It is widely believed that selective packaging of nucleic acids, especially microRNAs, into exosomes secreted by the cancer cells not only ensures their growth and survival but also helps in the escape from immune surveillance. Keeping in view the fact that human cellular miR-2909 has emerged to regulate genes involved in oncogenesis and immunity, the present study was addressed to reveal the nature of miR-2909 expression within cancer cells of different tissue origin and its incorporation into exosomes secreted by these cells. Post-transcriptional modification, especially 3'-end adenylation and uridylation of miR-2909, exerts opposing effects that may contribute to direct its sorting into exosomes secreted by cancer cells. Our study also revealed that selective partitioning of adenosine kinase, between cancer cells and their secreted exosomes, may be responsible for the nature of post-transcriptional modification of miR-2909 observed within these cells.
Exosomes represent secretory membranous vesicles used for the information exchange between cells and organ-to-organ communication. Exosome crosstalk mechanisms are involved in the regulation of several IBD-associated pathophysioloc intestinal processes such as barrier function, immune responses and intestinal flora. Functional biomolecules, mainly non-coding RNAs (ncRNAs), are believed to be transmitted between the mammalian cells via exosomes which likely play important roles in cell-to-cell communication, both locally and systemically. MicroRNAs (miRNAs) encapsulated in exosomes have generated substantial interest because of their critical roles in multiple pathophysiological processes. In addition, exosomal miRNAs are implicated in the gut health. MiRNAs are selectively and actively loaded into the exosomes and then transferred to the target recipient cell where they manipulate cell function through post-transcriptional silencing of target genes. Intriguingly, miRNA profile of exosomes differ from their cellular counterparts suggesting an active sorting and packaging mechanism of exosomal miRNAs. Even more exciting is the involvement of posttranscriptional modifications in the specific loading of miRNAs into exosomes, but the underlying mechanisms of how these modifications direct ncRNA sorting have not been established. This review gives a brief overview of the status of exosomes and exosomal miRNAs in IBD and also discusses potential mechanisms of exosomal miRNA sorting and delivering.
SUMMARYExtrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate “enhancer rewiring” events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.
NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NFkB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3 0 K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3 0 k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively.
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