Clinical value of serum DJ-1 in lung adenocarcinoma.

Objective: DJ-1 is an oncoprotein secreted by cancer cells. However, the physiological and pathological significance of DJ-1 secretion is not clearly understood. This study investigated the clinical value of serum DJ-1 in lung adenocarcinoma (LUAD). Methods: The study involved 224 LUAD patients, 110 patients with benign pulmonary disease and 100 healthy controls from the First Affiliated Hospital of Nanjing Medical University. We detected the expression of DJ-1 in lung cell lines in vitro. Meanwhile, serum concentrations of DJ-1, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment (CYFRA21-1) were measured. The diagnostic performance of LUAD was obtained using receiver operating characteristic (ROC) curves. Kaplan-Meier, univariate and multivariate Cox regression analyses were performed for progression-free survival (PFS). Results: DJ-1 was highly expressed in LUAD cell lines. Serum DJ-1 levels were significantly higher in the LUAD group compared to the benign pulmonary disease group (5.04 vs. 3.66 ng/mL, P < 0.001) and healthy controls (5.04 vs. 3.51 ng/mL, P < 0.001). DJ-1 levels were associated with gender (P = 0.002), smoking history (P = 0.042) and lymph node metastasis (P = 0.040). ROC curve analysis of DJ-1 revealed an area under the curve (AUC) of 0.758 (95% CI [0.714-0.803], P < 0.001) with a sensitivity of 63.8% and specificity of 78.6% at a cutoff value of 4.62 ng/mL for the detection of LUAD. Univariate and multivariate analyses confirmed that the preoperative serum DJ-1 level, tumor stage and smoking history were independent prognostic factors of PFS. Conclusion: Our study is the first to explore the clinical value of serum DJ-1 in LUAD comprehensively. Serum DJ-1 could be a potential diagnostic and prognostic biomarker for LUAD.

Effects of butylphthalide on the levels of serum C-reactive protein, Parkinson disease protein 7 and neurotrophin-3 and neurological function in patients with acute cerebral infarction.

To explore the effects of butylphthalide on the levels of serum CRP, PAPK7, NT-3 and neurological function in patients with acute cerebral infarction (ACI). 120 patients with ACI who were treated at Peking University First Hospital from September 2014 to June 2016 were selected as the research objects. The patients were randomly divided into a control group and an observation group, with 60 cases in each group. Conventional methods were adopted in the control group, and the observation group used butylphthalide for treatment. Two months later, the clinical efficacy, serum C-reactive protein (CRP), Parkinson's disease protein 7 (PAPK7), neurotrophic factor-3 (NT-3) levels, and the National Institutes of Health Stroke Scale (NIHSS) score before and after treatment were put into comparison and analysis. Before treatment, the NIHSS score showed no significant difference between the two groups (p>0.05); An observably higher NIHSS score of the observation group compared with the control group was seen after treatment (p=0.000). Butylphthalide has a significant therapeutic effect on patients with ACI. It can effectively restore the patients' neurological function, and remarkably improve the serum CRP, PAPK7 and NT-3 levels, which is worthy of clinical promotion.

A longitudinal study of alterations of circulating DJ-1 and miR203a-3p in association to olanzapine medication in a sample of first episode patients with schizophrenia.

Among different proposed pathophysiological mechanisms, redox imbalance has been suggested to be a potential contributor in the pathogenesis of schizophrenia. DJ-1 is a redox-sensitive protein that has been shown to have neuroprotective function in the brain in Parkinson's disease and other neurodegenerative diseases. However, a role for DJ-1 in schizophrenia is unknown. Bioinformatic analysis suggested that microRNA (miR)-203a-3p could target the 3' untranslated region (UTR) of DJ-1. In whole blood and blood-derived exosomes of 11 first episode antipsychotic naïve schizophrenia patients, DJ-1 protein and mRNA demonstrated decreased DJ-1 mRNA and protein and increased miR203a-3p levels compared to healthy controls. In whole blood, antipsychotic monotherapy with olanzapine for 6 weeks increased DJ-1 and attenuated miR203a-3p levels, whereas in blood derived exosomes, olanzapine returned DJ-1 and miR203a-3p to levels seen healthy controls. Consistent with this finding, we showed that human umbilical vein endothelial cells (HUVACs) transfected with a DJ-1-3' UTR luciferase reporter construct displayed reduced gene expression when subjected to the oxidative stressor H2O2. Transfection of a miR203a-3p mimic into HUVACs reduced DJ-1-3 'UTR reporter gene expression, while transfection of an anti miR-203a-3p prevented the H2O2-induced downregulation of the reporter gene. We conclude that miR-203a-3p is an essential mediator of oxidative stress in schizophrenia via its ability to target the 3' UTR of DJ-1 and antipsychotic monotherapy restores DJ-1 antioxidant levels by regulating miR203a-3p expression. miR-203a-3p and DJ-1 might represent attractive targets for the treatment of pathologies such as schizophrenia that has underlying oxidative stress.

Flexible platinum electrodes as electrochemical sensor and immunosensor for Parkinson's disease biomarkers.

In this study, platinum electrodes were fabricated on the bio-based poly(ethylene terephthalate) (Bio-PET) substrates for the development of flexible electrochemical sensors for the detection of Parkinson's disease biomarkers. Dopamine was detected by voltammetric measurements, displaying a 3.5 × 10-5 mol L-1 to 8.0 × 10-4 mol L-1 linear range with a limit of detection of 5.1 × 10-6 mol L-1. Parkinson's disease protein 7 (PARK7/DJ-1) was successfully detected by electrochemical impedance spectroscopy after electrode functionalization with specific anti-PARK7/DJ-1 antibodies. In this case, analytical curves presented a linear behavior from 40 ng mL-1 to 150 ng mL-1 of PARK7/DJ-1 with a limit of detection of 7.5 ng mL-1. Besides, the electrodes did not suffer any change in the electrochemical response after manual tests of mechanical tension. The proposed sensor and immunosensor were applied for the determination of Parkinson's disease biomarkers concentrations found in the human body, being adequate as an alternative method to diagnose this disease.

Expression and significance of Parkinson disease protein 7 in placental, serum and umbilical cord blood in preeclampsia.

OBJECTIVES: To study the role of changes in the expression of human Parkinson's disease protein 7 (PARK7/DJ-1) in preeclampsia. MATERIAL AND METHODS: We selected 120 gravidas, including 60 cases of severe preeclampsia group and control group, and divided into early onset preeclampsia group (< 34 weeks), late onset preeclampsia group (≥ 34 weeks) and control group according to the onset of pregnancy. The expression level of DJ-1 was detected by ELISA. The expression level of DJ-1 in placenta tissue of gravidas was detected by Western-blot and RT-PCR. RESULTS: The level of DJ-1 in serum and cord blood of preeclampsia group was higher than that of control group. The relative level of DJ-1 protein and DJ-1 mRNA in placenta tissue of preeclampsia group was higher than that of control group. CONCLUSIONS: The expression level of DJ-1 in serum, umbilical cord blood and placenta tissue increased in preeclampsia patients, suggesting that DJ-1 may take part in the pathophysiology process of preeclampsia.

NRG-1 Stimulates Serum DJ-1 Increase in Breast Cancers.

To explore the relationship between the expression of DJ-1/HER3 and tumor grade in breast cancer, and investigate the effect of HER3 on NRG-1-mediated serum DJ-1 level in vivo. We analyze the expression level of DJ-1 and HER3 in 68 patients with different grades of breast cancer by immunostaining the tissue microarray. Besides, we investigated the serum DJ-1 level by ELISA. We found that the detectable DJ-1 protein expression is decreased, and the HER3 expression is increased in tumor tissue with the progression of breast cancer. There is a significant rise of DJ-1 in serum in vivo with the stimulation of NRG-1. Meanwhile, we found that HER3 knockdown abolishes NRG-1-induced serum DJ-1 increase and HER3 overexpress improves NRG-1-induced serum DJ-1 increase. This study provides a serum biomarker for breast cancer. The results showed that DJ-1 was associated with clinical stage of breast cancer, and NRG-1 increased the dissociation of HER3 and DJ-1, with promoting the level of DJ-1 in peripheral blood. It is suggested that the level of DJ-1 in peripheral blood may be conducive to assess the prognosis of patients with breast cancer and serum DJ-1 levels can serve as an indicator of therapeutic effectiveness for the development of HER3 targeting breast cancer antibody therapies.

Elevation of Serum PARK7 and IL-8 Levels Is Associated With Acute Lung Injury in Patients With Severe Sepsis/Septic Shock.

OBJECTIVE: Methods containing only clinical information fail to meet the needs of prediction of acute lung injury (ALI) because of the relatively low positive predictive value. This study aimed to investigate the feasibility of using biomarkers as predictors of ALI in populations with severe sepsis/septic shock and to explore difference among biomarkers after adjustment for potential confounders. METHODS: Serum specimens were collected from patients with severe sepsis/septic shock (n = 172) presented to the emergency department. Patients should be ruled out from the study if they were already suffering from ALI or if they deteriorated into ALI within 6 hours after specimen collection. The development of ALI of the remaining patients was tracked. RESULTS: Of all patients with severe sepsis/septic shock who encountered ALI more than 6 hours succeeding to specimen collection, 19 deteriorated into ALI. Elevation in serum interleukin 8 (IL-8) and Parkinson disease 7 (PARK7) levels had significant connection with higher risk of developing ALI (P = .006; P = .0001). Sepsis treatment and vasopressor application led to a robust connection between PARK7 and succeeding ALI development. Patients who deteriorated into ALI were distinguished accurately from patients who avoided ALI using PARK7 or Lung Injury Prediction Score (LIPS; area under the receiver operating characteristic curve [AUROC], 0.73 and 0.72 for each). Combination of PARK7 and LIPS ameliorated AUROC to 0.86 (vs 0.73, P = .05). On the contrary, serum soluble receptor for advanced glycation end products and von Willebrand factor made no contribution to the prediction of ALI development. CONCLUSIONS: Patients with PARK7 or IL-8 levels above normal are more vulnerable to ALI. Patients vulnerable to ALI can be distinguished with the combination of serum biomarkers and clinical prediction scores. In addition, the early rise in PARK7 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.

Role of PARK7 and NDKA in stroke management: a review of PARK7 and NDKA as stroke biomarkers.

AIM: Biomarkers are molecules measured in plasma, serum or other body fluids to characterize a disease. PARK7 and NDKA roles in the management of stroke are still on study. Therefore, their potentials need to be developed in totality. The aim of this review is to demonstrate that PARK7 and NDKA could present more clinical important information as biomarkers for management of stroke disease. Main contents: Four main aspects of PARK7 and NDKA are exploited in this review. First, their diagnostic value is discussed in order to demonstrate their possible role as stroke diagnosis markers. Second, this article will exploit the correlation of both markers with time, by showing their dynamic changes in serum and plasma. Third, it describes the observed relationship of their levels with NIH Stroke Scale. The last aspect visits the possibility of their implementation in stroke therapy. CONCLUSION: This article explores recent findings and proposes the potential roles that PARK7 and NDKA play in the management of acute stroke disease.

DJ-1 is a useful biomarker for invasive extrahepatic cholangiocarcinoma.

We have previously reported that DJ-1 protein is up-regulated in cholangiocarcinoma compared with non-neoplastic epithelium of the bile duct in a study using liquid-chromatography mass spectrometry-based proteomics. The aim of this study was to clarify whether DJ-1 expression offers a biomarker for patients with invasive extrahepatic cholangiocarcinoma (EHCC) who undergo surgical resection with curative intent. Positive immunohistochemical (IHC) staining of DJ-1 was significantly more frequent in the cytoplasm of 96 invasive EHCCs (n = 28, 29.2%) than in that of 66 non-neoplastic epithelial lesions adjacent to invasive EHCC (n = 7, 10.6%; P = .006). No significant difference in clinicopathological features was evident between invasive EHCC patients with negative (n = 68) and positive (n = 28) IHC staining. However, negative IHC staining for DJ-1 in cytoplasm was selected as an independent risk factor for adverse prognosis on multivariate analysis (P = .004, hazard ratio 2.13, 95% confidence interval 1.28-3.57). Serum levels of DJ-1 in 16 invasive EHCC patients with metastasis were compared with 12 invasive EHCC patients without metastasis. Serum levels of DJ-1 tended to be higher in 16 patients with metastasis (median, 40.9 ng/ml) than in 12 patients without (27.6 ng/ml, P = .137). In addition, patients with high serum levels (≥ 40 ng/ml) of DJ-1 tended to have metastasis more frequently than those without (P = .054, Fisher's exact test). We concluded that IHC staining pattern and serum level of DJ-1 in patients with invasive EHCC might be predictive of prognosis and metastasis, respectively.

The clinical significance of DJ-1 and HE4 in patients with endometrial cancer.

BACKGROUND: The non-invasive diagnostic approach for early detection of endometrial cancer (EC) remains limited. To date, human epididymis protein 4 (HE4) has been intensively studied but its diagnostic is controversial in EC. DJ-1 is an oncoprotein secreted by cancer cells, recently identified as a potential diagnostic biomarker for breast cancer, melanoma, and pancreatic cancer. The aim of this study was to compare the diagnostic performances of DJ-1 and HE4 measured in EC patients and healthy controls (HC). METHODS: Forty-five patients (63.9±12.0 years) with EC and 29 (63.2±13.3 years) HC were enrolled. Serum concentrations of DJ-1 and HE4 were measured using ELISA kits developed by R&D (Minneapolis, USA) and Fujirebio Diagnostic (Malvern, PA, USA), respectively. Differences between EC patients and HC were assessed by Mann-Whitney test and associations were tested by Spearman's correlation. The diagnostic performance was assessed using receiver operating characteristics (ROC) curves analysis. RESULTS: Serum DJ-1 concentrations were found to be higher in EC patients than in HC (9533.6 vs 1988.5 pg/mL; P<.0001). The area under the ROC curve (ROC-AUC) was 0.95 (P<.0001). At the cut-off of 3654 pg/mL, the sensitivity and specificity were 0.89 and 0.90, respectively. HE4 serum levels were higher in EC patients than in HC (75.3 vs 56.2 pmol/L; P=.019), with an AUC of 0.66 (P=.020). The AUC obtained by the combination of the two markers resulted 0.96 (P<.0001). CONCLUSION: These results suggest that increased serum DJ-1 levels are associated with EC and that this biomarker may be potentially useful for diagnosing EC.

Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease.

Exercise has been recommended to improve motor function in Parkinson patients, but its value in altering progression of disease is unknown. In this study, we examined the neuroprotective effects of running wheel exercise in mice. In adult wild-type mice, one week of running wheel activity led to significantly increased DJ-1 protein concentrations in muscle and plasma. In DJ-1 knockout mice, running wheel performance was much slower and Rotarod performance was reduced, suggesting that DJ-1 protein is required for normal motor activity. To see if exercise can prevent abnormal protein deposition and behavioral decline in transgenic animals expressing a mutant human form of α-synuclein in all neurons, we set up running wheels in the cages of pre-symptomatic animals at 12 months old. Activity was monitored for a 3-month period. After 3 months, motor and cognitive performance on the Rotarod and Morris Water Maze were significantly better in running animals compared to control transgenic animals with locked running wheels. Biochemical analysis revealed that running mice had significantly higher DJ-1, Hsp70 and BDNF concentrations and had significantly less α-synuclein aggregation in brain compared to control mice. By contrast, plasma concentrations of α-synuclein were significantly higher in exercising mice compared to control mice. Our results suggest that exercise may slow the progression of Parkinson's disease by preventing abnormal protein aggregation in brain.

DJ-1 as a Biomarker of Parkinson's Disease.

Parkinson's disease is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1 has been identified as a causative gene of a familial form of Parkinson's disease, PARK7, and plays a significant role in antioxidative defense, protecting cells from oxidative stress. A cysteine residue of DJ-1 at position 106 (Cys-106) is preferentially oxidized under oxidative stress. This reactive Cys-106 plays a critical role in the biological function of DJ-1, which could act as a sensor of oxidative stress by regulating antioxidative defense depending on Cys-106 oxidation. Thus, the levels of Cys-106-oxidized DJ-1 (oxDJ-1) could be a possible biomarker of oxidative stress. This chapter focuses on the properties of DJ-1 and oxDJ-1 levels as a biomarker of Parkinson's disease. In particular, the usability of these biomarkers to prevent and treat this neurodegenerative disease is discussed. Further, this section deals with the importance of identifying a biomarker of early-phase Parkinson's disease. Finally, this chapter summarizes the features of oxDJ-1 levels in the brain and blood as a biomarker candidate for early-phase Parkinson's disease based on our results using oxDJ-1-specific antibodies.

DJ-1 is a reliable serum biomarker for discriminating high-risk endometrial cancer.

New reliable approaches to stratify patients with endometrial cancer into risk categories are highly needed. We have recently demonstrated that DJ-1 is overexpressed in endometrial cancer, showing significantly higher levels both in serum and tissue of patients with high-risk endometrial cancer compared with low-risk endometrial cancer. In this experimental study, we further extended our observation, evaluating the role of DJ-1 as an accurate serum biomarker for high-risk endometrial cancer. A total of 101 endometrial cancer patients and 44 healthy subjects were prospectively recruited. DJ-1 serum levels were evaluated comparing cases and controls and, among endometrial cancer patients, between high- and low-risk patients. The results demonstrate that DJ-1 levels are significantly higher in cases versus controls and in high- versus low-risk patients. The receiver operating characteristic curve analysis shows that DJ-1 has a very good diagnostic accuracy in discriminating endometrial cancer patients versus controls and an excellent accuracy in distinguishing, among endometrial cancer patients, low- from high-risk cases. DJ-1 sensitivity and specificity are the highest when high- and low-risk patients are compared, reaching the value of 95% and 99%, respectively. Moreover, DJ-1 serum levels seem to be correlated with worsening of the endometrial cancer grade and histotype, making it a reliable tool in the preoperative decision-making process.

DJ-1/PARK7 Impairs Bacterial Clearance in Sepsis.

RATIONALE: Effective and rapid bacterial clearance is a fundamental determinant of outcomes in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. OBJECTIVES: Because cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain- and loss-of-function experiments, plasma, and cells from patients with sepsis. MEASUREMENTS AND MAIN RESULTS: Stimulation of bone marrow-derived macrophages (BMMs) with endotoxin resulted in increased DJ-1 mRNA and protein expression. Cellular and mitochondrial ROS was increased in DJ-1-deficient (-/-) BMMs compared with wild-type. In a clinically relevant model of polymicrobial sepsis (cecal ligation and puncture), DJ-1-/- mice had improved survival and bacterial clearance. DJ-1-/- macrophages exhibited enhanced phagocytosis and bactericidal activity in vitro, and adoptive transfer of DJ-1-/- bone marrow-derived mononuclear cells rescued wild-type mice from cecal ligation and puncture-induced mortality. In stimulated BMMs, DJ-1 inhibited ROS production by binding to p47phox, a critical component of the NADPH oxidase complex, disrupting the complex and facilitating Nox2 (gp91phox) ubiquitination and degradation. Knocking down DJ-1 (siRNA) in THP-1 (human monocytic cell line) and polymorphonuclear cells from patients with sepsis enhanced bacterial killing and respiratory burst. DJ-1 protein levels were elevated in plasma from patients with sepsis. Higher levels of circulating DJ-1 were associated with increased organ failure and death. CONCLUSIONS: These novel findings reveal DJ-1 impairs optimal ROS production for bacterial killing with important implications for host survival in sepsis.

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis.

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage.

Diagnostic and prognostic value of serum thioredoxin and DJ-1 in non-small cell lung carcinoma patients.

In response to reactive oxygen species (ROS), thioredoxin and DJ-1 are upregulated to counteract the detrimental effect of ROS under normal condition. However, cancer cells can take advantage of thioredoxin and DJ-1 against ROS-induced cell damage. In several human cancer types, thioredoxin and DJ-1 were found to be overexpressed. The present study aimed to explore the serum levels of thioredoxin and DJ-1 in non-small cell lung cancer (NSCLC) patients and its relationship to the diagnosis and prognosis of this particular malignancy. Sera from 134 NSCLC patients and 168 healthy controls were obtained. Using the enzyme-linked immunosorbent assay (ELISA) method, the levels of serum thioredoxin and DJ-1 were measured and correlated to the clinicopathological characteristics of NSCLC patients. The diagnostic and prognostic significance of the biomarkers were evaluated by using receiver operating curve (ROC), Kaplan-Meier curve, and log-rank analyses and the Cox proportional hazard model, respectively. Serum thioredoxin and DJ-1 levels were significantly higher in the NSCLC patients than that in the controls (23.5 ± 6.57 vs. 13.8 ± 2.49 and 7.11 ± 2.02 vs. 5.18 ± 1.26, respectively). NSCLC patients at later stage cancer showed significantly higher levels of serum thioredoxin and DJ-1 than those at the early stages (P < 0.01 and P < 0.05, respectively). Multivariate logistic regression analysis showed that high serum thioredoxin level was an independent risk factor for lymph nodal metastases and distant metastases (OR = 2.18, 95 % CI 1.26-3.41 and OR = 3.68, 95 % CI 2.16-5.33, respectively). In addition, an increase in the serum DJ-1 level was also identified as an independent risk factor for nodal metastases (OR = 1.37, 95 % CI 1.11-3.04). For predicting the development of NSCLC, ROC/area under the curve (AUC) analysis for thioredoxin indicated an AUC of 0.80 (sensitivity 0.62, specificity 0.92), and ROC/AUC analysis for DJ-1 showed an AUC of 0.78 (sensitivity 0.66, specificity 0.89). NSCLC patients with high serum thioredoxin and DJ-1 levels had lower survival rates than those with low levels, and multivariate analyses for overall survival revealed that high serum thioredoxin levels served as an independent prognostic factor for NSCLC (HR = 2.07, 95 % CI 1.19-3.48). Serum levels of thioredoxin and DJ-1 were significantly higher in NSCLC patients; therefore, these may be utilized as novel diagnostic and prognostic biomarkers for NSCLC.