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Summary: The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-μM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2−/− mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.

Cardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and frequently leads to massive heart injury and the loss of billions of cardiac muscle cells and associated vasculature. Critical work in the last 2 decades demonstrated that these lost cells can be partially regenerated by the epicardium, the outermost mesothelial layer of the heart, in a process that highly recapitulates its role in heart development. Upon cardiac injury, mature epicardial cells activate and undergo an epithelial-mesenchymal transition (EMT) to form epicardium-derived progenitor cells (EpiPCs), multipotent progenitors that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells. In mammals, this process alone is insufficient for significant regeneration, but it might be possible to prime it by administering specific reprogramming factors, leading to enhanced EpiPC function. Here, we show that oxytocin (OXT), a hypothalamic neuroendocrine peptide, induces epicardial cell proliferation, EMT, and transcriptional activity in a model of human induced pluripotent stem cell (hiPSC)-derived epicardial cells. In addition, we demonstrate that OXT is produced after cardiac cryoinjury in zebrafish, and that it elicits significant epicardial activation promoting heart regeneration. Oxytocin signaling is also critical for proper epicardium development in zebrafish embryos. The above processes are significantly impaired when OXT signaling is inhibited chemically or genetically through RNA interference. RNA sequencing data suggests that the transforming growth factor beta (TGF-β) pathway is the primary mediator of OXT-induced epicardial activation. Our research reveals for the first time an evolutionary conserved brain-controlled mechanism inducing cellular reprogramming and regeneration of the injured mammalian and zebrafish heart, a finding that could contribute to translational advances for the treatment of cardiac injuries.

Elicitors are the agents that stimulate the defense responses of plants, and accumulate specialized metabolites in plant tissue culture. This study investigated the elicitor-feeding response of H. pinifolia suspension cell cultures (SCC) for metabolomics analysis and screening of specialized compounds against Candida albicans. Methyl jasmonate (MeJA) was used as an elicitor, and treatment of SCC at a concentration of 20 µM MeJA resulted in the maximum rosmarinic acid (RA) accumulation (117 mg/g dry weight), with transcript levels of RA biosynthetic genes HpPAL, HpC4H, and Hp4CL being 4.2, 2.5, and 3.7-fold higher, respectively, than the controls. GC-MS-based metabolomics analysis revealed a total of 47 metabolites, including 30 organic acids, six amino acids, six flavonoids, two sugars, two plant growth regulators, and one vitamin, which were significantly different between control and MeJA-treated cells. Furthermore, five phenolic acids were discovered at higher concentrations, including p-anisic acid, p-coumaric acid, caffeic acid, vanillic acid, and rosmarinic acid, and were purified and structurally elucidated for alternative antifungal screening against C. albicans and the evaluation of ADMET properties. The results from antifungal screening revealed that RA at MIC of 31.25 mg/L exhibited the lowest growth percentage of C. albicans (1.99%), with higher inhibition of isocitrate lyase 1 (ICL 1) enzyme (93.1%), followed by p-anisic acid (86.2%) and caffeic acid (85.1%), respectively. The drug likeliness and ADMET properties of RA exhibited promising results, with a bioactivity score of 0.57, 0.15, and 0.24 for nuclear receptor ligand, protease inhibitor, and enzyme inhibitor, respectively. Therefore, MeJA appears to have a significant effect on enhanced RA accumulation in H. pinifoia cells with phenylpropanoid transcript expression, and acts as an ICL1 inhibitor of C. albicans.