Search

Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimer's Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase , Pla2g2f , whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that maintains lipid homeostasis to counteract aging-associated cognitive decline.

The drug discovery and development process encompasses the interrogation of metabolites arising from the biotransformation of drugs. Here we look at why, when and how metabolites of small-molecule drugs are synthesised from the perspective of a specialist contract research organisation, with particular attention paid to projects for which regulatory oversight is relevant during this journey. To illustrate important aspects, we look at recent case studies, trends and learnings from our experience of making and identifying metabolites over the past ten years, along with with selected examples from the literature., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Natural cases of zooanthroponotic transmission of SARS-CoV-2 to animals have been reported during the COVID-19 pandemic, including to free-ranging white-tailed deer ( Odocoileus virginianus ) in North America and farmed American mink ( Neovison vison ) on multiple continents. To understand the potential for angiotensin-converting enzyme 2 (ACE2)-mediated viral tropism we characterised the distribution of ACE2 receptors in the respiratory and intestinal tissues of a selection of wild and semi-domesticated mammals including artiodactyls (cervids, bovids, camelids, suids and hippopotamus), mustelid and phocid species using immunohistochemistry. Expression of the ACE2 receptor was detected in the bronchial or bronchiolar epithelium of several European and Asiatic deer species, Bactrian camel ( Camelus bactrianus ), European badger ( Meles meles ), stoat ( Mustela erminea ), hippopotamus ( Hippopotamus amphibious ), harbor seal ( Phoca vitulina ), and hooded seal ( Cystophora cristata ). Further receptor mapping in the nasal turbinates and trachea revealed sparse ACE2 receptor expression in the mucosal epithelial cells and occasional occurrence in the submucosal glandular epithelium of Western roe deer ( Capreolus capreolus ), moose ( Alces alces alces ), and alpaca ( Vicunga pacos ). Only the European badger and stoat expressed high levels of ACE2 receptor in the nasal mucosal epithelium, which could suggest high susceptibility to ACE2-mediated respiratory infection. Expression of ACE2 receptor in the intestinal cells was ubiquitous across multiple taxa examined. Our results demonstrate the potential for ACE2-mediated viral infection in a selection of wild mammals and highlight the intra-taxon variability of ACE2 receptor expression, which might influence host susceptibility and infection., Competing Interests: The authors declare no conflict of interests., (© 2023 Published by Elsevier B.V.)

The purpose of this study was to determine the effect of rivaroxaban (RIV) on haemostatic parameters assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT) and kaolin-activated thromboelastography (TEG) in apparently healthy dogs administered 1 mg kg -1 orally once daily for 1 week. Eleven dogs had a baseline complete blood count (CBC), fibrinogen, platelet count, serum chemistry profile, PT, aPTT, and TEG performed. Each dog was then administered approximately 1.0 mg kg -1 of RIV orally once daily for 1 week and the CBC, fibrinogen, platelet count, serum chemistry profile, PT, aPTT, and TEG was re-evaluated. Any side effects attributed to RIV were noted at this time. One dog was excluded due to identification of a macrocytic thrombocytopenia on pre-treatment blood work. The remaining 10 enrolled dogs completed the study. Dogs received a median dose of 1.02 mg kg -1 (range 0.94-1.17 mg kg -1 ) of RIV once daily and was associated with a significant increase in pulse, packed cell volume, total solids, platelet count, fibrinogen and a significant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration. There was no significant change in PT, aPTT or any TEG parameters. The RIV appeared well tolerated with one dog having one episode of vomiting on day 4 but otherwise no other side effects were identified clinically or on recheck blood work. The results of this study suggests that RIV at a dose of 1 mg kg -1 orally once daily is safe and well tolerated but does not cause a significant prolongation of PT, aPTT or TEG parameters., (© 2019 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes. A workflow is discussed whereby microbial strains are initially screened for their ability to form the putative metabolites of interest, followed by a scale-up to afford quantities sufficient to perform definitive identification and further studies. Examples of the microbial synthesis of several difficult-to-synthesize hydroxylated metabolites and three difficult-to-synthesize glucuronidated metabolites are described, and the use of microbial biotransformation in drug discovery and development is discussed.

During a clinical placement on a general medical ward in my third year of training, I started managing a caseload of my own patients.

A fusidane triterpene, 16-deacetoxy-7-beta-hydroxy-fusidic acid (1), was isolated from a fermentation of the mitosporic fungus Acremonium crotocinigenum. Full unambiguous assignment of all (1)H and (13)C data of 1 was carried out by extensive one- and two-dimensional NMR studies employing HMQC and HMBC spectra. Compound 1 was tested against a panel of multidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) strains and showed minimum inhibitory concentration values of 16 microg/ml.