Fructooligosaccharides production by solid-state fermentation with Aspergillus niger PSH

Fructoligosacharides (FOS) belong to prebiotics group that are non- digestible oligosacharides but fermentable by the bacteria in the gut microbiota1 . FOS can be produced by inulin degradation, which results in products with long fructoligomer chains2 . Alternatively, FOS can be obtained by conversion of the sucrose using fructosyltransferase (FTase) or β- fructofuranosidase (FFase) enzymes from bacterial and fungal sources2 . The curent proces for industrial production of FOS uses FTase produced by Aspergilus niger, and reaches an yield value of aprox. 60%3 . The present study evaluated the FOS production by solid-state fermentation (SSF) with the objective of finding a technology able to produce FOS with higher yield

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Abstract P087: Hydralazine and Nitroglycerin Combination Improves Excitation-Contraction Coupling in Failing Cardiomyocytes

Although hydralazine and organic nitrates have proven clinical benefits for heart failure, the underlying mechanism of action of this combination remains obscure. Spontaneously Hypertensive Heart Failure (SHHF) rats are a representative heart failure model which shares common phenotypic features with human failing hearts. We have recently shown that SHHF cardiomyocytes exhibit depressed contractility and calcium transient amplitude in response to increasing rate and increased sarcoplasmic reticulum (SR) calcium leak, typical characteristics observed in heart failure. The purpose of this study was to test the hypothesis that hydralazine, alone or in combination with nitroglycerin, restores calcium cycling and contractile performance in cardiomyocytes from SHHF rats. We measured sarcomere length (SL) shortening and calcium transient amplitude (Δ[Ca 2+ ] i ) in isolated cardiac myocytes from male SHHF rats (22–24 months old, n=4) and their normotensive controls Wistar-Kyoto rats (18–22 months old, n=4) during pacing (0.5–4 Hz). Both SL shortening and Δ[Ca 2+ ] i responses to increasing pacing in SHHF cardiomyocytes were augmented by 10 μM hydralazine. The same concentration of nitroglycerin alone did not significantly affect these parameters. In response to the combination of these two drugs, there was a strong trend toward improved contractility and normal Δ[Ca 2+ ] i . We also assessed SR Ca 2+ leak by a brief incubation with tetracaine following by a caffeine challenge, a regimen designed to test SR Ca 2+ load. At matched SR Ca 2+ content, Ca 2+ leak was not significantly changed by nitroglycerin or hydralazine alone. However, in combination they restored the leak in SHHF myocytes to the normal levels seen in WKY myocytes. Hydralazine improves cardiac excitation-contraction coupling that is impaired in this model, whereas nitroglycerin does not exert a significant effect on this response. However, when administered together, nitroglycerin appears to modulate the enhancing effect induced by hydralazine and helps to restore normal SR calcium leakage. These data offer new insights into the mechanisms underlying the actions of hydralazine and organic nitrates on heart failure

S-Glutathionylation: A Redox-Sensitive Switch Participating in Nitroso-Redox Balance

S-Glutathionylation Uncouples eNOS and Regulates Its Cellular and Vascular Functio

Abstract 15371: Mice Lacking S-Nitrosoglutathione Reductase (GSNOR -/- ), a Mouse Model of Preeclampsia, Exhibited Nitroso-Redox Imbalance and Deterioration of Cardiovascular Structure and Function in Postpartum Mothers

Abstract only Introduction: Preeclampsia (PE), a leading cause of maternal mortality, is linked to persistent pathological changes in the heart, predisposing the mother to increased risk of chronic cardiovascular (CV) disease later in life. PE is characterized by increased S-nitrosylated (SNO) proteins and nitroso-redox imbalance. We recently showed that mice lacking S-nitrosoglutathione reductase (GSNOR -/- mice), a denitrosylase that regulates protein S-nitrosylation, exhibit the clinical features of PE including maternal hypertension, blunted increase in cardiac output, abnormal remodeling of left ventricular (LV) cardiac structure, dysregulation in nitrosylation and nitroso-redox imbalance. Hypothesis: The nitroso-redox imbalance seen during pregnancy in GSNOR -/- mice persists in postpartum (PP), leading to increased maternal susceptibility to CV injury. Methods: Pregnant control (WT [C57Bl/6J]) and GSNOR -/- mice (N=5) were examined at baseline, late-stage pregnancy (17.5 dpc) and 6 weeks PP. LV structure, cardiac output and stroke volume were determined using echocardiography (Vevo 2100). Cardiomyocytes (CM) were isolated at 6 weeks PP and ROS and peroxynitrite levels determined using fluorescent dyes. Results: In WT mice, all normal maternal CV adaptions to pregnancy, reverted to pre-pregnant levels 6 weeks PP. In contrast, GSNOR -/- mice exhibited increased cardiac output (+21% vs. -19% in WT), stroke volume (+21% vs. -41% in WT), and LV chamber dimension (+13% vs. -4% in WT) at 6 weeks PP, indicating high cardiac output LV cardiomyopathy. CM isolated from GSNOR -/- hearts showed ~5-fold more ROS generation (9.9x10 -4 ±9x10 -5 vs. 2.1x10 -4 ±1.5 x10 -4 ΔF/F max .min -1 ) and elevated peroxynitrite levels (0.318±0.011 vs. 0.243±0.012 ΔF/F 0 ) compared to WT at 6 weeks PP, suggesting the presence of nitroso-redox imbalance. All changes P<0.05. Conclusion: Postpartum GSNOR -/- (preeclamptic) mothers exhibited cardiac dysfunction which was accompanied by the presence of of nitroso-redox imbalance. These changes may predispose the mother to higher risk for future CV injury

Abstract P3100: Mice Lacking S-nitrosoglutathione Reductase (gsnor -/- ), A Mouse Model Of Preeclampsia, Exhibit Increases In Oxidative And Nitrosative Stress And Deterioration Of Cardiovascular Structure And Function In The Mother Postpartum

Abstract only Introduction: Preeclampsia (PE), a leading cause of maternal mortality, is linked to persistent pathological changes in the heart, predisposing the mother to increased risk of chronic cardiovascular (CV) disease later in life. PE is characterized by increased S-nitrosylated (SNO) proteins and nitrosative stress. We recently showed that mice lacking S-nitrosoglutathione reductase (GSNOR -/ - mice), a denitrosylase that regulates protein S-nitrosylation, exhibit the clinical features of PE including maternal hypertension, blunted increase in cardiac output, abnormal remodeling of left ventricular (LV) cardiac structure, dysregulation in nitrosylation and increased nitrosative stress. We hypothesize that the aberrant nitrosylation and nitrosative stress seen during pregnancy persist postpartum (PP), leading to increased maternal susceptibility to CV injury. Methods: Pregnant control (WT [C57Bl/6J]) and GSNOR -/- mice (N=5) were examined at baseline, late-stage pregnancy (17.5 dpc) and 6 weeks PP. LV structure, cardiac output and stroke volume were determined using echocardiography (Vevo 2100). Cardiomyocytes (CM) were isolated at 6 weeks PP and ROS and peroxynitrite levels determined using fluorescent dyes. Results: In WT mice, all normal maternal CV adaptions to pregnancy, reverted to pre-pregnant levels 6 weeks PP. In contrast, GSNOR -/- mice exhibited increased cardiac output (+21% vs. -19% in WT), stroke volume (+21% vs. -41% in WT), and LV chamber dimension (+13% vs. -4% in WT) at 6 weeks PP, indicating high cardiac output LV cardiomyopathy. CM isolated from GSNOR -/- hearts showed ~5-fold more ROS generation (9.9x10 -4 ±9x10 -5 vs. 2.1x10 -4 ±1.5 x10 -4 ΔF/F max .min -1 ) and elevated peroxynitrite levels (0.318±0.011 vs. 0.243±0.012 ΔF/F 0 ) compared to WT at 6 weeks PP, suggesting the presence of oxidative and nitrosative stress. All changes P<0.05. Conclusion: Postpartum GSNOR -/- (preeclamptic) mothers exhibited cardiac dysfunction characterized by high cardiac output LV cardiomyopathy, which was accompanied by elevated levels of oxidative and nitrosative stress. These changes may predispose the mother to higher risk for future CV injury

Abstract P2009: Mice Lacking S-nitrosoglutathione Reductase (gsnor -/- ), A Mouse Model Of Preeclampsia, Exhibit Abnormal Calcium Regulation And Cardiac Hypertrophy During Pregnancy

Abstract only Introduction: We recently showed that mice lacking S-nitrosoglutathione reductase (GSNOR -/- mice), a denitrosylase that regulates protein S-nitrosylation, exhibit the clinical features of preeclampsia (PE) a leading cause of maternal mortality. PE predisposes the mother to increased risk of cardiovascular (CV) injury later in life and is linked to cardiac hypertrophy and impaired relaxation. Cardiac hypertrophy and relaxation are regulated by calcium cycling. We hypothesized that GSNOR deficiency in pregnant mice alters calcium cycling, leading to hypertrophy and impaired cardiac relaxation. Methods: Pregnant control (WT [C57B6]) and GSNOR -/- mice were examined at non-pregnant (NP) and late pregnancy (17.5 dpc). Cardiomyocytes (CMs) (N=3-4 mice/group; n=8-24 CMs/heart) were isolated and assessed for intracellular calcium and sarcomere shortening using IonOptix system. Dynamic parameters associated with calcium decay and sarcomere relaxation were recorded (time to peak (ttp), time to 50% of baseline (tt50%); d SL/ d t min , time to d [Ca]/ d t min , etc.). Experiments were conducted at 37°C. Results: At late pregnancy, systolic calcium levels were significantly elevated in CMs isolated from GSNOR -/- as compared to WT mothers. Despite the increased cytosolic calcium, CMs from pregnant GSNOR -/- mice exhibited no change in contractility. The improved calcium decay rate observed in CMs from pregnant versus NP WT mice, was absent in GSNOR -/- mothers. Similarly, sarcomere relaxation parameters and sarcomere resting length, which were also improved by pregnancy in WT CMs, were impaired in CMs from pregnant versus NP GSNOR -/- mice. In addition, hearts were significantly enlarged in GSNOR -/- mothers as compared to WT, even when normalized to tibia length. Conclusion: The elevated systolic calcium levels, impaired cardiac relaxation, and cardiac hypertrophy seen in pregnant GSNOR -/- mice may predisposes them to higher risk for CV injury during pregnancy and later in life