Hong Pan,Qi Luo,Qiuyi Jing,Lin Chen,Ni Li,Chao Fang,Fuguo Shi
Acetaminophen (APAP)-induced liver injury is a leading cause of liver injury cases in some Western countries. Although APAP hepatotoxicity is well-documented, the precise mechanisms underlying its pathogenesis remain incompletely understood. This study investigates the role of endogenous aldehydes in exacerbating APAP-induced liver injury through covalent modification of hepatic proteins. Here, 74 free biogenic aldehydes were identified in the mouse liver following APAP administration. Among these, 47 aldehydes exhibited the ability to covalently bind to hepatic proteins, with 29 being reported in the liver for the first time. Protein adducts of 29 aldehydes peaked at 2-3 hours post-APAP treatment. Inhibition of APAP metabolic activation using the CYP2E1 inhibitor 4-methylpyrazole significantly reduced aldehyde-mediated protein adduction. Furthermore, activation of aldehyde dehydrogenase-2 by Alda-1 and the nucleophilic trapping reagent N-acetyl-L-lysine attenuated both protein adduction by aldehydes and APAP-induced liver injury. Notably, these biogenic aldehydes demonstrated intrinsic hepatotoxicity, with their combined effects leading to liver injury through additive covalent protein modifications. Additionally, aldehydes induced c-Jun amino-terminal kinase phosphorylation, further amplifying APAP-induced liver damage. In conclusion, our findings reveal that endogenous aldehydes triggered by the reactive metabolite of APAP amplify liver damage through “additive effects” on covalent protein modification. This study provides novel insights into the mechanisms of APAP hepatotoxicity and highlights potential therapeutic targets for mitigating liver injury.
The selective hydrogenation of cinnamaldehyde (CAL) to prepare cinnamyl alcohol (COL) is challenging as the unwanted hydrogenation of C C bond in CAL is thermodynamically more favorable than the hydrogenation of C O bond. We herein designed core–shell structured nanoparticles (NPs) that consisted of Pt cores and Sn shells to catalyze the CAL to COL conversion. By simply changing the amount of Sn precursor, we generated Pt@Sn NPs with different Sn shell thickness and catalytic performance. Among the samples, Pt@Sn/SiO 2 with Pt/Sn of 1/1 achieved the highest CAL conversion (87.2 %) as well as the COL selectivity (95.4 %), which were 5-fold and 6-fold, respectively, higher than those of Pt/SiO 2 . This catalyst was also applicable to the hydrogenation of other α, β-unsaturated aldehyde and unsaturated carbonyl compounds. Both experiments and theoretical calculations indicated that the strong Pt-Sn interaction and the partial coverage of Pt by Sn facilitated their adsorption of C O bonds, thus enhancing the conversion of CAL and the selectivity towards COL.
Changeable substituent groups of organic molecules can provide an opportunity to clarify the antibacterial mechanism of organic molecules by tuning the electron cloud density of their skeleton. However, understanding the antibacterial mechanism of organic molecules is challenging. Herein, we reported a molecular view strategy for clarifying the antibacterial switch mechanism by tuning electron cloud density of cinnamaldehyde molecule skeleton. The cinnamaldehyde and its derivatives were self-assembled into nanosheets with excellent water solubility, respectively. The experimental results show that α-bromocinnamaldehyde (BCA) nanosheets exhibits unprecedented antibacterial activity, but there is no antibacterial activity for α-methylcinnamaldehyde nanosheets. Therefore, the BCA nanosheets and α-methylcinnamaldehyde nanosheets achieve an antibacterial switch. Theoretical calculations further confirmed that the electron-withdrawing substituent of the bromine atom leads to a lower electron cloud density of the aldehyde group than that of the electron-donor substituent of the methyl group at the α-position of the cinnamaldehyde skeleton, which is a key point in elucidating the antimicrobial switch mechanism. The excellent biocompatibility of BCA nanosheets was confirmed by CCK-8. The mouse wound infection model, H&E staining, and the crawling ability of drosophila larvae show that as-prepared BCA nanosheets are safe and promising for wound healing. This study provides a new strategy for the synthesis of low-cost organic nanomaterials with good biocompatibility. It is expected to expand the application of natural organic small molecule materials in antimicrobial agents.
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