39 research outputs found
Hydroxycarboxylic acid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
The hydroxycarboxylic acid family of receptors (ENSFM00500000271913, nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [32, 10]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [47, 54, 57]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA2 receptors only and is unlikely to be the natural ligand [54, 57]
Tumor Necrosis FactorâAlpha Gene Expression in Human Whole Blood
Tumor necrosis factorâalpha (TNF) is recognized as a principal mediator of a variety of pathophysiologic and immunologic events. Lipopolysaccharide (LPS) challenge, either in vitro or in vivo, results in significant TNF production. In this study we present data demonstrating LPSâinduced TNF mRNA expression and bioactivity using an in vitro tissue system of whole blood (WB). The kinetics of LPSâinduced TNF production by WB was significantly accelerated as compared to isolated cultured peripheral blood monocytes (PBM). At postâLPS challenge, plasma from WB demonstrated a rapid rise in TNF bioactivity, peaking by 4 hr (1,021 units/ml/106 cells), plateauing between 4 and 8 hr, and then decreasing over the next 16 hr. In contrast, the highest measured TNF bioactivity from PBM did not occur until the 24âhr timeâpoint (175 units/ml/106 cells). Whole blood buffyâcoat TNF mRNA was assessed by Northern blot analysis, and demonstrated significant TNF mRNA accumulation at 1 hr and a peak 2 hr postâLPS challenge. By 8 hr TNF mRNA was undetectable. Concomitant administration of LPS with either prostaglandin E2 (10â6M) or Dexamethasone (10â6M) resulted in significant suppression of LPSâinduced TNF production. This data supports WB as a useful in vitro medium for the molecular and cellular analyis of TNF. As specialized connective tissue, WB may provide an important environment to study the pharmacologic manipulation of TNF mRNA and bioactivity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141678/1/jlb0366.pd
Hydroxycarboxylic acid receptors in GtoPdb v.2023.1
The hydroxycarboxylic acid family of receptors (ENSFM00500000271913, nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [36, 12]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [53, 60, 65]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA2 receptors only and is unlikely to be the natural ligand [60, 65]
Kupffer cellâderived cytokines induce the synthesis of a leukocyte chemotactic peptide, interleukin-8, in human hepatoma and primary hepatocyte cultures
Communication circuits operating between activated monocytes/macrophages and adjacent hepatocytes in the liver effect important alterations in hepatocyte function. We demonstrate here that primary human hepatocytes and hepatoma cells are able to function as effector cells in the recruitment of inflammatory cells in hepatic disease and inflammatory states by synthesizing a neutrophil/lymphocyte chemotactic factor, interleukin-8. We have further investigated the possibility that endogenous factors elaborated by activated peripheral blood monocytes and Kupffer cells in the liver are mediators of hepatocytederived interleukin-8 expression. Twenty-four-hour conditioned medium from lipopolysaccharidestimulated peripheral blood monocytes and nonparenchymal human liver cells enriched for Kupffer cells induced a time-dependent increase in interleukin-8 messenger RNA levels in SK-hepatoma cells over a 24-hr period, similar to that seen for tumor necrosis factor-Î or interleukin-1Î induction of interleukin-8 in primary hepatocytes. Exogenously added lipopolysaccharide or recombinant interleukin-6 had no effect. Cell-associated interleukin-8 antigen was present in SK-hepatoma and primary hepatocytes that had been incubated with macrophage-conditioned medium, tumor necrosis factor or interleukin-1Î. Similarly, neutrophil chemotactic activity was secreted by SKhepatoma cells, a significant proportion of which could be blocked with interleukin-8âspecific antiserum. Preincubation of macrophage-conditioned medium with neutralizing antibodies to tumor necrosis factor-Î or interleukin-1Î reduced its interleukin-8 messenger RNA-inducing capacity. Exposure of SK-hepatoma to conditioned medium followed by removal of the stimulus resulted in a rapid down-regulation of interleukin-8 messenger RNA to 50% of the maximum level within the first hour. These data suggest that products derived from activated Kupffer cells can modulate hepatoma cells and primary hepatocyte interleukin-8 gene expression. In addition, macrophage/monocyte-derived tumor necrosis factor-Î and interleukin-1Î have major roles in the positive regulatory component of this modulation. (H EPATOLOGY 1992;15:1112â1122.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38368/1/1840140627_ftp.pd
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe
Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study
Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28â2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65â3·22], p\textless0·0001), American Society of Anesthesiologists grades 3â5 versus grades 1â2 (2·35 [1·57â3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01â2·39], p=0·046), emergency versus elective surgery (1·67 [1·06â2·63], p=0·026), and major versus minor surgery (1·52 [1·01â2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research
Profiling and Application of Photoredox C(sp<sup>3</sup>)âC(sp<sup>2</sup>) Cross-Coupling in Medicinal Chemistry
Recent
visible-light photoredox catalyzed CÂ(sp<sup>3</sup>)âCÂ(sp<sup>2</sup>) cross-coupling provides a novel transformation to potentially
enable the synthesis of medicinal chemistry targets. Here, we report
a profiling study of photocatalytic CÂ(sp<sup>3</sup>)âCÂ(sp<sup>2</sup>) cross-coupling, both decarboxylative coupling and cross-electrophile
coupling, with 18 pharmaceutically relevant aryl halides by using
either Kessil lamp or our newly developed integrated photoreactor.
Integrated photoreactor accelerates reaction rate and improves reaction
success rate. Cross-electrophile coupling gives higher success rate
with broad substrate scope on alkyl halides than that of the decarboxylative
coupling. In addition, a successful application example on a discovery
program demonstrates the efficient synthesis of medicinal chemistry
targets via photocatalytic CÂ(sp<sup>3</sup>)âCÂ(sp<sup>2</sup>) cross-coupling by using our integrated photoreactor
Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines
ABSTRACT Severe acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELR-containing CXC chemokines such as macrophage inflammatory protein-2 (MIP-2), epithelial neutrophil-activating protein-78 (ENA-78), or interleukin 8. Intravenous administration of ELR-CXC chemokines or N-acetyl-cysteine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, when the intervention was delayed until 10 h after acetaminophen challenge, only ELR-CXC chemokines significantly reduced liver injury and mouse mortality. The delayed addition of ELR-CXC chemokines to cultured hepatocytes maintained the proliferation of these cells in a CXCR2-dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observations demonstrate that ELR-CXC chemokines represent novel hepatic regenerative factors that exhibit prolonged therapeutic effects after acetaminophen-induced hepatotoxicity.âHogaboam
Chemoselective Peptide Modification via Photocatalytic Tryptophan ÎČâPosition Conjugation
Targeting tryptophan
is a promising strategy to achieve high levels
of selectivity for peptide or protein modification. A chemoselective
peptide modification method via photocatalytic tryptophan ÎČ-position
conjugation has been discovered. This transformation has good substrate
scope for both peptide and Michael acceptor, and has good chemoselectivity
versus other amino acid residues. The endogenous peptides, glucagon
and GLP-1 amide, were both successfully conjugated at the tryptophan
ÎČ-position. Insulin was studied as a nontryptophan control molecule,
resulting in exclusive B-chain C-terminal-selective decarboxylative
conjugation. This transformation provides a novel approach toward
peptide modification to support the discovery of new therapeutic peptides,
protein labeling and bioconjugation