Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury

Cytotoxicity of Platinum Anticancer Drugs in Mammalian Cell Lines of Metastatic Cancer

With the invention of advanced technology, focus has been put on understanding and looking for potential cures for many diseases, one of which is cancer. The difference in the leaving and non-leaving ligands of the FDA approved cancer drugs contributes to the differential cell specific cytotoxic effects. These drugs such as oxaliplatin approved for colorectal cancer, cisplatin approved for testicular cancer, and their analogs were used to treat different cancer cell lines in an MTT assay. This project aims to determine how changing the molecular shape of these compounds affects their uptake and toxicity into different cell lines. The assay used the metabolism of MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliuM bromide to its insoluble purple colored formazan. The cytotoxicity of these compounds are measured using the absorbance which decreases with increasing drug concentration to calculate the IC50. This value gives the concentration of compound that inhibits mitochondrial reductase by 50%. The cell lines used in these experiments are the NTERA-2 cells, most notably the prostate cancer cell lines with the 293 Human Embryonic Kidney (HEK), a noncancerous line, cells as the control. The IC50 for the compound Pt (S, S-dach) (ox) was 20 μm. There was no significant increase in its effect on the NTERA-2 cells when the concentration was higher while the compound Pt(Me2dach) (ox) did not inhibit up to 50% cell survival in the NTERA-2 cells even at a concentration was 100 μm. Pt(en)2 did not give an IC50 value in the HEK cells (control cells). For the experiments on NTERA-2 cancer cells, Pt-(S, S-dach) (ox) was more effective and cytotoxic than Pt(Me2dach) (ox)

TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy

Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed autophagy ). RNA-seq of flow-sorted macrophages postinfarction revealed that Mϕ-TFEB upregulated key targets involved in lysosomal lipid metabolism. Specifically, inhibition of the TFEB target, lysosomal acid lipase, in vivo abrogated the beneficial effect of Mϕ-TFEB on postinfarction ventricular function. Thus, TFEB reprograms macrophage lysosomal lipid metabolism to attenuate remodeling after IR, suggesting an alternative paradigm whereby lysosome function affects inflammation