Albumin and apolipoprotein H mRNAs in human plasma as potential clinical biomarkers of liver injury: analyses of plasma liver-specific mRNAs in patients with liver injury

Apolipoprotein-H (Apo-H, Mw ≃ 50 kDa) is a carbohydrate-rich human-plasma protein which exists in blood serum in the free form as well as distributed between several classes of lipoproteins. Single crystals of apo-H have been obtained and crystallographic data sets have been collected. The crystals belong to the orthorhombic space group C2221, with cell dimensions a = 158.47, b = 169.25, c = 113.28 Å (at 100 K). The data indicate that the crystallographic asymmetric unit contains one tetramer of the protein.

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Posttransplantation Bone Marrow Assessment by Quantifying Hematopoietic Cell–Derived mRNAs in Plasma Exosomes/Microvesicles

Clinical Chemistry ◽

10.1373/clinchem.2013.213850 ◽

2014 ◽

Vol 60 (4) ◽

pp. 675-682 ◽

Cited By ~ 20

Author(s):

Jun Aoki ◽

Kazuteru Ohashi ◽

Masato Mitsuhashi ◽

Taku Murakami ◽

Melanie Oakes ◽

...

Keyword(s):

Bone Marrow ◽

Human Plasma ◽

Medical Procedure ◽

Rt Pcr ◽

Hematopoietic Stem ◽

Reverse Transcription Pcr ◽

Hematological Analysis ◽

Hematopoietic Precursor ◽

Specific Mrnas ◽

New Biomarkers

Abstract BACKGROUND Bone marrow (BM) aspiration often can be a painful medical procedure. It is unavoidable, however, because hematopoietic precursor cells (HPC) exist only in BM and few escape to peripheral blood (PB). We hypothesized that HPCs might release exosomes and microvesicles (EMV) in BM, and the resulting EMV would penetrate into PB. Such BM-derived EMV might be identified in PB by measuring specific mRNAs produced by HPC. METHODS Human plasma was applied to an EMV-capture filter plate. After centrifugation, captured EMV were lysed on the filter plate. Resulting lysates were transferred to an oligo(dT)-immobilized microplate for mRNA isolation followed by reverse transcription PCR (RT-PCR). Using this system, myeloid-, erythroid-, and megakaryocyte-lineage–specific poly(A)+ mRNAs were quantified in plasma obtained from 18 patients who had undergone hematopoietic stem cell transplantation (HSCT). RESULTS When fluorescent liposomes were applied to the filter plate, more than 95% of applied liposomes were absorbed. When human plasma was applied, a scanning electron microscope showed EMV-like particles on the membrane of the filter plate. After RT-PCR, various HPC-specific mRNAs were detected, and the results were equivalent to those derived from the standard ultracentrifugation method. The levels of these mRNAs were undetectable after HSCT and became detectable 1–2 weeks after HSCT, a substantially earlier time point than with traditional hematological analysis. The recovery of EMV mRNA at day 15 corresponded to the final clinical outcome at day 180. CONCLUSIONS HPC-derived mRNAs in plasma EMV may represent new biomarkers for the assessment of BM condition and could reduce the necessity for frequent BM aspiration.

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The Development of Clinical Biomarkers for the Safety Use of Medications Using Toxicogenomics Approaches: The Predictive Methods for the Development of Flutamide-Induced Liver Injury

Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics ◽

10.3999/jscpt.47.173 ◽

2016 ◽

Vol 47 (4) ◽

pp. 173-175

Author(s):

Hitoshi ANDO

Keyword(s):

Liver Injury ◽

Clinical Biomarkers ◽

Predictive Methods

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Hepatitis B virus Dane particles bind to human plasma apolipoprotein H

Hepatology ◽

10.1053/jhep.2001.20531 ◽

2001 ◽

Vol 33 (1) ◽

pp. 207-217 ◽

Cited By ~ 27

Author(s):

I Stefas

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Human Plasma ◽

Apolipoprotein H ◽

B Virus ◽

Dane Particles ◽

Plasma Apolipoprotein

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Identification of Novel Liver-Specific mRNAs in Plasma for Biomarkers of Drug-Induced Liver Injury and Quantitative Evaluation in Rats Treated With Various Hepatotoxic Compounds

Toxicological Sciences ◽

10.1093/toxsci/kfs340 ◽

2013 ◽

Vol 132 (1) ◽

pp. 21-31 ◽

Cited By ~ 12

Author(s):

Shingo Okubo ◽

Makoto Miyamoto ◽

Kenji Takami ◽

Masayuki Kanki ◽

Atsushi Ono ◽

...

Keyword(s):

Liver Injury ◽

Quantitative Evaluation ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Specific Mrnas

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Absolute measurement of the tissue origins of cell-free DNA in the healthy state and following paracetamol overdose

10.1101/715888 ◽

2019 ◽

Cited By ~ 1

Author(s):

Danny Laurent ◽

Fiona Semple ◽

Philip J. Starkey Lewis ◽

Elaine Rose ◽

Holly A. Black ◽

...

Keyword(s):

Liver Injury ◽

Absolute Measurement ◽

Clinical Samples ◽

Mouse Strains ◽

Cell Free Dna ◽

Tissue Specific ◽

Apap Overdose ◽

Clinical Biomarkers ◽

Free Dna ◽

Clinical Biomarker

AbstractBackgroundDespite the emergence of cell-free DNA (cfDNA) as a clinical biomarker in cancer, the tissue origins of cfDNA in healthy individuals have to date been inferred only by indirect and relative measurement methods, such as tissue-specific methylation and nucleosomal profiling.MethodsWe performed the first direct, absolute measurement of the tissue origins of cfDNA, using tissue-specific knockout mouse strains, in both healthy mice and following paracetamol (APAP) overdose. We then investigated the utility of total cfDNA and the percentage of liver-specific cfDNA as clinical biomarkers in patients presenting with APAP overdose.ResultsAnalysis of cfDNA from healthy tissue-specific knockout mice showed that cfDNA originates predominantly from white and red blood cell lineages, with minor contribution from hepatocytes, and no detectable contribution from skeletal and cardiac muscle. Following APAP overdose in mice, total plasma cfDNA and the percentage fraction originating from hepatocytes increased by ~100 and ~19-fold respectively. Total cfDNA increased by an average of more than 236-fold in clinical samples from APAP overdose patients with biochemical evidence of liver injury, and 18-fold in patients without biochemically apparent liver injury. Measurement of liver-specific cfDNA, using droplet digital PCR and methylation analysis, revealed that the contribution of liver to cfDNA was increased by an average of 175-fold in APAP overdose patients with biochemically apparent liver injury compared to healthy subjects, but was not increased in overdose patients with normal liver function tests.ConclusionsWe present a novel method for measurement of the tissue origins of cfDNA in healthy and disease states and demonstrate the potential of cfDNA as a clinical biomarker in APAP overdose.

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A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients

Toxicological Sciences ◽

10.1093/toxsci/kfz138 ◽

2019 ◽

Cited By ~ 1

Author(s):

Mireia López-Riera ◽

Isabel Conde ◽

José V Castell ◽

Ramiro Jover

Keyword(s):

Liver Injury ◽

Time Course ◽

Operating Characteristic ◽

Characteristic Curve ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Hepatocellular Damage ◽

Clinical Biomarkers ◽

Diagnosis And Classification ◽

First Time

AbstractDrug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.

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