Zinc(ii) complex of (Z)-4-((4-Nitrophenyl)Amino)Pent-3-en-2-one, a potential antimicrobial agent: synthesis, characterization, antimicrobial screening, DFT calculation and docking study

Herein, the synthesis and characterizations of (Z)-4-((4-nitrophenyl)amino)pent-3-en-2-one (HL) ligand and its Zn(II) complex are reported. The compounds were characterized using elemental and thermogravimetric (TGA) analysis, electrochemical studies, FTIR, UV-Vis, 1H and 13C{H}NMR, HRMS, and PXRD techniques. Antimicrobial activity was screened on some Gram-positive and Gram-negative bacteria. DFT predictions were achieved using B3LYP, ωB97XD and M06-2X functional with 6-31+G(d,p) and LANL2DZ basis sets for nonmetallic and metallic atoms, respectively. The therapeutic potentials of the compounds were evaluated based on protein binding affinity, ADME/T and drug-likeness properties. The experimental results revealed the formation of a complex in which two ligands coordinated to the zinc ion in a tetrahedral arrangement through their carbonyl and amino groups. The antimicrobial study showed that the complex possesses higher antimicrobial activity than free ligand and the control (Streptomycin). B3LYP emerged as the best performing functional having yielded the best IR spectra and geometrical parameters relative to the experimental data. The density functional theory (DFT) predictions revealed that the complex is more active than the ligand, and its formation is thermodynamically feasible and exothermic. The docking results revealed that the binding affinities of the compounds are in agreement with the in-vitro data, and they possess drug-like properties

Effects of honey on postprandial hyperlipidemia and oxidative stress in wistar rats: role of HMG-CoA reductase inhibition and antioxidant effect

Summary: Postprandial hyperlipidemia is associated with oxidative stress and is an important risk factor for atherosclerosis and cardiovascular disease. The aims of this study were to investigate the antihyperlipidemic effect of honey administered 5 or 60 minutes before a high-fat diet (HFD), to explore the role of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in antihyperlipidemic effect of honey and to investigate the effect of honey on postprandial oxidative stress. Rats were fasted and randomized into 5 groups. Groups 1 and 2 were administered portable water. After 60 minutes, the groups were given portable water and HFD, respectively. Group 3 was administered honey. After 5 minutes, the rats were given HFD. Groups 4 and 5 were administered honey and simvastatin, respectively. After 60 minutes, the rats were given HFD. Four hours after portable water or HFD administration, the rats were sacrificed. Group 2 had significantly (p < 0.01) higher total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, catalase activity and significantly (p < 0.05) lower high density lipoprotein (HDL) cholesterol and HMG-CoA: mevalonate (p < 0.001) compared with Group 1. Group 3 had significantly (p < 0.01) higher TG and VLDL cholesterol and lower HMG-CoA: mevalonate compared with Group 1. Groups 4 and 5 exhibited significantly (p < 0.05 or p < 0.001) higher HDL cholesterol and HMG-CoA: mevalonate and lower LDL cholesterol compared with group 2. Honey pretreatment 60 minutes before HFD feeding exerts more significant antihyperlipidemic effect and attenuates more considerably postprandial hyperlipidemia-induced oxidative stress than honey administered 5 minutes before HFD in Wistar rats. This marked antihyperlipidemic effect of honey pretreatment is mediated in part via inhibition of HMG-CoA reductase.Keywords: Honey, Postprandial hyperlipidemia, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, Oxidative stressNiger. J. Physiol. Sci. 33(December 2018) 129-13

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s)

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s)

Outcomes of Patients Presenting with Mild Acute Respiratory Distress Syndrome: Insights from the LUNG SAFE Study

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Hospital mortality in acute respiratory distress syndrome is approximately 40%, but mortality and trajectory in "mild" acute respiratory distress syndrome (classified only since 2012) are unknown, and many cases are not detected WHAT THIS ARTICLE TELLS US THAT IS NEW: Approximately 80% of cases of mild acute respiratory distress syndrome persist or worsen in the first week; in all cases, the mortality is substantial (30%) and is higher (37%) in those in whom the acute respiratory distress syndrome progresses BACKGROUND:: Patients with initial mild acute respiratory distress syndrome are often underrecognized and mistakenly considered to have low disease severity and favorable outcomes. They represent a relatively poorly characterized population that was only classified as having acute respiratory distress syndrome in the most recent definition. Our primary objective was to describe the natural course and the factors associated with worsening and mortality in this population. METHODS: This study analyzed patients from the international prospective Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) who had initial mild acute respiratory distress syndrome in the first day of inclusion. This study defined three groups based on the evolution of severity in the first week: "worsening" if moderate or severe acute respiratory distress syndrome criteria were met, "persisting" if mild acute respiratory distress syndrome criteria were the most severe category, and "improving" if patients did not fulfill acute respiratory distress syndrome criteria any more from day 2. RESULTS: Among 580 patients with initial mild acute respiratory distress syndrome, 18% (103 of 580) continuously improved, 36% (210 of 580) had persisting mild acute respiratory distress syndrome, and 46% (267 of 580) worsened in the first week after acute respiratory distress syndrome onset. Global in-hospital mortality was 30% (172 of 576; specifically 10% [10 of 101], 30% [63 of 210], and 37% [99 of 265] for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively), and the median (interquartile range) duration of mechanical ventilation was 7 (4, 14) days (specifically 3 [2, 5], 7 [4, 14], and 11 [6, 18] days for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively). Admissions for trauma or pneumonia, higher nonpulmonary sequential organ failure assessment score, lower partial pressure of alveolar oxygen/fraction of inspired oxygen, and higher peak inspiratory pressure were independently associated with worsening. CONCLUSIONS: Most patients with initial mild acute respiratory distress syndrome continue to fulfill acute respiratory distress syndrome criteria in the first week, and nearly half worsen in severity. Their mortality is high, particularly in patients with worsening acute respiratory distress syndrome, emphasizing the need for close attention to this patient population

Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: One-Year Follow-up.

Declines in stroke admission, intravenous thrombolysis, and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the impact of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), intravenous thrombolysis (IVT), and mechanical thrombectomy over a one-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020). We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, intravenous thrombolysis treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. There were 148,895 stroke admissions in the one-year immediately before compared to 138,453 admissions during the one-year pandemic, representing a 7% decline (95% confidence interval [95% CI 7.1, 6.9]; p<0.0001). ICH volumes declined from 29,585 to 28,156 (4.8%, [5.1, 4.6]; p<0.0001) and IVT volume from 24,584 to 23,077 (6.1%, [6.4, 5.8]; p<0.0001). Larger declines were observed at high volume compared to low volume centers (all p<0.0001). There was no significant change in mechanical thrombectomy volumes (0.7%, [0.6,0.9]; p=0.49). Stroke was diagnosed in 1.3% [1.31,1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82,2.97], 5,656/195,539) of all stroke hospitalizations. There was a global decline and shift to lower volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared to the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year. This study is registered under NCT04934020