18 research outputs found
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Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.
The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease
A Novel Near-Infrared Fluorescence Imaging Probe for in Vivo Neutrophil Tracking
The development and validation of a multiscopic near-infrared fluorescence (NIRF) probe, cinnamoyl-F-(D)L-F-(D)L-F-PEG-cyanine7 (cFlFlF-PEG-Cy7), that targets formyl peptide receptor on neutrophils using a mice ear inflammation model is described. Acute inflammation was induced in mice by topical application of phorbol-12-myristate-13-acetate to left ears 24 hours before probe administration. Noninvasive NIRF imaging was longitudinally performed up to 24 hours following probe injection. The in vivo neutrophil-targeting specificity of the probe was characterized by a blocking study with preadministration of excess nonfluorescent peptide cFlFlF-PEG and by an imaging study with a scrambled peptide probe cLFFFL-PEG-Cy7. NIRF imaging of mice injected with cinnamoyl-L-F-F-F-L-PEG-cyanine7 (cFlFlF-PEG-Cy7) revealed that the fluorescence intensity for inflamed left ears was approximately fourfold higher than that of control right ears at 24 hours postinjection. In comparison, the ratios acquired with the scrambled probe and from the blocking study were 1.5- and 2-fold at 24 hours postinjection, respectively. Moreover, a microscopic immunohistologic study confirmed that the NIRF signal of cFlFlF-PEG-Cy7 was associated with activated neutrophils in the inflammatory tissue. With this probe, in vivo neutrophil chemotaxis could be correlatively imaged macroscopically in live animals and microscopically at tissue and cellular levels
Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase
In a continuing study of potent bifunctional
anti-HIV agents, we
rationally designed a novel chimeric inhibitor utilizing thymidine
(THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a
polymethylene linker (ALK). The nucleoside, 5′-hydrogen-phosphonate
(H-phosphonate), and 5′-triphosphate forms of this chimeric
inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity
profiles were evaluated at the enzyme and cellular level. The nucleoside
triphosphate (<b>11</b>) and the H-phosphonate (<b>10</b>) derivatives inhibited RT polymerization with an IC<sub>50</sub> value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside
(<b>9</b>) and H-phosphonate (<b>10</b>) derivatives reduced
HIV replication in a cell-based assay with low nanomolar antiviral
potencies