Accessible miRNAs as Novel Toxicity Biomarkers

Abstract

Novel tissue injury biomarkers have recently been identified that outperform or add value to the conventional safety biomarkers. These novel biomarkers have enhanced sensitivity and/or specificity in monitoring drug-induced tissue injury in a variety of tissues, included liver, kidney, and skeletal muscle. Among these novel biomarkers, microRNAs (miRNAs) are one type in particular that have received much attention in recent years. These microRNAs are short, endogenous noncoding nucleic acids that are involved in modulation and regulation of mRNA transcripts. Other attributes of miRNAs are that they exist in tissues at high abundance, and individual miRNAs can be highly tissue-specific. These miRNAs can be readily assayed in blood, urine, or cerebral spinal fluid, making them attractive as accessible biomarkers of tissue injury. Further, the miRNA processing involves embedding the miRNA within a protein complex, making them stable in plasma upon leakage from injured tissues. This review article will highlight the discovery of tissue-specific miRNAs and their evolution as novel toxicity biomarkers in recent years.

Circulating miRNAs Associated With ER Stress and Organ Damage in a Preclinical Model of Trauma Hemorrhagic Shock

“…Indeed, we found that the most upregulated miRNAs by THS in our study are likely not only involved in organ damage as liver injury (miR-151a-5p), brain injury (miR-135b-5p), and cardiac injury (miR-199a-5p) but there are also miRNAs in this group which are reported to be involved in processes related to ER stress (miR-663a, miR-215-5p) and UPR activities such as cell survival (miR-346) (references are indicated in Supplementary Table 1). Considering the marked release of the miRNAs upon THS, we also assume that the miRNA profile obtained may not only reflect regulation of ER stress and organ injury but also possible cellular disruption followed by a passive release of miRNA into the bloodstream, which was previously observed during drug-induced organ damage (46,47). Furthermore, the upregulation of miR-24-3p (log 2 fold change = 1.79) observed here in the animals subjected to THS (p < 0.001) concurs with the overexpression of miR-24-3p reported in trauma patients associated with trauma-induced coagulopathy by preventing the production of coagulation Factor X (42).…”

Systems analysis of miRNA biomarkers to inform drug safety

“…This issue may be solved by use of panels of multiple miRs, with miR panel profiles having potential to reflect the type of liver injury, such as differentiating between acute or chronic and hepatocellular or cholestatic phenotypes (Yamaura et al 2012). Glaab et al (2018) demonstrated liver-specific (-122, -192) and muscle-specific (-1, -133a/b, -206) miRs outperformed, in terms of sensitivity and specificity, ALT and AST in monitoring the liver and AST and CK for monitoring skeletal muscle for drug-induced injury. The biomarkers were also able to sensitively monitor bile duct injury (necrosis and hyperplasia) seen with ANIT, methapyrilene and phalloidin.…”

“…Table 1 Biofluid-detectable miRs that are altered by toxicants in different organs. Adapted from (Schraml et al 2017;Laterza et al 2009;Wang et al 2009;Saikumar et al 2012;Haghikia et al 2012;Yokoi and Nakajima 2013;Nassirpour et al 2014Nassirpour et al , 2015Ogata et al 2015;Nishimura et al 2015;Piegari et al 2016;Raitoharju et al 2016;Bergman et al 2016;Koenig et al 2016;Yan and Jiao 2016;Rouse et al 2017;Bailey and Glaab 2018;Huang et al 2018;Bailey et al 2019;Erdos et al 2020). The number of targets from miRTarBase to some of the miRs are shown in parentheses.…”

Small RNA Sequencing to Discover Circulating MicroRNA Biomarkers of Testicular Toxicity in Dogs

“…Thus, because miRNAs are readily accessible in biofluids, exhibit tissue-specific expression, and are often conserved across species, they are attractive candidates as translatable safety biomarkers for monitoring organ-specific toxicities. 13,14…”

“…Thus, because miRNAs are readily accessible in biofluids, exhibit tissue-specific expression, and are often conserved across species, they are attractive candidates as translatable safety biomarkers for monitoring organ-specific toxicities. 13,14 One of the first demonstrations of using an miRNA as a tissue injury marker was miR-122 in acetaminophen-induced liver injury. 15 Since then, a large body of literature has reported several candidate miRNAs to detect drug-induced tissue injury and/or disease in rodents and humans; for example, miR-216a in pancreatic injury, miR-21 in kidney injury, and miR-499 in acute myocardial infarction.…”