% CI, 0.74-0.99). Volatile anesthetics were also associated with lower stroke severity: Every 1-unit increase in minimum alveolar concentration was associated with a 0.006-unit decrease in the National Institutes of Health Stroke Scale (95% CI, -0.01 to -0.002, P=0.002). The effects were robust throughout various sensitivity analyses including adjustment for anesthesia providers as random effect. Conclusions Among patients undergoing noncardiac surgery, volatile anesthetics showed a dose-dependent protective effect on the incidence and severity of early postoperative ischemic stroke.
| S-EPMC8174248 | biostudies-literature
Project description:Macrophage-1 antigen (Mac-1, ?M?2) is a leukocyte adhesion molecule that plays a significant role in leukocyte crawling and phagocytosis, and is homologous to its sister protein leukocyte function-associated antigen-1 (LFA-1, ?L?2). The authors have previously demonstrated that volatile anesthetics isoflurane and sevoflurane bound to and inhibited LFA-1. Here, the hypothesis tested was that isoflurane and sevoflurane would inhibit Mac-1. A binding assay of Mac-1 to its ligand inter-cellular adhesion molecule-1 (ICAM-1) using V-bottom plates was established. The effect of isoflurane and sevoflurane on Mac-1 was examined using this ICAM-1 binding assay and by probing exposure of activation-sensitive epitopes. The docking program Glide was used to predict anesthetic binding site(s) on Mac-1. The functional role of this predicted binding site was then assessed by introducing point mutations in this region. Lastly, the effect of anesthetic on activating mutants was evaluated. The results indicated that isoflurane inhibited binding of Mac-1 to ICAM-1, but sevoflurane did not. Isoflurane also attenuated the exposure of the activation-sensitive epitopes. The docking simulation predicted the isoflurane binding site to be at the cavity underneath the ?7 helix of the ligand binding domain (the ?M I domain). Point mutants at this predicted binding site contained both activating and deactivating mutants, suggesting its functional significance. The binding of activating mutants ?M-Y267A ?2-WT and ?M-L312A ?2-WT to ICAM-1 was not affected by isoflurane, but binding of another activating mutant ?M-WT ?2-L132A was inhibited supporting the binding of isoflurane to this cavity. The conclusion reached from these findings was that isoflurane inhibited Mac-1 binding to ICAM-1 by binding to the cavity underneath the ?7 helix of the ?M I domain, but sevoflurane did not. Thus, because these common clinical volatile anesthetics demonstrated different effects on Mac-1, this implied their effects on the immune system might differ.
| S-EPMC4701639 | biostudies-literature
Project description:BackgroundPerioperative infections, particularly surgical site infections pose significant morbidity and mortality. Phagocytosis is a critical step for microbial eradication. We examined the effect of commonly used anesthetics on macrophage phagocytosis and its mechanism.MethodsThe effect of anesthetics (isoflurane, sevoflurane, propofol) on macrophage phagocytosis was tested using RAW264.7 mouse cells, mouse peritoneal macrophages, and THP-1 human cells. Either opsonized sheep erythrocytes or fluorescent labeled Escherichia coli were used as phagocytic objects. The activation of Rap1, a critical protein in phagocytosis was assessed using the active Rap1 pull-down and detection kit. To examine anesthetic binding site(s) on Rap1, photolabeling experiments were performed using azi-isoflurane and azi-sevoflurane. The alanine scanning mutagenesis of Rap1 was performed to assess the role of anesthetic binding site in Rap1 activation and phagocytosis.ResultsMacrophage phagocytosis was significantly attenuated by the exposure of isoflurane (50% reduction by 1% isoflurane) and sevoflurane (50% reduction by 1.5% sevoflurane), but not by propofol. Photolabeling experiments showed that sevoflurane directly bound to Rap1. Mutagenesis analysis demonstrated that the sevoflurane binding site affected Rap1 activation and macrophage phagocytosis.ConclusionsWe showed that isoflurane and sevoflurane attenuated macrophage phagocytosis, but propofol did not. Our study showed for the first time that sevoflurane served as a novel small GTPase Rap1 inhibitor. The finding will further enrich our understanding of yet-to-be determined mechanism of volatile anesthetics and their off-target effects. The sevoflurane binding site was located outside the known Rap1 functional sites, indicating the discovery of a new functional site on Rap1 and this site would serve as a pocket for the development of novel Rap1 inhibitors.
| S-EPMC6508649 | biostudies-literature
Project description:ObjectiveFibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT [sWAT] and visceral AT [vWAT]), and brown (interscapular brown AT [iBAT]) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity.MethodsWe used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (18F-fluorodeoxyglucose) and lipid (18F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways.ResultsConsistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT.ConclusionsThese data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis.
| S-EPMC6889485 | biostudies-literature
Project description:The aim of this randomized controlled trial was to investigate whether volatile anesthetics used for postoperative sedation have any beneficial effects on myocardial injury in cardiac surgery patients after on-pump valve replacement.Anesthesia was performed with propofol. After arrival in the intensive care unit (ICU), 117 patients were randomized to be sedated for at least 4 hours with either propofol or sevoflurane. Sevoflurane was administered by using the anesthetic-conserving device. Troponin T, creatine kinase, creatine kinase from heart muscle tissue, myoglobin, and oxygenation index were determined on arrival at the ICU, 4 hours after sedation, and in the morning of the first postoperative day (POD1). Primary end points were cardiac injury markers on POD1. As secondary end points oxygenation, postoperative pulmonary complications, and ICU and hospital stay were documented.Fifty-six patients were analyzed in the propofol arm, and 46 patients in the sevoflurane arm. Treatment groups were comparable with regard to patient demographics and intraoperative characteristics. Concentration of troponin T as the most sensitive marker for myocardial injury at POD1 was significantly lower in the sevoflurane group compared with the propofol group (unadjusted difference, -0.4; 95% CI, -0.7 to -0.1; P < 0.01; adjusted difference, -0.2; 95% CI, -0.4 to -0.02; P = 0.03, respectively).The data presented in this investigation indicate that late postconditioning with the volatile anesthetic sevoflurane might mediate cardiac protection, even with a late, brief, and low-dose application.ClinicalTrials.gov: NCT00924222.
| S-EPMC3682293 | biostudies-literature
Project description:Dendritic spines form the postsynaptic contact sites for most excitatory synapses in the brain. Spines occur in a wide range of different shapes that can vary depending on an animal's experience or behavioral status. Recently we showed that spines on living neurons can change shape within seconds in a process that depends on actin polymerization. We have now found that this morphological plasticity is blocked by inhalational anesthetics at concentrations at which they are clinically effective. These volatile compounds also block actin-based motility in fibroblasts, indicating that their action is independent of neuron-specific components and thus identifying the actin cytoskeleton as a general cellular target of anesthetic action. These observations imply that inhibition of actin dynamics at brain synapses occurs during general anesthesia and that inhalational anesthetics are capable of influencing the morphological plasticity of excitatory synapses in the brain.
| S-EPMC17906 | biostudies-literature
Project description:An inverse correlation between vegetable consumption and the incidence of cancer has long been described. This protective effect is stronger when cruciferous vegetables are specifically consumed. The beneficial properties of vegetables are attributed to their bioactive components like fiber, antioxidants vitamins, antioxidants, minerals, and phenolic compounds. Cruciferous vegetables contain all these molecules; however, what makes them different are their sulfurous components, called glucosinolates, responsible for their special smell and taste. Glucosinolates are inactive biologically in the organism but are hydrolyzed by the enzyme myrosinase released as a result of chewing, leading to the formation of active derivatives such as isothiocyanates and indoles. A considerable number of in vitro and in vivo studies have reported that isothiocyanates and indoles elicit chemopreventive potency through multiple mechanisms that include modulation of phases I and II detoxification pathway enzymes, regulation of cell cycle arrest, and control of cell growth, induction of apoptosis, antioxidant activity, anti-angiogenic effects, and epigenetic regulation. Nuclear erythroid 2-related factor 2 (Nrf2) and Nuclear factor-?B (NF-?B) are key and central regulators in all these processes with a main role in oxidative stress and inflammation control. It has been described that isothiocyanates and indoles regulate their activity directly and indirectly. Today, the metabolic syndrome (central obesity, insulin resistance, hyperlipidemia, and hypertension) is responsible for a majority of deaths worldwide. All components of metabolic syndrome are characterized by chronic inflammation with deregulation of the PI3K/AKT/mTOR, MAPK/EKR/JNK, Nrf2, and NF-?B signaling pathways. The effects of GLSs derivatives controlling these pathways have been widely described in relation to cancer. Changes in food consumption patterns observed in the last decades to higher consumption of ultra-processed foods, with elevation in simple sugar and saturated fat contents and lower consumption of vegetables and fruits have been directly correlated with metabolic syndrome prevalence. In this review, it is summarized the knowledge regarding the mechanisms by which cruciferous glucosinolate derivatives (isothiocyanates and indoles) directly and indirectly regulate these pathways. However, the review places a special focus on the knowledge of the effects of glucosinolates derivatives in metabolic syndrome, since this has not been reviewed before.
| S-EPMC7492599 | biostudies-literature
Project description:An enigma of modern medicine has persisted for over 150 years. The mechanisms by which volatile anesthetics (VAs) produce their effects (loss of consciousness, analgesia, amnesia, and immobility) remain an unsolved mystery. Many attractive putative molecular targets have failed to produce a significant effect when genetically tested in whole-animal models [1-3]. However, mitochondrial defects increase VA sensitivity in diverse organisms from nematodes to humans [4-6]. Ndufs4 knockout (KO) mice lack a subunit of mitochondrial complex I and are strikingly hypersensitive to VAs yet resistant to the intravenous anesthetic ketamine [7]. The change in VA sensitivity is the largest reported for a mammal. Limiting NDUFS4 loss to a subset of glutamatergic neurons recapitulates the VA hypersensitivity of Ndufs4(KO) mice, while loss in GABAergic or cholinergic neurons does not. Baseline electrophysiologic function of CA1 pyramidal neurons does not differ between Ndufs4(KO) and control mice. Isoflurane concentrations that anesthetize only Ndufs4(KO) mice (0.6%) decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) only in Ndufs4(KO) CA1 neurons, while concentrations effective in control mice (1.2%) decreased sEPSC frequencies in both control and Ndufs4(KO) CA1 pyramidal cells. Spontaneous inhibitory postsynaptic currents (sIPSCs) were not differentially affected between genotypes. The effects of isoflurane were similar on evoked field excitatory postsynaptic potentials (fEPSPs) and paired pulse facilitation (PPF) in KO and control hippocampal slices. We propose that CA1 presynaptic excitatory neurotransmission is hypersensitive to isoflurane in Ndufs4(KO) mice due to the inhibition of pre-existing reduced complex I function, reaching a critical reduction that can no longer meet metabolic demands.
| S-EPMC5007115 | biostudies-literature
Project description:To investigate the mechanism of action of volatile anesthetics, we are studying mutants of the yeast Saccharomyces cerevisiae that have altered sensitivity to isoflurane, a widely used clinical anesthetic. Several lines of evidence from these studies implicate a role for ubiquitin metabolism in cellular response to volatile anesthetics: (i) mutations in the ZZZ1 gene render cells resistant to isoflurane, and the ZZZ1 gene is identical to BUL1 (binds ubiquitin ligase), which appears to be involved in the ubiquitination pathway; (ii) ZZZ4, which we previously found is involved in anesthetic response, is identical to the DOA1/UFD3 gene, which was identified based on altered degradation of ubiquitinated proteins; (iii) analysis of zzz1Delta zzz4Delta double mutants suggests that these genes encode products involved in the same pathway for anesthetic response since the double mutant is no more resistant to anesthetic than either of the single mutant parents; (iv) ubiquitin ligase (MDP1/RSP5) mutants are altered in their response to isoflurane; and (v) mutants with decreased proteasome activity are resistant to isoflurane. The ZZZ1 and MDP1/RSP5 gene products appear to play important roles in determining effective anesthetic dose in yeast since increased levels of either gene increases isoflurane sensitivity whereas decreased activity decreases sensitivity. Like zzz4 strains, zzz1 mutants are resistant to all five volatile anesthetics tested, suggesting there are similarities in the mechanisms of action of a variety of volatile anesthetics in yeast and that ubiquitin metabolism affects response to all the agents examined.
| S-EPMC84909 | biostudies-literature
Project description:Acute respiratory distress syndrome (ARDS) remains to pose a high morbidity and mortality without any targeted therapies. Sedation, usually given intravenously, is an important part of clinical practice in intensive care unit (ICU), and the effect of sedatives on patients' outcomes has been studied intensively. Although volatile anesthetics are not routine sedatives in ICU, preclinical and clinical studies suggested their potential benefit in pulmonary pathophysiology. This review will summarize the current knowledge of ARDS and the role of volatile anesthetic sedation in this setting from both clinical and mechanistic standpoints. In addition, we will review the infrastructure to use volatile anesthetics.
| S-EPMC6433148 | biostudies-other