Aims Mesenchymal stromal cells (MSCs) gradually become attractive candidates for cardiac inflammation modulation, yet understanding of the mechanism remains elusive. Strikingly, recent studies indicated that exosomes secreted by MSCs might be a novel mechanism for the beneficial effect of MSCs transplantation after myocardial infarction. We therefore explored the role of MSC-derived exosomes (MSC-Exo) in the immunomodulation of macrophages after myocardial ischaemia/reperfusion (I/R) and its implications in cardiac injury repair. Methods and results Exosomes were isolated from the supernatant of MSCs using gradient centrifugation method. Administration of MSC-Exo to mice through intramyocardial injection after myocardial I/R reduced infarct size and alleviated inflammation level in heart and serum. Systemic depletion of macrophages with clodronate liposomes abolished the curative effects of MSC-Exo. MSC-Exo modified the polarization of M1 macrophages to M2 macrophages both in vivo and in vitro . miRNA sequencing of MSC-Exo and bioinformatics analysis implicated miR-182 as a potent candidate mediator of macrophage polarization and toll-like receptor 4 (TLR4) as a downstream target. Diminishing miR-182 in MSC-Exo partially attenuated its modulation of macrophage polarization. Likewise, knock down of TLR4 also conferred cardioprotective efficacy and reduced inflammation level in a mouse model of myocardial I/R. Conclusion Our data indicate that MSC-Exo attenuates myocardial I/R injury in mice via shuttling miR-182 that modifies the polarization status of macrophages. This study sheds new light on the application of MSC-Exo as a potential therapeutic tool for myocardial I/R injury.

Dietary plants and herbal preparations have been traditionally used as medicine in developing countries and obtained a resurgence of use in the United States and Europe. Research carried out in last few decades has validated several such claims of use of traditional medicine plants. Popularity of pumpkin in various systems of traditional medicine for several ailments (antidiabetic, antihypertensive, antitumor, immunomodulation, antibacterial, antihypercholesterolemia, intestinal antiparasitia, antiinflammation, antalgic) focused the investigators' attention on this plant. Considerable evidence from several epidemiological studies concerning bioactivities leads have stimulated a number of animal model, cell culture studies and clinical trials designed to test this pharmacological actions. In addition, it was found that technologies such as germination and fermentation could reduce antinutritional materials and affect the pharmacological activities of pumpkin. This review will focus on the main medicinal properties and technologies of pumpkin, and point out areas for future research to further elucidate mechanisms whereby this compound may reduce disease risk.

WW domains are protein modules that mediate protein-protein interactions through recognition of prolinerich peptide motifs and phosphorylated serine/threonine-proline sites. To pursue the functional properties of WW domains, we employed mass spectrometry to identify 148 proteins that associate with 10 human WW domains. Many of these proteins represent novel WW domain-binding partners and are components of multiprotein complexes involved in molecular processes, such as transcription, RNA processing, and cytoskeletal regulation. We validated one complex in detail, showing that WW domains of the AIP4 E3 proteinubiquitin ligase bind directly to a PPXY motif in the p68 subunit of pre-mRNA cleavage and polyadenylation factor Im in a manner that promotes p68 ubiquitylation. The tested WW domains fall into three broad groups on the basis of hierarchical clustering with respect to their associated proteins; each such cluster of bound proteins displayed a distinct set of WW domain-binding motifs. We also found that separate WW domains from the same protein or closely related proteins can have different specificities for protein ligands and also demonstrated that a single polypeptide can bind multiple classes of WW domains through separate prolinerich motifs. These data suggest that WW domains provide a versatile platform to link individual proteins into physiologically important networks.Many signaling proteins contain modular domains that mediate specific protein-protein interactions, frequently through the recognition of short peptide motifs in their binding partners (56). In many cases these interactions are regulated by posttranslational modifications, such as phosphorylation. Interaction domains can thereby control the subcellular localization, enzymatic activity, and substrate specificity of regulatory proteins and the assembly of multiprotein complexes, and thus the flow of information through signaling pathways.WW domains comprise a family of protein-protein interaction modules that are found in many eukaryotes and are present in approximately 50 human proteins (6; see Fig. 1). Within these polypeptides, WW domains are joined to a number of distinct interaction modules, including phosphotyrosinebinding domains (i.e., in the FE65 protein) and FF domains (CA150 and FBP11), as well as protein localization domains, such as C2 (NEDD4 family proteins) and pleckstrin homology domains (PLEKHA5). WW domains are also linked to a variety of catalytic domains, including HECT E3 protein-ubiquitin ligase domains (in NEDD4 family proteins), rotomerase/peptidyl prolyisomerase domains (Pin1), and Rho GTPase-activating protein domains. Consequently, WW domain-containing proteins are involved in a variety of cellular processes, including transcription, RNA processing, protein trafficking, receptor signaling, and control of the cytoskeleton (32,33,68). WW domain-mediated interactions have been implicated in cancer (4, 75), in hereditary disorders, such as Liddle's syndrome (66) and Rett's syndrome (8), as well as in Alzheimer's (46, ...

Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases. This may promote Lyn and Syk ubiquitination in a fashion that contributes to a block in B-cell signaling. LMP2A may potentiate a normal mechanism by which Nedd4 family E3 enzymes regulate B-cell signaling.

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Oligomeric proanthocyanidins were extracted from mangosteen pericarps and fractionated by a Sephadex LH-20 column to give 0.66% yield (dry matter). (13)C and (1)H NMR signals showed the presence of predominantly procyanidins together with a few prodelphinidin units along with small amounts of stereoisomers of afzelechin/epiafzelechin, catechin/epicatechin, and gallocatechin/epigallocatechin. Depolymerization with benzylmercaptan resulted in epicatechin thioether as the major product, and the mean degree of polymerization was determined to be 6.6. The electron spray ionization-mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectra revealed the dominant B type oligomers with mainly epicatechin units and with a small amount of A type oligomers. The isolated proanthocyanidins are potent peroxyl radical scavengers as evidenced by the high oxygen radical scavenging capacity at 1.7 x 10 (4) micromol TE/g, much higher than that of pine bark and grape seed extracts.