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Many anticancer therapies cause serious cardiovascular complications that degrade quality of life and cause early mortality in treated patients. Specifically, doxorubicin is known as an effective anticancer agent that causes cardiomyopathy in treated patients. There has been growing interest in defining the role of endothelial cells in cardiac damage by doxorubicin. We have shown in the present study that endothelial nuclei accumulate more intravenously administered doxorubicin than other cardiac cell types. Doxorubicin enhanced cardiac production of the transforming growth factor-β (TGF-β) ligands and nuclear translocation of phospho-Smad3 in both cultured and in vivo cardiac endothelial cells. To examine the role of the TGF-β/mothers against decapentaplegic homolog 3 (Smad3) pathway in cardiac damage by doxorubicin, we used both

The persistence of hepatotoxicity induced by N-acetyl-para-aminophenol (Acetaminophen or Paracetamol, abbreviated as APAP) as the most common cause of acute liver failure in the United States, despite the availability of N-acetylcysteine, illustrates the clinical relevance of additional therapeutic approaches. While human mesenchymal stem cells (MSCs) have shown protection in mouse models of liver injury, the MSCs used are generally not cleared for human use and it is unclear whether these effects are due to xenotransplantation. Here we evaluated GMP manufactured clinical grade human Wharton's Jelly mesenchymal stem cells (WJMSCs), which are currently being investigated in human clinical trials, in a mouse model of APAP hepatotoxicity in comparison to human dermal fibroblasts (HDFs) to address these issues. C57BL6J mice were treated with a moderate APAP overdose (300 mg/kg) and WJMSCs were administered 90 min later. Liver injury was evaluated at 6 and 24 h after APAP. WJMSCs treatment reduced APAP-induced liver injury at both time points unlike HDFs, which showed no protection. APAP-induced JNK activation as well as AIF and Smac release from mitochondria were prevented by WJMSCs treatment without influencing APAP bioactivation. Mechanistically, WJMSCs treatment upregulated expression of Gclc and Gclm to enhance recovery of liver GSH levels to attenuate mitochondrial dysfunction and accelerated recovery of pericentral hepatocytes to re-establish liver zonation and promote liver homeostasis. Notably, preventing GSH resynthesis with buthionine sulfoximine prevented the protective effects of WJMSCs. These data indicate that these GMP-manufactured WJMCs could be a clinically relevant therapeutic approach in the management of APAP hepatotoxicity in humans.

Cardiovascular (CV) outcomes can be improved with commonality between provider and patient regarding gender and race/ethnicity. Slow growth in CV care provider diversity is an obstacle for women and underrepresented groups. The hope for more equitable outcomes is unlikely to be realized unless trends change in selection of CV fellows and program directors (PDs). We investigate longitudinal trends of gender and racial/ethnic composition of CV FITs. De-identified demographic data were compiled in a descriptive cross-sectional study from AAMC of internal medicine (IM) residents and CV FITs from 2011 through 2021 to evaluate gender and race/ethnicity trends among CV trainees. Trends of CV fellows who later became program directors were analyzed. In the US between 2011 and 2021, 53% of IM residents were male while 40% female (7% unreported). Among CV FITs, 78% were male and 21% female. Races/ethnicities among CV FITs consisted of 36% non-Hispanic white, 28% non-Hispanic Asian, 5% Hispanic, 4%Black, and 25% were classified within other race/ethnicity categories. The proportion who became CV program directors followed similarly: 79% of PDs were male and 21% female. Demographic profiles for CV FITs have not significantly changed over the past decade despite increased diversity among IM residents. Efforts to improve diversity of CV FITs and PDs need to be analyzed. Slow growth of diversity in CV FITs is outpaced by rising patient diversity, leading to disparities in care and poorer CV outcomes for women and underrepresented minorities. Recruiting, training, and retaining diverse CV FITs is necessary.

Histone modifying enzymes regulate chromatin architecture through covalent modifications and ultimately control multiple aspects of cellular function. Disruption of histone modification leads to changes in gene expression profiles and may lead to disease. Both small molecule inhibitors and intermediary metabolites have been shown to modulate histone modifying enzyme activity although our ability to identify successful drug candidates or novel metabolic regulators of these enzymes has been limited. Using a combination of large scale in silico screens and in vivo phenotypic analysis, we identified several small molecules and intermediary metabolites with distinctive HME activity. Our approach using unsupervised learning identifies the chemical fingerprints of both small molecules and metabolites that facilitate recognition by the enzymes active sites which can be used as a blueprint to design novel inhibitors. Furthermore, this work supports the idea that histone modifying enzymes sense intermediary metabolites integrating genes, environment and cellular physiology.