Biology subjects

Coenen, S.

Publications and source records attributed to Coenen, S..

4 recordsLinked to original sources

bioRxiv2024

Bridging immunotypes and enterotypes using a systems immunology approach

Unveiling the systemic effects of disease and health requires an holistic approach that has mainly revolved around well established, directly determinable molecular relationships such as the protein synthesis cascade and epigenetic mechanisms. In this study, involving 394 individuals, we found direct linkage of branches spanning human biological functions often not studied in conjunction, using clinical data, gut microbial abundances, blood immune cell repertoires, blood transcriptomic and blood T cell receptor data. Contrary to current paradigms, we demonstrate that immunotypes and enterotypes are orthogonal, likely fulfilling distinct roles in maintaining homeostasis, only bridged via the blood transcriptome. We also identified two distinct inflammatory profiles: the first driven by interferon signalling and the other characterised by non-viral, NF-kB and IL-6 markers. Lastly, we present compelling data showing strong associations of the Ruminococcaceae and Christensenellaceae bacteria with a healthy immunotype and transcriptomic pattern, highlighting their potential role in immune health. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/625344v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@c6b5eorg.highwire.dtl.DTLVardef@15d0c3forg.highwire.dtl.DTLVardef@1cf29eeorg.highwire.dtl.DTLVardef@1c9ff8d_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

ER stress relief drives beta cell proliferation

Regenerating endogenous pancreatic {beta}-cells is a potentially curative yet currently elusive strategy for diabetes therapy. Mimicking the microenvironment of the developing pancreas and leveraging vascular signals that support pancreatic endocrinogenesis may promote {beta}-cell regeneration. We aimed to investigate whether recovery from experimental hypovascularization of the endocrine pancreas, achieved by modulating the transgenic production of a VEGF-A blocker in {beta}-cells, could trigger mouse {beta}-cell proliferation. Serendipitously, we found that transgene overexpression in {beta}-cells induces endoplasmic reticulum (ER) stress and that subsequent relief from this stress stimulates {beta}-cell proliferation independent of vessel recovery. Transient GFP overexpression in vivo and chemical induction of ER stress in vitro replicated this {beta}-cell cycling response. Our findings highlight the potential side effects of ER stress due to transgene overexpression in {beta}-cells and assert that ER stress relief serves as a potent regenerative stimulus.

molecular biology↗

bioRxiv2022

Diclofenac and other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are Competitive Antagonists of the human P2X3 Receptor

The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents. To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology. We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC50 values of 138.2 {micro}M and 76.7 {micro}M, respectively). A weaker inhibition of hP2X1R, hP2X4R and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) proved to inhibit hP2X3R, rP2X3R and hP2X7R (IC50 values of 221{micro}M, 264.1{micro}M and [~] 900{micro}M, respectively), questioning its widespread use as a nonselective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of the hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP-application or increasing concentrations of the agonist ,{beta}-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results strongly support a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains inhibits gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R and hP2X7R. Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac may contribute to the analgesic effect as well as the side effect of taste disturbances of diclofenac and represent an additional mode of action besides the well-known high potency COX inhibition.

pharmacology and toxicology↗

bioRxiv2022

Live biotherapeutic throat spray for respiratory virus inhibition and interferon pathway induction

Respiratory viruses such as influenza viruses, respiratory syncytial virus (RSV), and coronaviruses initiate infection at the mucosal surfaces of the upper respiratory tract (URT), where the resident respiratory microbiome has an important gatekeeper function. In contrast to gut-targeting administration of beneficial bacteria against respiratory viral disease, topical URT administration of probiotics is currently underexplored, especially for the prevention and/or treatment of viral infections. Here, we report the selection and formulation of a broad-acting throat spray with live lactobacilli which induce interferon regulatory pathways and are able to inhibit respiratory viruses. Rational selection of Lactobacillaceae strains was based on safety, applicability, and potential antiviral and immunostimulatory efficacy in the URT. Three strains, Lacticaseibacillus casei AMBR2, Lacticaseibacillus rhamnosus GG and Lactiplantibacillus plantarum WCFS1 significantly reduced the cytopathogenic effects of RSV, influenza A/H1N1 and B viruses, and HCoV-229E coronavirus in co-culture models with bacteria, virus and host cells. Subsequently, these strains were formulated in a throat spray and human monocytes were employed to confirm the formulation process did not reduce the interferon regulatory pathway-inducing capacity. Administration of the throat spray in healthy volunteers revealed that the lactobacilli were capable of temporary colonization of the throat in a metabolically active form.

microbiology↗