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Acute myocarditis is an unpredictable heart disease that is caused by inflammation-associated cell death. Although viral infection and drug exposure are known to induce acute myocarditis, the molecular basis for its development remains undefined. Using proteomics and molecular analyses in myosin-induced rat experimental autoimmune myocarditis (EAM), we identified that elevated expression of aldolase 1A, retrogene 1 (Aldoart1) is critical to induce mitochondrial dysfunction and acute myocarditis development. Here, we demonstrate that cardiac cell death is associated with increased expressions of proapoptotic genes in addition to high levels of glucose, lactate, and triglyceride in metabolite profiling. The functional protein association network analysis also suggests that Aldoart1 upregulation correlates with high levels of dihydroxyacetone kinase and triglyceride. In H9c2 cardiac cells, lipopolysaccharides (LPS) or high glucose exposure significantly increases the cytochrome c release and the conversion of pro-caspase 3 into the cleaved form of caspase 3. We also found that LPS- or glucose-induced toxicities are almost completely reversed by siRNA-mediated knockdown of Aldoartl, which consequently increases cell viability. Together, our study strongly suggests that Aldoart1 may be involved in inducing mitochondrial apoptotic processes and can be a novel therapeutic target to prevent the onset of acute myocarditis or cardiac apoptosis. Key words: H9c2, experimental autoimmune myocarditis, apoptosis, high glucose, Aldoart1. La myocardite aigue est une maladie cardiaque imprevisible causee par une mort cellulaire associee a de l'inflammation. On sait que des infections virales ainsi que l'exposition a certains medicaments peuvent provoquer une myocardite aigue, mais les bases moleculaires de son apparition demeurent a definir. A l'aide de la proteomique et d'analyses moleculaires dans un modele de myocardite auto-immune experimentale (MAE) provoquee par la myosine chez le rat, nous avons etabli qu'une augmentation de l'expression de l'aldolase 1A, retrogene 1 (Aldoart1) est cruciale pour engendrer un dysfonctionnement mitochondrial et l'apparition d'une myocardite aigue. Ici, nous montrons que la mort des cellules cardiaques est associee avec une augmentation de l'expression de genes pro-apoptotiques, en plus d'une augmentation des taux de glucose, de lactate et de triglycerides dans le profilage des metabolites. L'analyse de reseaux d'association de proteines fonctionnelles laisse aussi entrevoir que la regulation a la hausse de l'Aldoart1 est proportionnelle a l'augmentation des taux de dihydroxyacetone kinase et des triglycerides. Dans les cellules cardiaques H9c2, l'exposition a des lipopolysaccharides (LPS) ou a des taux de glucose eleves entraine une augmentation notable de la liberation de cytochrome c, ainsi que la conversion de la pro-caspase 3 en caspase 3, sa forme clivee. Nous avons aussi observe que la toxicite engendree par les LPS ou le glucose est presque entierement inversee avec la repression (<< knockdown >>) de l'Aldoartl a l'aide de siRNA, ce qui entraine une augmentation consecutive de la vitalite des cellules. Dans l'ensemble, notre etude laisse fortement entendre que l'Aldoart1 pourrait jouer un role dans l'induction de processus apoptotiques mitochondriaux, et qu'il pourrait constituer une nouvelle cible therapeutique en vue de prevenir l'apparition de la myocardite aigue ou l'apoptose cardiaque. [Traduit par la Redaction] Mots-cles: H9c2, myocardite auto-immune experimentale, apoptose, taux de glucose eleves, Aldoart1., Introduction Myocarditis is one of the inflammatory diseases caused by viral infection or drug exposure (Rose and Hill 1996). Myocarditis caused by viral infection begins when immune cells recognize particles [...]

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue‐specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor‐targeting peptides into the LNPs; the programmed death ligand 1 (PD‐L1) binding peptides are conjugated to PEGylated lipids via a copper‐free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD‐L1 proteins, which leads to the uptake of LNPs into PD‐L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN‐deficient triple‐negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy‐mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor‐targeted LNPs for mRNA‐based cancer therapy. [ABSTRACT FROM AUTHOR]

Novel 1‐phenoxy‐3‐(piperazin‐1‐yl)propan‐2‐ol derivatives were designed and synthesized as potential triple reuptake inhibitors, which simultaneously inhibit serotonin, norepinephrine, and dopamine transporters (SERT, NET, and DAT, respectively). Through neurotransmitter transporter uptake assays, inhibitory activities of 1‐phenoxy‐3‐(piperazin‐1‐yl)propan‐2‐ol derivatives were evaluated. We discovered compound 19 exhibited the most potent inhibitory activities against all three monoamine neurotransmitter transporters and the IC50 values of 19 against SERT, NET, and DAT were determined. In addition, binding modes of 19 with SERT, NET, and DAT were predicted by docking studies. [ABSTRACT FROM AUTHOR]