A Novel Micropeptide, \u3cem\u3eSlitharin\u3c/em\u3e, Exerts Cardioprotective Effects in Myocardial Infarction

Purpose: Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type. Experimental design: We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction. Results: We identified a novel 24-amino acid micropeptide (dubbed Slitharin [Slt]) with a non-canonical leucine start codon, arising from long intergenic non-coding (LINC) RNA 2099. Neonatal rat ventricular myocytes (NRVMs) exposed to Slt were protected from hypoxic injury in vitro compared to a vehicle or scrambled control. Transcriptomic analysis of cardiomyocytes exposed to Slt reveals cytoprotective capacity, putatively through regulation of stress-induced MAPK-ERK. Slt also exerted cardioprotective effects in rats with myocardial infarction as shown by reduced infarct size 48 h post-injury. Conclusions and clinical relavance: Thus, Slt is a non-coding RNA-derived micropeptide, identified in the extracellular space, with a potential cardioprotective function

Separation and Recycling for Rare Earth Elements by Homogeneous Liquid-Liquid Extraction (HoLLE) Using a pH-Responsive Fluorine-Based Surfactant

A selective separation and recycling system for metal ions was developed by homogeneous liquid-liquid extraction (HoLLE) using a fluorosurfactant. Sixty-two different elemental ions (e.g., Ag, Al, As, Au, B, Ba, Be, Bi, Ca, Cd, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Gd, Ge, Hf, Hg, Ho, In, Ir, La, Lu, Mg, Mn, Mo, Nb, Nd, Ni, Os, P, Pb, Pd, Pr, Pt, Re, Rh, Ru, Sb, Sc, Se, Si, Sm, Sn, Sr, Ta, Tb, Te, Ti, Tl, Tm, V, W, Y, Yb, Zn, and Zr) were examined. By changing pH from a neutral or alkaline solution (pH ≥ 6.5) to that of an acidic solution (pH < 4.0), gallium, zirconium, palladium, silver, platinum, and rare earth elements were extracted at >90% efficiency into a sedimented Zonyl FSA® (CF3(CF2)n(CH2)2S(CH2)2COOH, n = 6–8) liquid phase. Moreover, all rare earth elements were obtained with superior extraction and stripping percentages. In the recycling of rare earth elements, the sedimented phase was maintained using a filter along with a mixed solution of THF and 1 M sodium hydroxide aqueous solution. The Zonyl FSA® was filtrated and the rare earth elements were recovered on the filter as a hydroxide. Furthermore, the filtrated Zonyl FSA was reusable by conditioning the subject pH

Eed/Sox2 regulatory loop controls ES cell self-renewal through histone methylation and acetylation

The epigenetic state of chromatin plays an important role in regulating the self-renewal of embryonic stem cells. Here, Sox2 and Eed are shown to form a regulatory loop by which they regulate each other's expression, histone acetylation and methylation to control stem cell pluripotency

TDO2‐augmented fibroblasts secrete EVs enriched in immunomodulatory Y‐derived small RNA

Abstract Mounting evidence implicates extracellular vesicles (EVs) factors as mediators of cell therapy. Cardiosphere‐derived cells are cardiac‐derived cells with tissue reparative capacity. Activation of a downstream target of wnt/β‐catenin signalling, tryptophan 2,3 dioxygenase (TDO2) renders therapeutically inert skin fibroblasts cardioprotective. Here, we investigate the mechanism by which concentrated conditioned media from TDO2‐augmented fibroblasts (TDO2‐CCM) exert cardioprotective effects. TDO2‐CCM is cardioprotective in a mouse model of MI compared to CCM from regular fibroblasts (HDF‐CCM). Transcriptomic analysis of cardiac tissue at 24 h demonstrates broad suppression of inflammatory and cell stress markers in animals given TDO2‐CCM compared to HDF‐CCM or vehicle. Sequencing analysis of TDO2‐EV RNA demonstrated abundance of a small Y‐derived small RNA dubbed ‘NT4’. Purification of TDO2‐EVs by size‐exclusion chromatography and RNAse protection assays demonstrated that NT4 is encapsulated inside EVs. Consistently with TDO2‐CCM, macrophages exposed to NT4 showed suppression of the inflammatory and cell stress mediators, particularly p21/cdkn1a. NT4‐depleted TDO2‐CCM resulted in diminished immunomodulatory capacity. Finally, administration of NT4 alone was cardioprotective in an acute model of myocardial infarction. Taken together, these findings elucidate the mechanism by which TDO2 augmentation mediates potency in secreted EVs through enrichment of NT4 which suppresses upstream cell stress mediators including p21/cdkn1a