Exosomes are a subset of nano-sized extracellular vesicles originating from endosomes. Exosomes mediate cell-to-cell communication with their cargos, which includes mRNAs, miRNAs, lncRNAs, and circRNAs. Exosomal RNAs have cell specificity and reflect the conditions of their donor cells. Notably, their detection in biofluids can be used as a diagnostic marker for various diseases. Exosomal RNAs are ideal biomarkers because their surrounding membranes confer stability and they are detectable in almost all biofluids, which helps to reduce trauma and avoid invasive examinations. However, knowledge of exosomal biomarkers remains scarce. The present review summarizes the biogenesis, secretion, and uptake of exosomes, the current researches exploring exosomal mRNAs, miRNAs, lncRNAs, and circRNAs as potential biomarkers for the diagnosis of human diseases, as well as recent techniques of exosome isolation.

/pdf/exosomal-rnas-novel-potential-biomarkers-for-diseases-a-3iolgrpm.pdf

Exosomal RNAs: Novel Potential Biomarkers for Diseases—A Review

Circular RNAs (circRNAs) are a class of covalently closed, endogenous ncRNAs. Most circRNAs are derived from exonic or intronic sequences by precursor RNA back-splicing. Advanced high-throughput RNA sequencing and experimental technologies have enabled the extensive identification and characterization of circRNAs, such as novel types of biogenesis, tissue-specific and cell-specific expression patterns, epigenetic regulation, translation potential, localization and metabolism. Increasing evidence has revealed that circRNAs participate in diverse cellular processes, and their dysregulation is involved in the pathogenesis of various diseases, particularly cancer. In this review, we systematically discuss the characterization of circRNAs, databases, challenges for circRNA discovery, new insight into strategies used in circRNA studies and biomedical applications. Although recent studies have advanced the understanding of circRNAs, advanced knowledge and approaches for circRNA annotation, functional characterization and biomedical applications are continuously needed to provide new insights into circRNAs. The emergence of circRNA-based protein translation strategy will be a promising direction in the field of biomedicine. 

New insight into circRNAs: characterization, strategies, and biomedical applications

The Novel Organic Cation Transporter, OCTN1, is the first member of the OCTN subfamily; it belongs to the wider Solute Carrier family SLC22, which counts many members including cation and anion organic transporters. The tertiary structure has not been resolved for any cation organic transporter. The functional role of OCNT1 is still not well assessed despite the many functional studies so far conducted. The lack of a definitive identification of OCTN1 function can be attributed to the different experimental systems and methodologies adopted for studying each of the proposed ligands. Apart from the contradictory data, the international scientific community agrees on a role of OCTN1 in protecting cells and tissues from oxidative and/or inflammatory damage. Moreover, the involvement of this transporter in drug interactions and delivery has been well clarified, even though the exact profile of the transported/interacting molecules is still somehow confusing. Therefore, OCTN1 continues to be a hot topic in terms of its functional role and structure. This review focuses on the most recent advances on OCTN1 in terms of functional aspects, physiological roles, substrate specificity, drug interactions, tissue expression, and relationships with pathology.

/pdf/octn1-a-widely-studied-but-still-enigmatic-organic-cation-2f38we6t.pdf

OCTN1: A Widely Studied but Still Enigmatic Organic Cation Transporter Linked to Human Pathology and Drug Interactions

Aims This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing regimens. Methods A PBPK model of imatinib was built in the Simcyp Simulator (version 17) integrating in vitro drug metabolism and clinical pharmacokinetic data. The model accounts for ethnic differences in body size and abundance of drug-metabolising enzymes and proteins involved in imatinib disposition. Utility of this model for prediction of imatinib pharmacokinetics was evaluated across different dosing regimens and ethnic groups. The impact of ethnicity on imatinib dosing was then assessed based on the established range of trough concentrations (Css,min ). Results The PBPK model of imatinib demonstrated excellent predictive performance in describing pharmacokinetics and the attained Css,min in patients from different ethnic groups, shown by prediction differences that were within 1.25-fold of the clinically-reported values in published studies. PBPK simulation suggested a similar dose of imatinib (400 - 600 mg/d) to achieve the desirable range of Css,min (1,000 - 3,200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulation indicated that patients of African ancestry may benefit from a higher initial dose (600 - 800 mg/d) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups, however the clinical data to support this are currently limited. Conclusion PBPK simulations highlighted a potential ethnic difference in the recommended initial dose of imatinib, between populations of European and African ancestry, but not populations of Chinese and Japanese ancestry.

Physiologically-based pharmacokinetic model predictions of inter-ethnic differences in imatinib pharmacokinetics and dosing regimens

Circular RNAs (circRNAs) are a new category of endogenous non‐protein coding RNAs (ncRNAs), and show the characteristics of high conservation, stability, and tissue specificity. Due to rapid advances in next‐generation sequencing and transcriptome profiling technologies, circRNAs have been widely discovered in many organisms and participated in the development and progress of a variety of diseases. As a type of molecular sponge, circRNAs mainly absorb micro RNAs competitively and interplay with RNA‐binding proteins to modulate the splicing as well as transcription of target genes.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/iid3.725

Emerging roles of circRNAs in leukemia and the clinical prospects: An update

Background: CircRNA has appeared as a critical molecular in the development of various cancers. However, the cellular function of circRNAs and exosomal circRNAs has not been well explored in Chronic myeloid leukemia (CML). Methods: Differentially expressed circRNAs were identified by a human circRNA microarray analysis. The expression of hsa_circ_0058493 in peripheral blood mononuclear cells (PBMCs) and exosomes was verified using quantitative real-time PCR. Short hairpin RNAs against hsa_circ_0058493 were constructed to silence the expression of circ_0058493. CCK8, flow cytometry and EdU assay were performed to investigate the biological functions of circ_0058493. Results: Hsa_circ_0058493 was significantly overexpressed in the PBMCs of CML patients and high level of circ_0058493 was associated with the poor clinical efficacy of imatinib. Silencing the expression of circ_0058493 significantly inhibited the development of imatinib-resistant CML cells. miR-548b-3p was overexpressed in circ_0058493-downregulated CML cells. Bioinformatic analysis revealed that circ_0058493 might exert its regulatory function acting as a "sponge" of miR-548b-3p. Moreover, hsa_circ_0058493 was significantly enriched in the exosomes derived from imatinib-resistant CML cells. Conclusion: Hsa_circ_0058493 in PBMCs could be a promising prognostic biomarker and might provide a therapeutic target for CML treatment.

/pdf/circrna-microarray-profiling-reveals-hsa-circ-0058493-as-a-20rrej6e28.pdf

CircRNA Microarray Profiling Reveals hsa_circ_0058493 as a Novel Biomarker for Imatinib-Resistant CML.

Purpose: We investigated the relationship between imatinib trough concentrations and genetic polymorphisms with efficacy of imatinib in Chinese patients with chronic myeloid leukemia (CML). Methods: There were 171 eligible patients. Peripheral blood samples were collected from 171 eligible patients between 21 and 27 hours after the last imatinib administration. Complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) were used as metrics for efficacy. Nine single nucleotide polymorphisms in 5 genes, SLC22A4 (917 T>C, -248 C>G and -538 C>G), SLC22A5 (-945 T>G and -1889 T>C), SLCO1A2 (-361 G>A), SLCO1B3 (334 T>G and 699 G>A) and ABCG2 (421C>A) were selected for genotyping. Results: Patients with CCyR achieve higher trough concentrations than those without CCyR (1478.18±659.83 vs 984.89±454.06 ng mL-1, p A achieve higher CCyR and MMR rates (p=0.047, OR=4.320, 95% CI: 0.924-20.206; p=0.042, OR=2.825, 95% CI: 1.016-7.853, respectively). Both trough concentrations and SLCO1A2 -361G>A genotypes are independent factors affecting imatinib efficacy. The positive and negative predictive values for CCyR are 71.01% and 68.75%, respectively. The positive and negative predictive values for MMR are 62.86% and 69.70%, respectively. Conclusion: Imatinib trough concentrations and SLCO1A2 -361G>A genotypes are associated with imatinib efficacy in Chinese patients with CML. Keywords: Efficacy, Imatinib, Polymorphisms, Trough concentration

/pdf/effects-of-trough-concentration-and-solute-carrier-r7vwhzaqgf.pdf

Effects of Trough Concentration and Solute Carrier Polymorphisms on Imatinib Efficacy in Chinese Patients with Chronic Myeloid Leukemia.

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CircRNA Microarray Profiling Reveals hsa_circ_0058493 as a Novel Biomarker for Imatinib-Resistant CML.

Effects of Trough Concentration and Solute Carrier Polymorphisms on Imatinib Efficacy in Chinese Patients with Chronic Myeloid Leukemia.