Inhibition of histamine receptor 3 alleviates sevoflurane-induced hypomyelination and neurobehavioral deficits.

Background: Inhalational anesthetic sevoflurane can cause myelination damage in developing brain. This study examines the effects of histamine receptor 3 (H3) antagonist thioperamide on sevoflurane-induced hypomyelination and neurobehavioral deficits.

Methods: Neonatal C57BL/6 mice were exposed to sevoflurane for consecutive three days and treated with H3 receptor antagonist thioperamide.

The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) expression and activity, which shifts intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA).

Sevoflurane enhances autophagy via Rac1 to attenuate lung ischaemia‒reperfusion injury.

Sevoflurane can attenuate lung ischaemia‒reperfusion injury (LIRI). However, the protective mechanism is unclear. In this study, we developed a LIRI model in vivo that animals (SD, n = 15) were subjected to the administration of 2.

Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling.

Purpose: α2-adrenoceptor agonist dexmedetomidine (DEX) has been reported to promote tumorigenesis. Stem-cell protein Piwil2 is associated with cancer progression. Whether Piwil2 plays a role in tumor-promoting effects of DEX is unknown.

Parecoxib sodium attenuates acute lung injury following burns by regulating M1/M2 macrophage polarization through the TLR4/NF-κB pathway.

High temperature-induced burn injury often leads to an excessive inflammatory cascade resulting in multiple organ dysfunction syndrome, such as acute lung injury (ALI), in addition to skin tissue damage. As a specific COX2 inhibitor, parecoxib sodium suppresses the inflammatory response during burn injury. The effect of parecoxib sodium on ALI induced by burn injury and the associated molecular mechanism still need to be investigated.

Propofol modulates neural dynamics of thalamo-cortical system associated with anesthetic levels in rats.

Unlabelled: The thalamocortical system plays an important role in consciousness. How anesthesia modulates the thalamocortical interactions is not completely known.  We simultaneously recorded local field potentials(LFPs) in thalamic reticular nucleus(TRN) and ventroposteromedial thalamic nucleus(VPM), and electrocorticographic(ECoG) activities in frontal and occipital cortices in freely moving rats ( = 11).

Methylene blue targets PHD3 expression in murine microglia to mitigate lipopolysaccharide-induced neuroinflammation and neurocognitive impairments.

Methylene blue (MB) has anti-inflammatory properties, however, its underlying molecular mechanism remains elusive. This study aimed to investigate whether and how MB could attenuate lipopolysaccharide (LPS)-induced microglial activation, neuroinflammation, and neurobehavioral deficits. We measured the expression of pro-inflammatory factors and performed three neurobehavioral tests to assess the effect of MB on neuroinflammation and neurocognitive dysfunction in LPS-treated adult C57BL/6N male mice or LPS-stimulated microglia cells.

Efficient oral delivery of water-soluble CT contrast agent using an W/O/W alginate hydrogel matrix.

Hypothesis: Iohexol (IOH) is a commonly used second-generation nonionic iodinated contrast agent. However, low gastrointestinal mucosal adherence and high downstream speed limit its application in intestinal Computed tomography (CT) imaging. We hypothesize that oral IOH delivery carriers composed of environmentally responsive materials enable the intestinal targeted delivery and prolong the intestinal residence time of IOH, enhancing the intestinal disease detection efficiency.

Inhibition or Deletion of Hydroxylases-Prolyl-4-Hydroxyases 3 Alleviates Lipopolysaccharide-induced Neuroinflammation and Neurobehavioral Deficiency.

It is well known that neuroinflammation plays a key role in neurodegenerative diseases. Hypoxia-inducible factor (HIF) and its hydroxylases-Prolyl-4-hydroxyases (PHDs) have been found to modulate the inflammatory processes. Here, the effects of PHDs enzyme onlipopolysaccharide-induced neuroinflammation and neurocognitive deficits were investigated.

Predictive Value of Eosinophil Count on COVID-19 Disease Progression and Outcomes, a Retrospective Study of Leishenshan Hospital in Wuhan, China.

Background: The potential protective role of eosinophils in the COVID-19 pandemic has aroused great interest, given their potential virus clearance function and the infection resistance of asthma patients to this coronavirus. However, it is unknown whether eosinophil counts could serve as a predictor of the severity of COVID-19.

Methods: A total of 1004 patients with confirmed COVID-19 who were admitted to Leishenshan Hospital in Wuhan, China, were enrolled in this study, including 905 patients in the general ward and 99 patients in the intensive care unit (ICU).

Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors.

Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays.

Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd-Catalyzed Regiodivergent Couplings between Indazoles and Isoprene.

Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd-hydride catalysis, the 1,2- or 4,3-insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands.

Preoperative Acute Pain Is Associated with Postoperative Delirium.

Background: Studies have provided some evidence that pain is a risk factor for postoperative delirium (POD). Therefore, we investigated the relationship between preoperative pain and POD after noncardiac surgery.

Methods: POD was assessed with the Montreal Cognitive Assessment, and preoperative cognition was assessed with the Mini-Mental State Examination.

Clinical characteristics and outcomes of five critical COVID-19 patients treated with extracorporeal membrane oxygenation in Leishenshan Hospital in Wuhan.

• Providing early ECMO support due to carbon dioxide retention and on-time decannulation may be more beneficial to patients. • The duration from tracheal intubation to ECMO cannulation was more than 7 days in some patients. • The application rules of ECMO vary in different regions.

Preoperative Chronic and Acute Pain Affects Postoperative Cognitive Function Mediated by Neurotransmitters.

The effective prevention of postoperative cognitive dysfunction (POCD) needs to be explored, and the effect of preoperative pain on POCD remains unclear. We established a chronic pain model induced by chronic constriction injury (CCI) and models of acute pain and anxiety without pain in mice that were subsequently subjected to partial hepatectomy surgery. Morris water maze (MWM) tests were performed to evaluate the learning and memory abilities of the mice.

Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.

Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives.

Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is consistently associated with increased morbidity and mortality. However, its mechanism remains poorly understood. We hypothesized that central cholinergic neuronal degeneration facilitates the development of POCD.

Central cholinergic system mediates working memory deficit induced by anesthesia/surgery in adult mice.

Background: Postoperative cognitive dysfunction (POCD) is consistently associated with increased morbidity and mortality, which has become a major concern of patients and caregivers. Although POCD occurs mainly in aged patients, it happens at any age. Previous studies demonstrated that anesthesia/surgery had no effects on reference memory of adult mice.

A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors.

The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions.

Data for the crystal structure of APRIL-BAFF-BAFF heterotrimer.

The TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) modulate B cell function by forming homotrimers and heterotrimers. To determine the structure of a heterotrimer of BAFF and APRIL, these ligands were expressed as a single chain protein in HEK 293 cells, purified by affinity and size exclusion chromatographies, and crystallized. Crystals belonging to the orthorhombic crystal system with a space group of C2221 diffracted to 2.

Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.

The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized.

Epitope characterization of an anti-PD-L1 antibody using orthogonal approaches.

The binding of programmed death ligand 1 protein (PD-L1) to its receptor programmed death protein 1 (PD-1) mediates immunoevasion in cancer and chronic viral infections, presenting an important target for therapeutic intervention. Several monoclonal antibodies targeting the PD-L1/PD-1 signaling axis are undergoing clinical trials; however, the epitopes of these antibodies have not been described. We have combined orthogonal approaches to localize and characterize the epitope of a monoclonal antibody directed against PD-L1 at good resolution and with high confidence.