PubMed · 13485983
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E F LUSCHER. 1957-10-02. [Fibrin-stabilizing factor from thrombocytes].. https://pubmed.ncbi.nlm.nih.gov/13485983/
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OBJECTIVES: Platelet storage lesion (PSL) severely impairs platelet function during storage, presenting a major hurdle in transfusion medicine; however, the dynamic interplay between global proteomic changes and post-translational modifications (PTMs) underlying these functional deteriorations remains insufficiently characterized. Here, we report the first comprehensive multi-omics analysis integrating global proteomics, acetylomics, and succinylomics to dissect the molecular dynamics during platelet storage. METHODS: We performed quantification of global proteomics, acetylome and succinylome based on TMT-labeled LC-MS/MS analysis, combined with antibody-affinity enrichment and purification. Dynamic molecular changes and functional transformation of platelet were also characterized under proper conditions stored for 1, 3, 5, 7 days, respectively. RESULTS: We systematically characterized 3,609 proteins, 1,308 acetylation sites, and 1,947 succinylation sites across multiple storage time points (D1, D3, D5, D7). We distinct temporal patterns of post-translational modifications, with succinylation showing more extensive coverage than acetylation in platelets. Pathway enrichment analysis revealed extensive metabolic reprogramming involving complement activation, energy metabolism, and cellular detoxification processes. The identification of specific motif patterns provided mechanistic insights into the functional specificity of these modifications. Random forest machine learning identified 20 core regulatory proteins representing critical nodes in PSL development. Furthermore, we employed real - time quantitative polymerase chain reaction (RT - QPCR) to measure the expression levels of key genes related to platelet function and PTM - associated pathways. CONCLUSION: By mapping the interplay between proteomic abundance shifts and PTM dynamics, this study provides a multidimensional understanding of PSL, establishing a foundational framework for optimizing storage protocols and enhancing transfusion safety.
The only published report of the purification of native human soluble guanylyl cyclase (sGC) used placenta as starting material. This enzyme preparation showed low fold-activation by NO and a maximal absorption of the prosthetic heme-group at 417nm indicative of a prosthetic heme-group in a hexa-coordinate state. These data are in contrast to what has subsequently been found for the recombinant human enzymes. Apart from this placental enzyme preparation, a native functional human NO-sensitive sGC has not been successfully purified. The aim of the current study was to purify and characterize native human sGC from another source, to see whether the discrepancies between native and recombinant sGC seen for placenta are a general phenomenon. We chose human platelets as starting material since the properties of this enzyme are directly relevant for the development of innovative antiplatelet and antianginal drugs. Our results indicate that the native platelet enzyme exists as a highly NO-sensitive, heterodimeric enzyme with an alpha(1) and beta(1) subunit. In contrast to the native human placental enzyme and in accordance with the human recombinant enzymes, the native human platelet enzyme contains a ferrous, penta-coordinate heme group. To our knowledge this is the first report of the successful purification and characterization of the native human nitric oxide sensitive alpha(1)/beta(1) isoform of sGC which is widely expressed in the cardiovascular system and is an important target of innovative drugs.
Midazolam is widely used as a sedative and anesthetic induction agent. The aim of this study was to systematically examine the inhibitory mechanisms of midazolam in platelet aggregation. In this study, midazolam concentration-dependently (15 and 30 microM) inhibited platelet aggregation in washed human platelets stimulated by thrombin (0.05 U/ml). Midazolam (15 and 30 microM) also inhibited phosphoinositide breakdown and intracellular Ca(+2) mobilization in platelets stimulated by thrombin (0.05 U/ml). In addition, midazolam (15 and 30 microM) increased the formation of cyclic AMP but not cyclic GMP or nitric oxide. The thrombin-evoked increase in pHi was markedly inhibited in the presence of midazolam (15 and 30 microM). Rapid phosphorylation of a platelet protein of molecular weight (Mr.) 47,000 (P47), a marker of protein kinase C activation, was triggered by thrombin (0.05 U/ml). This phosphorylation was markedly inhibited by midazolam (15 and 30 microM). Midazolam (30 microM) did not significantly reduce the electron spin resonance signal intensity of hydroxyl radicals in activated platelets. In the vivo study, intravenous injection of midazolam (10 microg/g) significantly prolonged the latent period of inducing platelet plug formation in mesenteric venules. These results indicate that midazolam can significantly prevent thrombus formation in vivo. Its antiplatelet activity may be involved in the inhibition of the activation of phospholipase C and the Na(+)/H(+) exchanger and increased cyclic AMP formation. These lead to lower intracellular Ca(+2) mobilization and phosphorylation of P47.