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1.
J Burn Care Res ; 38(1): e133-e143, 2017.
Article in English | MEDLINE | ID: mdl-26204385

ABSTRACT

The objective of this study was to determine whether urine ubiquitin levels are elevated after burns and to assess whether urine ubiquitin could be useful as a noninvasive biomarker for burn patients. Forty burn patients (%TBSA: 20 ± 22; modified Baux scores: 73 ± 26) were included (control: 11 volunteers). Urine was collected in 2-hour intervals for 72 hours, followed by 12-hour intervals until discharge from the intensive care unit. Ubiquitin concentrations were analyzed by enzyme linked immunosorbent assay and Western blot. Total protein was determined with a Bradford assay. Patient characteristics and clinical parameters were documented. Urine ubiquitin concentrations, renal ubiquitin excretion, and excretion rates were correlated with patient characteristics and outcomes. Initial urine ubiquitin concentrations were 362 ± 575 ng/ml in patients and 14 ± 18 ng/ml in volunteers (P < .01). Renal ubiquitin excretion on day 1 was 292.6 ± 510.8 µg/24 hr and 21 ± 27 µg/24 hr in volunteers (P < .01). Initial ubiquitin concentrations correlated with modified Baux scores (r = .46; P = .02). Ubiquitin levels peaked at day 6 postburn, whereas total protein concentrations and serum creatinine levels remained within the normal range. Total renal ubiquitin excretion and excretion rates were higher in patients with %TBSA ≥20 than with %TBSA <20, in patients who developed sepsis/multiple organ failure than in patients without these complications and in nonsurvivors vs survivors. These data suggest that ubiquitin urine levels are significantly increased after burns. Renal ubiquitin excretion and/or excretion rates are associated with %TBSA, sepsis/multiple organ failure, and mortality. Although these findings may explain previous correlations between systemic ubiquitin levels and outcomes after burns, the large variability of ubiquitin urine levels suggests that urine ubiquitin will not be useful as a noninvasive disease biomarker.


Subject(s)
Burns/mortality , Burns/urine , Ubiquitin/urine , Adult , Aged , Biomarkers/analysis , Blotting, Western , Body Surface Area , Burns/diagnosis , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Injury Severity Score , Linear Models , Male , Middle Aged , Multivariate Analysis , Prognosis , Reference Values , Survival Rate
2.
Mol Diagn Ther ; 12(5): 307-20, 2008.
Article in English | MEDLINE | ID: mdl-18803429

ABSTRACT

Alzheimer disease is the most common cause of dementia, yet its clinical diagnosis remains uncertain until an eventual postmortem histopathology examination. Currently, therapy for patients with Alzheimer disease only treats the symptoms; however, it is anticipated that new disease-modifying drugs will soon become available.Diagnostic tools for detecting Alzheimer disease at an incipient stage that can reliably differentiate the disease from other forms of dementia are of key importance for optimal treatment. Biomarkers have the potential to aid in a correct diagnosis, and great progress has been made in the discovery and development of potentially useful biomarkers in recent years. This includes single protein biomarkers in the cerebrospinal fluid, as well as multi-component biomarkers, and biomarkers based on gene expression. Novel biomarkers that use blood and urine, the more easily available clinical samples, are also being discovered and developed. The plethora of potential biomarkers currently being investigated may soon provide biomarkers that fulfill different functions, not only for diagnostic purposes but also for drug development and to follow disease progression.


Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/urine , Biomarkers , Alzheimer Disease/diagnosis , Amyloid beta-Protein Precursor/blood , Amyloid beta-Protein Precursor/cerebrospinal fluid , Amyloid beta-Protein Precursor/urine , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Biomarkers/urine , Dementia/blood , Dementia/cerebrospinal fluid , Dementia/urine , Humans , Isoprostanes/blood , Isoprostanes/cerebrospinal fluid , Isoprostanes/urine , Ubiquitin/blood , Ubiquitin/cerebrospinal fluid , Ubiquitin/urine , tau Proteins/blood , tau Proteins/cerebrospinal fluid , tau Proteins/urine
3.
Kidney Int ; 72(9): 1043-5, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17943150

ABSTRACT

Normal urine contains thousands of proteins, largely due to the presence of 'exosomes,' tiny vesicles secreted into the urine by renal epithelial cells. These exosomes, demonstrated by Keller and colleagues to be also retrievable from amniotic fluid, offer great promise for future disease biomarker discovery studies.


Subject(s)
Kidney/metabolism , Proteinuria/metabolism , Secretory Vesicles/metabolism , Amniotic Fluid/chemistry , Amniotic Fluid/metabolism , Biomarkers/urine , CD24 Antigen/urine , Calcium-Binding Proteins/urine , Carrier Proteins/urine , Cell Cycle Proteins/urine , Endosomal Sorting Complexes Required for Transport , Epithelium/metabolism , Epithelium/pathology , Humans , Kidney/pathology , Proteinuria/pathology , RNA, Messenger/urine , Ubiquitin/urine
4.
Blood ; 101(5): 1882-90, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-12406900

ABSTRACT

Ubiquitin is suggested to play a key role in essential intracellular functions, such as heat shock response, protein breakdown, and regulation of immune responses. Ubiquitin has also been detected in the extracellular space, but the function and biologic significance is unclear. We describe a new function of extracellular ubiquitin and show that extracellular ubiquitin specifically inhibits ex vivo secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha mRNA expression from peripheral blood mononuclear cells (PBMNCs) in response to endotoxin in a dose-dependent manner. In contrast, the TNF-alpha response to zymosan or Staphylococcus aureus as well as the interleukin-6 (IL-6) and IL-8 responses to endotoxin were unaffected by ubiquitin. Measurement of serum ubiquitin levels showed a significant 5- to 7-fold increase in sepsis and trauma patients, to the level required for inhibition of the PBMNC TNF-alpha response to endotoxin by ubiquitin. Elevated ubiquitin levels in serum were significantly correlated with a reduced TNF-alpha production. Antibodies to ubiquitin were able to (1) significantly increase (2- to 5-fold) the TNF-alpha response to endotoxin in whole blood from trauma and sepsis patients, (2) completely neutralize the inhibitory effect of trauma patients' serum on healthy donors' TNF-alpha production, and (3) partially neutralize the inhibitory effect of sepsis patients' serum on healthy donors' TNF-alpha production. Ubiquitin-depleted serum from trauma patients lost the inhibitory activity for TNF-alpha production, whereas extracted endogenous ubiquitin exerts the inhibitory activity. The results demonstrate that extracellular ubiquitin acts as a cytokinelike protein with anti-inflammatory properties and indicate that extracellular ubiquitin is involved in the regulation of immunodepression in critical illness.


Subject(s)
Endotoxins/pharmacology , Leukocytes, Mononuclear/drug effects , Multiple Trauma/physiopathology , Sepsis/physiopathology , Tumor Necrosis Factor-alpha/metabolism , Ubiquitin/pharmacology , Adult , Animals , Cattle , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Critical Illness , Depression, Chemical , Endotoxins/antagonists & inhibitors , Female , Gene Expression Regulation/drug effects , Humans , Interleukin-6/metabolism , Interleukin-8/metabolism , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Male , Multiple Trauma/metabolism , RNA, Messenger/biosynthesis , Sepsis/metabolism , Shock, Septic/metabolism , Shock, Septic/physiopathology , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/genetics , Ubiquitin/blood , Ubiquitin/urine , Wounds, Nonpenetrating/metabolism , Wounds, Nonpenetrating/physiopathology
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