Biology subjects

Henriksbo, B. D.

Publications and source records attributed to Henriksbo, B. D..

4 recordsLinked to original sources

bioRxiv2021

Exploration of 1 BAY 11-7082 as a novel antibiotic

Exposure of the Gram-negative pathogen Pseudomonas aeruginosa to sub-inhibitory concentrations of antibiotics increases formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity. We confirmed that BAY 11-7082 inhibits growth of P. aeruginosa and other priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, we measured the ability of select analogues to reduce IL-1{beta} production in mammalian macrophages, identifying minor differences in the structure-activity relationship for the anti-inflammatory and antibacterial properties of this scaffold. Although we could evolve stably resistant MRSA mutants with cross resistance to BAY 11-7082 and PSPC, their lack of shared mutations suggested that the two molecules could have multiple targets. Finally, we showed that BAY 11-7082 and its analogues potentiate the activity of penicillin G against MRSA, suggesting that this scaffold may serve as an interesting starting point for the development of antibiotic adjuvants. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/462244v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1387110org.highwire.dtl.DTLVardef@86f1ddorg.highwire.dtl.DTLVardef@170edaborg.highwire.dtl.DTLVardef@103a36d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

Metabolic endotoxemia is dictated by the type of lipopolysaccharide

Lipopolysaccharides (LPS) can promote metabolic endotoxemia, which is considered inflammatory and metabolically detrimental based on Toll-like receptor (TLR)4 agonists such as Escherichia coli-derived LPS. LPS from certain bacteria antagonize TLR4 yet contribute to endotoxemia measured by Endotoxin Units (EU). We found that E. coli LPS impaired gut barrier function and worsened glycemic control in mice, but equal doses of LPS from other bacteria did not. Matching the LPS dose from R. sphaeroides and E. coli by EU revealed that only E. coli LPS promoted dysglycemia, adipose inflammation, delayed intestinal glucose absorption, and augmented insulin and GLP-1 secretion. Metabolically beneficial endotoxemia promoted by R. sphaeroides LPS counteracted dysglycemia caused by an equal dose of E. coli LPS and promoted insulin sensitivity in obese mice. The concept of metabolic endotoxemia should be expanded beyond LPS load (EU) to include LPS characteristics, where the balance of deleterious and beneficial endotoxemia regulates host metabolism. HighlightsO_LIType of LPS dictates gut barrier function, inflammation, insulin, GLP-1, intestinal glucose absorption and blood glucose C_LIO_LIEndotoxin Units (EU) do not reflect how LPS influences blood glucose or hormones C_LIO_LILPS derived from certain types of bacteria are insulin sensitizers C_LIO_LIR. sphaeroides LPS promotes metabolically beneficial endotoxemia C_LIO_LILPS characteristics dictate metabolically beneficial versus deleterious endotoxemia C_LI

physiology↗

bioRxiv2020

Gut microbiota impairs insulin clearance during obesity

Hyperinsulinemia can be a cause and consequence of obesity and insulin resistance. Increased insulin secretion and reduced insulin clearance can contribute to hyperinsulinemia. The triggers for changes in insulin clearance during obesity are ill-defined. We found that oral antibiotics mitigated impaired insulin clearance in mice fed a high fat diet (HFD) for 12 weeks or longer. Short-term HFD feeding and aging did not alter insulin clearance in mice. Germ-free mice colonized with microbes from HFD-fed mice had impaired insulin clearance, but not C-peptide clearance, and only after mice were colonized for 6 weeks and then HFD-fed. Five bacterial taxa predicted >90% of the variance in insulin clearance. Our data indicate that gut microbes are an independent and transmissible factor that regulates obesity-induced changes in insulin clearance. A small cluster of microbes may be a target for mitigating defects in insulin clearance and the progression of obesity and Type 2 Diabetes. We propose that a small community in the gut microbiota can impair insulin clearance and increase insulin load and the risk of complications from hyperinsulinemia.

physiology↗

bioRxiv2020

Inflammation promotes adipocyte lipolysis via IRE1 kinase

Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipolysis separate from hormone or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis regulated by adrenergic or hormonal stimuli. Inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. Adipocyte-specific deletion of IRE1 in mice prevented inflammatory ligand-induced lipolysis in adipose tissue. IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. We found no role for canonical unfolded protein responses (UPR) or ABL kinases in linking ER stress to lipolysis. Lipolysis was unchanged in adipose tissue from GRP78/BiP+/- compared to littermate mice. Tyrosine kinase inhibitors (TKIs) such as imatinib, which reduce ER stress and IRE1 RNase activity, did not alter lipolysis from inflammatory stimuli. Inhibiting IRE1 kinase activity blocked adipocyte NF-{kappa}B activation and Interleukin-6 (Il6) production due to inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signalling in adipocytes. Therefore, inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. Our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation, including insulin resistance. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders. SignificanceAdipocytes maintain metabolic homeostasis by storing nutrients and releasing lipids into the blood via lipolysis. Catecholamines stimulate adrenergic-mediated lipolysis, whereas insulin inhibits lipolysis. Obesity is associated with elevated blood lipids and inflammation, which can impair insulin-mediated suppression of lipolysis (i.e. insulin resistance). It is unclear if inflammatory triggers of lipolysis require insulin resistance or if specific lipolytic triggers engage distinct cell stress components. We found that a specific ER stress response was required for inflammation-mediated lipolysis, not adrenergic-mediated lipolysis. Bacterial and cytokine-induced lipolysis required adipocyte IRE1 kinase activity, but not IRE1 RNase activity typical of the ER stress-related unfolded protein response. We propose that inflammatory triggers of lipolysis engage IRE1 kinase independent of catecholamine and hormone responses, including insulin resistance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/030148v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@c9ae43org.highwire.dtl.DTLVardef@cfb430org.highwire.dtl.DTLVardef@3ecd2aorg.highwire.dtl.DTLVardef@10fbafe_HPS_FORMAT_FIGEXP M_FIG C_FIG IRE1 kinase activity promotes an inflammation-specific adipocyte lipolytic program that is separate from hormonal or adrenergic regulation of lipolysis.

physiology↗