| 1. |
- Nogal, Ana, et al.
(författare)
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A Fecal Metabolite Signature of Impaired Fasting Glucose : Results From Two Independent Population-Based Cohorts
- 2023
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Ingår i: Diabetes. - 0012-1797. ; 72:12, s. 1870-1880
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Tidskriftsartikel (refereegranskat)abstract
- Prediabetes is a metabolic condition associated with gut mi-crobiome composition, although mechanisms remain elu-sive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicoti-nate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02–5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16–1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97–8], P = 0.0002). Although these are host-produced me-tabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset.
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| 2. |
- Zhao, Xin, et al.
(författare)
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Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:12, s. 5187-5198
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Tidskriftsartikel (refereegranskat)abstract
- Influenza pandemic is a constant major threat to public health caused by influenza A viruses (IAVs). IAVs are subcategorized by the surface proteins hemagglutinin (HA) and neuraminidase (NA), in which they are both essential targets for drug discovery. While it is of great concern that NA inhibitor oseltamivir resistant strains are frequently identified from human or avian influenza virus, structural and functional characterization of influenza HA has raised hopes for new antiviral therapies. In this study, we explored a structure-activity relationship (SAR) of pinanamine-based antivirals and discovered a potent inhibitor M090 against amantadine-resistant viruses, including the 2009 H1N1 pandemic strains, and oseltamivir-resistant viruses. Mechanism of action studies, particularly hemolysis inhibition, indicated that M090 targets influenza HA and it occupied a highly conserved pocket of the HA(2) domain and inhibited virus-mediated membrane fusion by "locking" the bending state of HA(2) during the conformational rearrangement process. This work provides new binding sites within the HA protein and indicates that this pocket may be a promising target for broad-spectrum anti-influenza A drug design and development.
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