scholarly journals Accessible miRNAs as Novel Toxicity Biomarkers

2018 ◽  
Vol 37 (2) ◽  
pp. 116-120 ◽  
Author(s):  
Wendy J. Bailey ◽  
Warren E. Glaab
Keyword(s):  
Tissue Injury ◽  
Review Article ◽  
Drug Induced ◽  
Tissue Specific ◽  
Enhanced Sensitivity ◽  
Monitoring Drug ◽  
Toxicity Biomarkers ◽  
Individual Mirnas ◽  
Mrna Transcripts ◽  
Novel Biomarkers

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.

scholarly journals Chimeric Maternal Cells with Tissue-Specific Antigen Expression and Morphology Are Common in Infant Tissues

2009 ◽  
Vol 12 (5) ◽  
pp. 337-346 ◽  
Author(s):  
Anne M. Stevens ◽  
Heidi M. Hermes ◽  
Meghan M. Kiefer ◽  
Joe C. Rutledge ◽  
J. Lee Nelson
Keyword(s):  
Islet Cells ◽  
Tissue Injury ◽  
Specific Antigen ◽  
Antigen Expression ◽  
Cell Types ◽  
Target Cells ◽  
Specific Cell ◽  
Tissue Specific ◽  
Renal Tubular Cells ◽  
Parenchymal Cells

Maternal microchimerism (MMc) has been purported to play a role in the pathogenesis of autoimmunity, but how a small number of foreign cells could contribute to chronic, systemic inflammation has not been explained. Reports of peripheral blood cells differentiating into tissue-specific cell types may shed light on the problem in that chimeric maternal cells could act as target cells within tissues. We investigated MMc in tissues from 7 male infants. Female cells, presumed maternal, were characterized by simultaneous immunohistochemistry and fluorescence in situ hybridization for X- and Y-chromosomes. Maternal cells constituted 0.017% to 1.9% of parenchymal cells and were found in all infants in liver, pancreas, lung, kidney, bladder, skin, and spleen. Maternal cells were differentiated: maternal hepatocytes in liver, renal tubular cells in kidney, and β-islet cells in pancreas. Maternal cells were not found in areas of tissue injury or inflammatory infiltrate. Maternal hematopoietic cells were found only in hearts from patients with neonatal lupus. Thus, differentiated maternal cells are present in multiple tissue types and occur independently of inflammation or tissue injury. Loss of tolerance to maternal parenchymal cells could lead to organ-specific “auto” inflammatory disease and elimination of maternal cells in areas of inflammation.

Abstract 15043: Circulating microRNA as Novel Biomarkers of Doxorubicin Induced Cardiotoxicity

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuri D’Alessandra ◽  
Marta Pontremoli ◽  
Giuseppina Milano ◽  
Alessandro Scopece ◽  
Giulio Pompilio ◽  
...  
Keyword(s):  
Disease Onset ◽  
Recovery Phase ◽  
Circulating Microrna ◽  
Circulating Biomarkers ◽  
Circulating Mirnas ◽  
Drug Induced ◽  
Heart Dysfunction ◽  
New Class ◽  
Novel Biomarkers ◽  
Circulating Levels

Background: Cardiotoxicity is a well-known side effect of Doxorubicin (Dox), leading to drug-induced heart dysfunction. Early prediction of disease onset is difficult, thus a new class of heart impairment biomarkers is needed. A role for miRNAs as circulating biomarkers of Dox-mediated heart dysfunction has never been tested. Purpose: To identify differentially expressed circulating miRNAs of early and late Dox-induced cardiotoxicity using an animal model. Methods: Healthy mice were administered 24 mg/Kg cumulative dose of Dox during a period of 2 weeks followed by 2-month recovery. Cardiotoxicity insurgence was detectable by echocardiography as early as 1 week after treatment. The expression of 367 miRNAs was analyzed in plasma samples from treated and untreated animals (n=6/group) at the end of the treatment (2 weeks) and 2 months post-administration (recovery phase) followed by singleplex qPCR validation of all miRNAs of interest. Results: We identified 5 Dox-regulated miRNAs of acute phase. MiR-34a, -34c, and -133a showed an upregulation (6.5, 14.9, and 15 folds, respectively, p≤0.01), whereas miR-16 and miR-451 were negatively regulated by the drug (-2.7 and -2.8 folds, respectively, p<0.05). We then investigated the expression of these miRNAs 2 months after the end of the treatment, but none showed a significant modulation. Conversely, miR-326 was positively regulated by Dox in the plasma of mice after 2 months of recovery (1.53 folds, p<0.05). Conclusions: This is the first study investigating the possible use of circulating miRNAs as biomarkers of both early and post-treatment Dox-induced cardiotoxicity. Our results revealed a strong regulation of 5 plasmatic miRNAs in response to early damage. Early responders returned to basal levels of expression 2 months after drug administration, indicating an acute damage induced release. This prompts for further studies in the clinical setting to test their suitability as toxicity markers beside cardiac troponin. By contrast, we could not identify strong markers of late damage, apart from a marginal difference in miR-326 circulating levels.

scholarly journals Mitophagy: mechanisms, pathophysiological roles, and analysis

2012 ◽  
Vol 393 (7) ◽  
pp. 547-564 ◽  
Author(s):  
Wen-Xing Ding ◽  
Xiao-Ming Yin
Keyword(s):  
Cell Death ◽  
Blood Cells ◽  
Energy Homeostasis ◽  
Recent Progress ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Terminal Differentiation ◽  
Cellular Functions ◽  
Drug Induced ◽  
Cellular Energy

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.

scholarly journals Systems analysis of miRNA biomarkers to inform drug safety

2021 ◽  
Author(s):  
Amy L. Schofield ◽  
Joseph P. Brown ◽  
Jack Brown ◽  
Ania Wilczynska ◽  
Catherine Bell ◽  
...  
Keyword(s):  
Drug Safety ◽  
Systems Approach ◽  
Tissue Injury ◽  
Point Of Care ◽  
Future Research ◽  
Drug Induced ◽  
Rna Molecules ◽  
Extracellular Milieu ◽  
Point Of Care Test ◽  
Organ Systems

AbstractmicroRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.

Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs

2014 ◽  
Vol 280 (1) ◽  
pp. 30-35 ◽  
Author(s):  
Xiaobing Zhou ◽  
Ben Ma ◽  
Zhi Lin ◽  
Zhe Qu ◽  
Yan Huo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Beagle Dogs ◽  
Drug Induced ◽  
Novel Biomarkers

scholarly journals New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity

2018 ◽  
Vol 46 (8) ◽  
pp. 1002-1005
Author(s):  
Mary B. Nabity ◽  
Joseph W. Polli ◽  
Vishal Vaidya ◽  
Andrzej Krolewski ◽  
Warren E. Glaab
Keyword(s):  
Renal Toxicity ◽  
Kidney Injury ◽  
Scientific Session ◽  
Diabetic Patients ◽  
Drug Induced ◽  
Research Areas ◽  
Novel Biomarkers ◽  
Mechanistic Basis ◽  
New Research

A scientific session entitled “New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity” focused on novel biomarkers to monitor kidney injury both preclinically and clinically, as well as providing mechanistic insight of the induced injury. Further, the role and impact of kidney membrane transporters in drug-induced kidney toxicity provided additional considerations when understanding kidney injury and the complex role of drug transporters in either sensitivity or resistance to drug-induced injury. The onset of nephropathy in diabetic patients was also presented, focusing on the quest to discover novel biomarkers that would differentiate diabetic populations more susceptible to nephropathy and renal failure. The session highlighted exciting new research areas and novel biomarkers that will enhance our understanding of kidney injury and provide tools for ensuring patient safety clinically.

Distinct Apoptotic Responses Imparted by c-myc and max

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 1003-1010 ◽  
Author(s):  
Chadd E. Nesbit ◽  
Saijun Fan ◽  
Hong Zhang ◽  
Edward V. Prochownik
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Ectopic Expression ◽  
Drug Induced ◽  
Enhanced Sensitivity ◽  
Contrast Enhanced ◽  
Apoptotic Pathways ◽  
American Society ◽  
Induced Apoptosis ◽  
Cytokine Deprivation

Abstract The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc– and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc–overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc–overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways. © 1998 by The American Society of Hematology.

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