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1.
Rapid Commun Mass Spectrom ; 38(5): e9681, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38355884

RESUMO

RATIONALE: There are a growing number of examples of protomers formed via electrospray ionization (ESI) that do not fragment under mobile proton conditions, giving rise to distinct tandem mass spectra. To model the N-protomer of 4-aminobenzoic acid, here we study the gas-phase unimolecular and bimolecular chemistry of the 4-(carboxyphenyl)trimethylammonium ion. METHODS: 4-(Carboxyphenyl)trimethylammonium iodide was synthesized, purified via recrystallization and transferred to the gas phase via ESI. 4-(Carboxyphenyl)trimethylammonium ion, 7, was mass selected and subjected to collision-induced dissociation and ion-molecule reactions in a linear ion trap mass spectrometer. RESULTS: The major fragmentation channel for the fixed-charge cation 7 is methyl radical loss, whereas loss of trimethylamine and CO2 represents minor pathways. The free carboxylic acid functional group of 7 is unreactive toward a number of neutral reagents (methanol, acetone, acetonitrile, and N,N'-diisopropylcarbodiimide). 7 reacts very slowly with trimethylborate via addition-elimination, consistent with density functional theory (DFT) calculations that show this reaction is slightly endothermic. The deuterated cation 7(D) undergoes slow D/H exchange with ethanol, and DFT calculations reveal that a flip-flop mechanism operates. CONCLUSIONS: The free carboxylic group of 7 is not very reactive toward neutral reagents in the gas phase.

2.
Antiviral Res ; 211: 105542, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36646387

RESUMO

Zika virus (ZIKV) infection arises as a global health threat owing to its association with Guillain-Barre syndrome and microcephaly in adults and fetuses since the most recent epidemics. Although extraordinary efforts have been underway globally to identify safe and effective treatments for ZIKV, therapeutic progressions seem to remain stagnant, especially for treating congenital ZIKV infection. Bio-compounds from medicinal plants evolutionarily optimized as drug-like molecules offer eligible sources of pharmaceuticals and lead drugs to fight against viral infections. Here, we identified desoxyrhapontigenin (DES), a naturally occurring bioactive product, as the strongest inhibitory compound against ZIKV infection among six conventional polyphenols in vitro. We also leveraged the trophoblast cell line, human trophoblast stem cells, and complex placental organoid models to provide solid evidence to support the anti-ZIKV bioactivity of DES. Notably, DES treatment effectively reduced the ZIKV burden in serum and target tissues, and correspondingly improved ZIKV-induced pathologic changes including weight loss, tissue inflammation, cell apoptosis, and adverse pregnancy outcomes, while it did not lead to obvious toxicity in both adult and pregnant mice. Furthermore, mechanistic studies revealed that DES could suppress ZIKV entry via dual mechanisms of direct targeting ZIKV E proteins and downregulating putative ZIKV receptors. These findings elucidate a previously unappreciated protective role of desoxyrhapontigenin against ZIKV infection both in vitro and in vivo, which shed light on the development of a novel and potent treatment for congenital ZIKV infection.


Assuntos
Infecção por Zika virus , Zika virus , Feminino , Gravidez , Humanos , Animais , Camundongos , Antivirais/farmacologia , Placenta
3.
Food Funct ; 13(21): 11298-11306, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36226621

RESUMO

Increasing evidence has shown that AGEs can impair insulin sensitivity and affect glucose homeostasis. Owing to the heterogeneity of AGEs, it is still unclear which one has the strongest potential to disrupt glucose metabolism. Our study explored the effects of different types of AGEs on hepatic glucose metabolism. Three typical AGEs representing different formation pathways, namely AGEs from a glucose and lysine reaction mixture, methylglyoxal-modified BSA (MGO-BSA) and carboxymethyl lysine (CML), were chosen to treat HepG2 cells. The results indicate that only CML and MGO-BSA could disturb glucose metabolism, and MGO-BSA was the most active in promoting insulin resistance, as manifested by the inactivation of insulin receptor substrate-1 and decreased phosphorylation of AKT. Moreover, mice fed with an MGO-BSA-enriched diet showed increased blood glucose as well as impaired glucose tolerance. The present study revealed the distinctive effects of various AGEs on glucose metabolism and suggested that AGEs with high molecular weight might exert a higher pathogenic effect than small AGEs.


Assuntos
Glucose , Resistência à Insulina , Camundongos , Animais , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Lisina/metabolismo , Óxido de Magnésio , Aldeído Pirúvico/metabolismo , Fígado/metabolismo
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