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1.
Environ Geochem Health ; 45(9): 6807-6822, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36445536

RESUMO

Owing to their widespread distribution and high bioaccumulation, microplastics (MPs) and mercury (Hg) are considered major threats to the ocean. MP interacts with Hg because of its high adsorption properties. However, their toxicological interactions with marine organisms, especially combined effects at the molecular level, are poorly understood. This study investigated the single and combined effects of MP and Hg on the metabolic profile of the brackish water flea Diaphanosoma celebensis. A total of 238 metabolites were significantly affected by MP, Hg, or MP + Hg. Metabolite perturbation patterns showed that toxicity of Hg and MP + Hg was similar and that of MP was not significant. Among the 223 metabolites affected by Hg, profiles of 32 unannotated metabolites were significantly different from those of MP + Hg, and combined effects of MP + Hg decreased the effect of Hg on 25 of these metabolites. Only 11 annotated metabolites were significantly affected by Hg or MP + Hg and were related to carbohydrate, lipid, vitamin, and ecdysteroid metabolism. Ten metabolites were decreased by Hg and MP + Hg and were not significantly different between the exposure groups. Enrichment analysis showed that galactose, starch, and sucrose metabolism were the most affected pathways. These findings suggest that MP has negligible toxic effect, and Hg can induce energy depletion, membrane damage, and disruption of growth, development, and reproduction. Although the impact of MP was negligible, the combined effects of MP + Hg could be metabolite specific. This study provides better understanding of the combined effects of MP and Hg on marine organisms.


Assuntos
Cladocera , Mercúrio , Compostos de Metilmercúrio , Poluentes Químicos da Água , Animais , Organismos Aquáticos , Mercúrio/análise , Mercúrio/toxicidade , Compostos de Metilmercúrio/toxicidade , Microplásticos/toxicidade , Plásticos , Águas Salinas , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise
2.
Exp Mol Med ; 54(9): 1563-1576, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131027

RESUMO

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/ß-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of "do not eat-me" signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of "eat-me" signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.


Assuntos
Neoplasias Colorretais , Fosfolipase D , Trifosfato de Adenosina , Antígeno CD47/metabolismo , Calreticulina , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , Morte Celular Imunogênica , Imunoterapia , Ligantes , Fosfolipase D/metabolismo , Microambiente Tumoral , Via de Sinalização Wnt
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