Background: Human-induced pluripotent stem cells (hiPSCs) with normal or upregulated levels of CCND2 expression were differentiated into cardiomyocytes (CCND2 WT CMs or CCND2 OE CMs, respectively) and injected into infarcted pig hearts. Methods: Acute myocardial infarction (AMI) was induced via a 60-minute occlusion of the left-anterior descending coronary artery. Immediately after reperfusion, CCND2 WT CMs or CCND2 OE CMs (3×10 7 cells each), or an equivalent volume of the delivery vehicle was injected around the infarct border zone area. Results: The number of the engrafted CCND2 OE CMs exceeded that of the engrafted CCND2 WT CMs from 6 to 8-fold, rising from 1 week to 4 weeks post-implantation. In contrast to the treatment with the CCND2 WT CMs or the delivery vehicle, the administration of CCND2 OE CM was associated with significantly improved left-ventricular function, as revealed by magnetic resonance imaging (MRI). This correlated with the reduction of infarct size, fibrosis, ventricular hypertrophy, CM apoptosis, and the increase of vascular density and arterial density, as per the histological analysis of the treated hearts. Expression of the cell proliferation markers (e.g., Ki67, phosphorylated histone 3 [PH3] and Aurora Kinase B [Aurora B]) was also significantly upregulated in the recipient CMs from the CCND2 OE CM-treated than from the CCND2 WT CM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured hiPSC-CMs were significantly greater after their treatment with exosomes isolated from the CCND2 OE CMs (CCND2 OE Exos) than from the CCND2 WT CMs (CCND2 WT Exos). As demonstrated by our study, CCND2 OE Exos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2 OE Exos vs. CCND2 WT Exos identified 206 and 91 miRNAs that were significantly upand down-regulated, respectively. Gene ontology (GO) enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis. Conclusions: We have demonstrated that an enhanced potency of the CCND2 OE CMs promoted myocyte proliferation in both grafts and the recipient tissue in a large mammal acute myocardial infarction (AMI) model. These results suggest that the CCND2 OE CMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.
The synthesis and biological activities of analogues of the peptide hormone angiotensin II (AT) for use in photoaffinity labeling and receptor isolation are described. In the modified sequence of AT, Sar-Arg-Val-Tyr-Val-His-Pro-Phe, the aromatic residues Tyr and Phe have been either singly or simultaneously replaced by L-4'-nitrophenylalanine, L-4'-amino-3',5'-diiodophenylalanine, L-4'-aminophenylalanine, L-4'-diazoniumphenylalanine, and L-4'-azidophenylalanine. The peptides were assembled by solid-phase synthesis and the functional groups in position 4 and/or 8 chemically modified. Radioactivity was introduced by catalytic tritiation of the iodinated peptides to form the photolabeling precursors containing L-4'-amino-3',5'-diiodophenylalanine. On rabbit aorta the AT analogues substituted in position 4 showed poor affinities (0--15%), in position 8 high relative affinities (16--118%), and in position 4 and 8 additive effects of simultaneous substitutions. It is also shown that the new Boc derivative of L-4'-amino-3',5'-diiodophenylalanine can be used in peptide synthesis without side-chain protection.
BackgroundDrug repositioning is a cost-efficient and time-saving process to drug development compared to traditional techniques. A systematic method to drug repositioning is to identify candidate drug's gene expression profiles on target disease models and determine how similar these profiles are to approved drugs. Databases such as the CMAP have been developed recently to help with systematic drug repositioning.MethodsTo overcome the limitation of connectivity maps on data coverage, we constructed a comprehensive in silico drug-protein connectivity map called DMAP, which contains directed drug-to-protein effects and effect scores. The drug-to-protein effect scores are compiled from all database entries between the drug and protein have been previously observed and provide a confidence measure on the quality of such drug-to-protein effects.ResultsIn DMAP, we have compiled the direct effects between 24,121 PubChem Compound ID (CID), which were mapped from 289,571 chemical entities recognized from public literature, and 5,196 reviewed Uniprot proteins. DMAP compiles a total of 438,004 chemical-to-protein effect relationships. Compared to CMAP, DMAP shows an increase of 221 folds in the number of chemicals and 1.92 fold in the number of ATC codes. Furthermore, by overlapping DMAP chemicals with the approved drugs with known indications from the TTD database and literature, we obtained 982 drugs and 622 diseases; meanwhile, we only obtained 394 drugs with known indication from CMAP. To validate the feasibility of applying new DMAP for systematic drug repositioning, we compared the performance of DMAP and the well-known CMAP database on two popular computational techniques: drug-drug-similarity-based method with leave-one-out validation and Kolmogorov-Smirnov scoring based method. In drug-drug-similarity-based method, the drug repositioning prediction using DMAP achieved an Area-Under-Curve (AUC) score of 0.82, compared with that using CMAP, AUC = 0.64. For Kolmogorov-Smirnov scoring based method, with DMAP, we were able to retrieve several drug indications which could not be retrieved using CMAP. DMAP data can be queried using the existing C2MAP server or downloaded freely at: http://bio.informatics.iupui.edu/cmapsConclusionsReliable measurements of how drug affect disease-related proteins are critical to ongoing drug development in the genome medicine era. We demonstrated that DMAP can help drug development professionals assess drug-to-protein relationship data and improve chances of success for systematic drug repositioning efforts.
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