Packed with biological information, extracellular vesicles (EVs) offer exciting promise for biomarker discovery and applications in therapeutics and non-invasive diagnostics. Currently, our understanding of EV contents is confined by the limited cells from which vesicles have been characterized utilizing the same enrichment method. Using sixty cell lines from the National Cancer Institute (NCI-60), here we provide the largest proteomic profile of EVs in a single study, identifying 6,071 proteins with 213 common to all isolates. Proteins included established EV markers, and vesicular trafficking proteins such as Rab GTPases and tetraspanins. Differentially-expressed proteins offer potential for cancer diagnosis and prognosis. Network analysis of vesicle quantity and proteomes identified EV components associated with vesicle secretion, including CD81, CD63, syntenin-1, VAMP3, Rab GTPases, and integrins. Integration of vesicle proteomes with whole-cell molecular profiles revealed similarities, suggesting EVs provide a reliable reflection of their progenitor cell content, and are therefore excellent indicators of disease.
Histone levels are tightly regulated to prevent harmful effects such as genomic instability and hypersensitivity to DNA damaging agents due to the accumulation of these highly basic proteins when DNA replication slows down or stops. Although chromosomal histones are stable, excess (non-chromatin bound) histones are rapidly degraded in a Rad53 kinase dependent manner in Saccharomyces cerevisiae. Here we demonstrate that excess histones associate with Rad53 in vivo, appear to undergo modifications such as tyrosine phosphorylation and polyubiquitylation, before their proteolysis by the proteasome. We have identified the tyrosine 99 residue of histone H3 as being critical for the efficient ubiquitylation and degradation of this histone. We have also identified the E2 proteins Ubc4 and Ubc5, as well as the E3 ubiquitin ligase Tom1, as enzymes involved in the ubiquitylation of excess histones. Regulated histone proteolysis has major implications for the maintenance of epigenetic marks on chromatin, genomic stability and the packaging of sperm DNA.
The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT1 and CysLT2. The CysLT1 receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT2 receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT1-receptor-mediated effects, and the role of the CysLT2 receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT2-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.
Balanced immune regulation is crucial for recognizing an invading pathogen, its killing, and elimination. Toll-like receptors (TLRs) are the key regulators of the innate immune system. It helps in identifying between self and nonself-molecule and eventually eliminates the nonself. Endosomal TLR, mainly TLR3, TLR7, TLR8, and membrane-bound TLR4, has a role in the induction of cytokine storms. TLR7/8 recognizes the ssRNA SARS-COV-2 and when it replicates to dsRNA, it is recognized by TLR3 and drives the TRIF-mediated inflammatory signaling like NF-κB, MAPK.Such signaling leads to significant transcription and translation of pro-inflammatory genes, releasing inflammatory molecules into the systemic circulation, causing an imbalance in the system. So, whenever an imbalance occurs, a surge in the proinflammatory mediators is observed in the blood, including cytokines like interleukin (IL)-2, IL-4, IL-6, IL-1β, IL-8, interferon (IFN)-γ, tumor necrosis factor (TNF)-α. IL-6 and IL-1β are one of the driving factors for bringing the cytokine storm into the systemic circulation, which migrates into the other organs, causing multiple organ failures leading to the death of the individual with severe illness.
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