Although anaerobic glycerol metabolism in Enterococcus faecalis requires exogenous fumarate for NADH oxidation, E. faecalis strain W11 can metabolize glycerol in the absence of oxygen without exogenous fumarate. In this study, metabolic end product analyses and reporter assays probing the expression of enzymes involved in pyruvate metabolism were performed to investigate this fumarate-independent anaerobic metabolism of glycerol in W11. Under aerobic conditions, the metabolic end products of W11 cultured with glycerol were similar to those of W11 cultured with glucose. However, when W11 was cultured anaerobically, most of the glucose was converted to L-lactate, but glycerol was converted to ethanol and formate. During anaerobic culture with glycerol, the expression of the L-lactate dehydrogenase and pyruvate dehydrogenase E1␣ genes in W11 was downregulated, whereas the expression of the pyruvate formate-lyase (Pfl) and aldehyde/alcohol dehydrogenase genes was upregulated. These changes in the expression levels caused the change in the composition of end products. A pflB gene disruptant (⌬pfl mutant) of W11 could barely utilize glycerol under anaerobic conditions, but the growth of the ⌬pfl mutant cultured with either glucose or dihydroxyacetone (DHA) under anaerobic conditions was the same as that of W11. Glucose metabolism and DHA generates one NADH molecule per pyruvate molecule, whereas glycerol metabolism in the dehydrogenation pathway generates two NADH molecules per pyruvate molecule. These findings demonstrate that NADH generated from anaerobic glycerol metabolism in the absence of fumarate is oxidized through the Pfl-ethanol fermentation pathway. Thus, Pfl is essential to avoid the accumulation of excess NADH during fumarate-independent anaerobic glycerol metabolism. E nterococci are the most common lactic acid bacteria in the human intestinal tract, and some strains are well-known opportunistic pathogens (1, 2). Physiological studies have shown that Enterococcus faecalis can use glycerol as a carbon source (3). Microorganisms utilize glycerol through a dehydrogenation pathway, a phosphorylation pathway, or both. The dehydrogenation pathway begins with the dehydrogenation of glycerol to produce dihydroxyacetone (DHA), which is catalyzed by glycerol dehydrogenase (GldA). The DHA produced is then phosphorylated by DHA kinase (4). In the phosphorylation pathway, glycerol is first phosphorylated to glycerol-3-phosphate (glycerol-3P) by a glycerol kinase and then oxidized to dihydroxyacetone phosphate by a glycerol-3P oxidase or a glycerol-3P dehydrogenase (4). In either pathway, the resulting dihydroxyacetone phosphate enters glycolysis. Lactic acid bacteria, such as several Lactobacillus species and Pediococcus pentosaceus, generally utilize glycerol through the phosphorylation pathway, rather than the dehydrogenation pathway (5, 6), although E. faecalis strains can utilize glycerol through either the dehydrogenation pathway or the phosphorylation pathway (7).In some E. faecalis strains, glycerol metabolis...
Some studies have suggested that radial access (RA) for percutaneous coronary intervention (PCI) reduces vascular complications and bleeding compared to femoral access (FA). The purpose of this study was to investigate the routine use of hemostatic devices and bleeding complications among RA, brachial access (BA), and FA. Between January 2015 and December 2015, 298 patients treated for PCI with RA were compared with 158 patients using BA and 206 patients using FA. The radial sheath was routinely removed with ADAPTY, the brachial sheath with BLEED SAFE, and the femoral sheath with Perclose ProGlide. In-hospital bleeding complications were investigated. Cardiogenic shock was most frequent in patients in the femoral group (RA 1.3%, BA 2.5%, FA 9.2%, p < 0.0001). The rate of major bleeding was highest in the femoral group (RA 1.0%, BA 2.5%, FA 5.3%, p = 0.01). Blood transfusion rates were highest in the femoral group (RA 0.7%, BA 1.3%, FA 4.4%, p = 0.01). Retroperitoneal bleeding was observed in 1.9% of patients in the femoral group. Patients in the brachial group had large hematomas (RA 0.7%, BA 4.4%, FA 1.5%, p = 0.01). Pseudoaneurysm formation needing intervention occurred most frequently in the brachial group (RA 0%, BA 1.3%, FA 0%, p = 0.04). In conclusion, compared to the brachial and femoral approaches, the radial approach appears to be the safest technique to avoid local vascular bleeding complications. The brachial approach has the highest risk of large hematoma and pseudoaneurysm formation among the three groups.
Warfarin, which consists of a racemic mixture of S-and Renantiomer, has been used as an anticoagulant agent. The anticoagulant activity of S-warfarin is 3-5 times greater than that of R-warfarin.1) This drug has a narrow therapeutic index and shows marked drug-drug interactions when coadministered with other agents that alter warfarin metabolism.2,3) The stereoselective metabolism of warfarin enantiomers in humans has been shown to be catalyzed by cytochrome P450 (CYP) such as CYP1A1/2, 2C9, and 3A4. 4,5) The 7-hydroxylation of S-warfarin is exclusively catalyzed by CYP2C9. RWarfarin is metabolized primarily by CYP1A2 to 6-and 8-hydroxywarfarin, and by CYP3A4 to 10-hydroxywarfarin. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), is also metabolized to 4Ј-hydroxydiclofenac by CYP2C9. 6,7)Ethanol is widely used as a pharmaceutical excipient for the solubilization of many hydrophobic drugs. Various drugs can pharmacokinetically or pharmacodynamically interact with alcohol. 8) Our previous study suggested that ethanol changes the binding of warfarin enantiomer to human serum albumin stereoselectively. 9) Acute intoxication by alcohol reduces the metabolism of warfarin by CYPs, causing increased anticoagulant effects, and leading to a risk of hemorrhage.10) Conversely, chronic alcohol ingestion might enhance metabolic enzyme activity, leading to a decrease in the anticoagulant effects of warfarin. Hamitouche et al. 11) showed that CYP2C9, as well as other CYPs such as CYP2E1, CYP1A2, and CYP3A4, is also able to metabolize ethanol, and indicated that these CYPs have a low affinity for ethanol for its metabolization. The apparent K m value determined for ethanol oxidation by various CYPs was around 10 mM. 11)Therefore, it is possible that ethanol affects the metabolism of other substrates by CYP2C9. Few studies on the effect of ethanol on warfarin metabolism by human CYP2C9 in vitro have been reported. The non-significant metabolic interaction of diclofenac (15 mM) with ethanol by CYP2C9 has been reported. 12) However, the effect of ethanol on the metabolism of diclofenac at lower concentrations by CYP2C9 has not been examined. In this paper, we have examined the effect of ethanol on the metabolism of S-warfarin and diclofenac by recombinant CYP2C9.1 microsomes (CYP2C9.1). MATERIALS AND METHODS Materials S-(Ϫ)-Warfarin, diclofenac sodium, ethanol, naproxen, NADPϩ , glucose-6-phosphate, MgCl 2 · 6H 2 O, and glucose-6-phosphate dehydrogenase were purchased from Wako Pure Chemical Ind. (Osaka, Japan). 4Ј-Hydroxydiclofenac was purchased from Sigma-Aldrich (MO, U.S.A.). 7-Hydroxywarfarin and human CYP2C9.1ϩP450 reductase microsomes derived from baculovirus expression systems were purchased from BD Gentest (MA, U.S.A.). All other chemicals and solvents were of analytical grade or higher.Inhibition Study According to the method of Iwakawa et al., 13) a metabolic inhibition study was performed. The time of incubation and concentration of microsomal protein in the study were determined to be in a linear range for ...
Rationale: The relationship between spontaneous coronary artery dissection (SCAD) and takotsubo syndrome (TTS) remains unclear. Coexistence of SCAD and TTS has been reported in the literature. However, the relationship between these two diseases has not yet been elucidated. Patient concerns: A 36-year-old breastfeeding woman was brought to our hospital 52 days after cesarean section because of discomfort in her left arm and convulsions. Diagnoses: She was diagnosed of acute myocardial infarction (AMI). The convulsions were attributed to lethal arrhythmia. Interventions: An immediate coronary angiography revealed that her left anterior descending artery (LAD) was Type 2a SCAD, but with no flow limitation. In addition, a 12-lead electrocardiogram (ECG) revealed improvement in ST-elevation. We chose the conservative treatment according to the patient's needs. Outcomes: Conservative treatment was unsuccessful. She developed another acute myocardial infarction requiring another percutaneous coronary intervention (PCI) during hospitalization. From the course of hospitalization, we suspected the coexistence of SCAD and TTS. Lessons: When we treat patients with SCAD, we should consider the possibility of coexistence of TTS and confirm left ventricular wall motion. Patients with SCAD may require invasive treatment, hence, should be monitored for a while. An urgent strategy for managing patients with SCAD who require PCI should be established.
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