DJ-1 Levels Research Articles

A review of high glycemic index (gi) in relation to risk of parkinson’s disease

Objective: The objective was to investigate whether a diet with high glycemic index (GI) is associated with Parkinson’s disease (PD) and changes that happen at levels of methylglyoxal (MGO), oligomeric α-synuclein (α-syn), and DJ-1. Materials and Methods: This reviewed study was carried out by doing search in Scholar Google, PubMed and Elsevier databases using keywords such as Parkinson’s disease, high glycemic index (GI), methylglyoxal (MGO), α-synuclein (α-syn), DJ-1. Approximately 40 articles were selected that were fully reviewed. Conclusions: High GI diets may be risk factor for developing PD by increasing a-syn oligomerization and advanced glycated end products (AGEs) formation. Intake of dietary fiber. Appear to be beneficial in reducing PD.

DJ-1 activates the noncanonical NF-κB pathway via interaction with Cezanne to inhibit the apoptosis and promote the proliferation of Ishikawa cells.

Endometrial cancer is generally one of the most evident malignant tumours of the female reproductive system, and the mechanisms underlying its cell proliferation and apoptosis are key to research in gynaecological oncology. In the paper, the in-depth molecular mechanism by which DJ-1 protein regulates the proliferation and apoptosis of Ishikawa cells was investigated. DJ-1 knockdown and overexpressing Ishikawa stable cell lines were established by lentiviral transduction. The levels of DJ-1 and noncanonical NF-κB signaling key proteins were evaluated by Western blotting. Cell counting kit-8 (CCK-8) and flow cytometry were applied to analyze the cell viability and apoptosis. Co-immunoprecipitation experiment was utilized to assess the DJ-1-Cezanne interaction. The results showed that DJ-1 overexpression conferred apoptosis resistance and high proliferation on Ishikawa cells, while DJ-1 knockdown in Ishikawa cells produced the opposite results. These findings again suggested that DJ-1 inhibits the apoptosis and promotes the proliferation of Ishikawa cells. More crucially, further data showed that the noncanonical NF-κB activation was required for the regulation of Ishikawa cell proliferation and apoptosis by DJ-1. Meanwhile, it was found that noncanonical NF-κB pathway may be activated by DJ-1 interacting with and negatively regulating Cezanne in Ishikawa cells. Overall, this work revealed that DJ-1 associates with and negatively regulates Cezanne and consequently triggers the noncanonical NF-κB activation, thereby regulating Ishikawa cell proliferation and apoptosis.

Fabrication of Micro-Nano Bioactive Glass Scaffold Incorporated with Siglec-15 for Bone Repair and Postoperative Treatment of Osteosarcoma

This study aimed to fabricate micro-nano bioactive glass (MNBG) scaffolds loaded with chemotherapeutics and siglec-15 monoclonal antibody with bone repair capability and high-active drug loading capability for postoperative treatment of osteosarcoma. Bioactive glass (BG) particles were incorporated with siglec-15 mAb and gemcitabine through mesopores and calcium ions on the surface. Dendritic cells (DCs) were treated with siglec-loaded BGs and gemcitabine. RT-qPCR analysis was conducted to detect DJ-1 and PTEN mRNA levels, CCK-8 technology to detect cell activity, and flow cytometry to detect cell apoptosis. Rats were administrated with siglec-15-MNBG composite scaffolds with/without gemcitabine. 3D printing was used to determine adhesion strength of each group. Administration of MNBG scaffold decreased the expression of PTEN and up-regulated expression of DJ-1 when inducing cell apoptosis. Combined treatment with gemcitabine augmented adhesion of material and enhanced phosphorylation activity of p-AKT, mitigating the inhibitory effect of scaffold loaded with siglec-15 on p-AKT protein expression. Collectively, MNBG scaffold loaded with siglec-15 might promote bone regeneration and incorporate with chemotherapeutic drugs to suppress tumor development and promote apoptosis through PTEN/PI3 K pathway. These findings provide a novel insight into postoperative treatment of osteosarcoma and help development of tumor immunotherapy/bone repair integrated materials.

Experimental study on nuclear-targeted plasmid-based short hairpin RNA (ShRNA) to hypoxia inducible factor-1α (PshHIF-1α) PshHIF-1α nano-drug carrier system for breast cancer treatment in rats

This study was aimed at exploring the regulatory mechanism of auclear-targeted pshHIF-1α nano-drug carrier system (NPNCS) in the treatment of breast cancer in rats. MDA-MB-231 cell was cultured and DJ-1 and PTEN mRNA level was detected by qRT-PCR along with analysis of cell viability by CCK-8 and apoptosis by means of flow cytometry. The rats were assigned into control group, nuclear-targeted pshHIF-1α nanopharmaceutical system treatment group, and nuclear-targeted pshHIF-1α nano-pharmaceutical system+PTEN inhibitor SF1670 group, followed by analysis of cell proliferation by EdU staining, cell apoptosis by flow cytometry, and the levels of DJ-1, PTEN, and p-AKT. Compared with MDA-MB-231 cells treated with NPNCS, cells without intervention showed decreased PTEN and increased DJ-1 level. NPNCS induced cell apoptosis. Administration of nuclear-targeted pshHIF-1α nano-drug delivery system down-regulated DJ-1 and up-regulated PTEN. Combined treatment with SF1670 promoted p-AKT level and decreased the inhibitory effect of NPNCS on p-AKT level. In conclusion, the nuclear-targeted pshHIF-1α nano-drug delivery system down-regulated DJ-1 and exerted a tumor suppressor and pro-apoptotic effect, which wasrelated to p-AKT phosphorylation and up-regulation of PTEN.

The Clinical Significance of DJ1 and L1CAM Serum Level Monitoring in Patients with Endometrial Cancer.

Circulating tumor markers are not routinely used in patients with endometrial cancer (EC). This pilot study evaluated the role of monitoring new biomarkers DJ1 and L1CAM, in correlation with CA125 and HE4, for the effects of anticancer treatment and preoperative management in EC patients. Serial serum levels of DJ1, L1CAM, CA125 and HE4 were collected in 65 enrolled patients. Serum DJ1, L1CAM, CA125 and HE4 levels were significantly higher at the time of diagnosis compared to those measured during follow-up (FU). In patients with recurrent disease, serum DJ1, CA125 and HE4 levels were significantly higher at the time of recurrence compared to levels in disease-free patients. Serum L1CAM levels were also higher in patients with recurrence but without reaching statistical significance. While DJ1 levels were not affected by any of the observed patient-related characteristics, L1CAM levels were significantly higher in patients with age ≥60 years who were overweight. At the time of EC diagnosis, DJ1 and L1CAM serum levels did not correlate with stage, histological type or risk of recurrence. This is a preliminary description of the potential of serial DJ1 and L1CAM serum level measurement for monitoring the effects of treatment in EC patients.

Cerebrospinal Fluid Biomarkers in Multiple System Atrophy Relative to Parkinson's Disease: A Meta-Analysis.

Objective To investigate the differences of candidate cerebrospinal fluid (CSF) biomarkers associated with multiple system atrophy (MSA) and Parkinson's disease (PD). Method Here, a systematic review and meta-analysis were conducted on studies related to CSF biomarkers associated with MSA and PD obtained from PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled where appropriate and used to calculate standardized mean differences (SMDs) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic while Egger's test was used to test for existing publication bias. Results MSA patients had higher CSF t-tau (SMD = 0.41, 95% CI: 0.10 to 0.72) and YKL-40 (SMD = 0.63, 95% CI 0.12 to1.15) as well as DJ-1 (SMD = 1.05, 95% CI 0.67 to 1.42) levels than PD patients, while CSF p-tau (SMD = −0.17, 95% CI, -0.31 to -0.02) and Aβ-42 (SMD = −0.33, 95% CI, -0.55 to -0.12) levels in MSA patients were lower than those in PD patients. There were no differences in CSF's GFAP and Flt3 ligand levels in both MSA and PD patients. Conclusion The study revealed the differences in CSF biomarker levels between MSA and PD cohorts that can be further explored to clinically distinguish MSA from PD.

DJ-1 alleviates oxidative stress injury by activating the Nrf2 pathway in rats with cerebral ischemia-reperfusion injury

To investigate the antioxidant effect of DJ-1 (Park7) in rats with cerebral ischemia/reperfusion (IR) injury and its potential mechanism. A total of 108 SD rats were randomly divided into sham-operated group, middle cerebral artery occlusion (MCAO) group, Scramble group, DJ-1 siRNA group, negative control (NC) group and DJ-1 overexpression group. Except for those in the sham group, all the rats were subjected to MCAO to establish models of cerebral IR injury. In DJ-1 siRNA and DJ-1 overexpression group, a DJ-1 siRNA and an adeno-associated virus vector carrying DJ-1 gene was injected into the lateral ventricle of the rats, respectively. In each group, neurological scores and brain water content were determined after the operation, and pathological changes of the brain tissue and neuronal injury in the cortical infarction area were assessed using HE and Nissl staining. Oxidative stress in the brain tissues was analyzed by detecting superoxide dismutase (SOD) and malondialdehyde (MDA). The expression levels of DJ-1, Nrf2, Ho-1 and NQO1 in the brain tissue were detected with Western blotting, and the expression and nucleation of Nrf2 was determined by immunofluorescence staining. Compared with those in MCAO group, the neurological scores (P < 0.001) and brain water content (P < 0.001) were significantly increased in DJ-1 siRNA group. Intracerebral injection of DJ-1 siRNA following MCAO obviously aggravated neuron injury in cerebral ischemia region, further reduced SOD activity and increased MDA content (P < 0.001), and significantly lowered the expression levels of Nrf2 and its downstream proteins HO-1 and NQO1 (P < 0.001). Intracerebral injection of the adenoviral vector for DJ-1 (P=0.003) overexpression significantly upregulated the levels of Nrf2 (P=0.006) and its downstream proteins HO-1 (P=0.004) and NQO1 (P=0.014). As an important neuroprotective factor, DJ-1 alleviates oxidative stress induced by cerebral IR injury in rats by activating the Nrf2 pathway.

Dj1 deficiency protects against atherosclerosis with anti-inflammatory response in macrophages

Inflammation is a key contributor to atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine/chemokine secretion. DJ1, an anti-oxidant protein, has shown to paradoxically protect against chronic and acute inflammation. However, the role of DJ1 in atherosclerosis remains elusive. To assess the role of Dj1 in atherogenesis, we generated whole-body Dj1-deficient atherosclerosis-prone Apoe null mice (Dj1−/−Apoe−/−). After 21 weeks of atherogenic diet, Dj1−/− Apoe−/−mice were protected against atherosclerosis with significantly reduced plaque macrophage content. To assess whether haematopoietic or parenchymal Dj1 contributed to atheroprotection in Dj1-deficient mice, we performed bone-marrow (BM) transplantation and show that Dj1-deficient BM contributed to their attenuation in atherosclerosis. To assess cell-autonomous role of macrophage Dj1 in atheroprotection, BM-derived macrophages from Dj1-deficient mice and Dj1-silenced macrophages were assessed in response to oxidized low-density lipoprotein (oxLDL). In both cases, there was an enhanced anti-inflammatory response which may have contributed to atheroprotection in Dj1-deficient mice. There was also an increased trend of plasma DJ-1 levels from individuals with ischemic heart disease compared to those without. Our findings indicate an atheropromoting role of Dj1 and suggests that targeting Dj1 may provide a novel therapeutic avenue for atherosclerosis treatment or prevention.

DJ-1 modulates Nrf2-mediated MRP1 expression by activating Wnt3a/β-catenin signalling in A549 cells exposed to cigarette smoke extract and LPS

BackgroundChronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by airway obstruction and abnormal inflammatory responses. Multidrug resistance-related protein 1 (MRP1) can reduce lung inflammation and damage by excreting various toxic exogenous substances and certain pro-inflammatory molecules. AimsWe studied whether DJ-1 modulates nuclear factor erythroid 2-related factor 2 (Nrf2) by activating the Wnt3a/β-catenin signalling pathway to further regulate MRP1 expression and pulmonary antioxidant defences in alveolar epithelial (A549) cells treated with smoke extract (CSE) and lipopolysaccharide (LPS). Main methodsMarker expression was studied by western blot analysis, quantitative real-time PCR and immunofluorescence staining of A549 cells. Key findingsA549 cells exposed to CSE and LPS showed downregulation of DJ-1, Wnt3a, MRP1 and haem oxygenase-1 (HO-1) and upregulation of inflammatory factors. Additionally, Nrf2 protein levels were significantly decreased, while there was no change in Nrf2 mRNA levels. Overexpression of DJ-1 and Wnt3a activated Nrf2 signalling, increased MRP1 and HO-1 levels and decreased IL-6 protein expression, while knockdown of DJ-1 and Wnt3a had the opposite effects. Furthermore, DJ-1 overexpression and DJ-1 knockdown increased and decreased, respectively, the levels of Wnt3a and β-catenin. Interestingly, Nrf2 and Wnt3a deficiency reduced the protective effects of Wnt3a and DJ-1, respectively, in A549 cells. However, the levels of DJ-1 and Wnt3a were not altered by Wnt3a and Nrf2 deletion, respectively. SignificanceIn A549 cells treated with CSE and LPS, DJ-1 regulates Nrf2-mediated MRP1 expression and antioxidant defences by activating the Wnt3a/β-catenin signalling pathway. These findings may provide potential therapeutic targets for COPD intervention.

A Comprehensive Phenotype of Non-motor Impairments and Distribution of Alpha-Synuclein Deposition in Parkinsonism-Induced Mice by a Combination Injection of MPTP and Probenecid.

Parkinson’s disease (PD) is characterized by non-motor symptoms as well as motor deficits. The non-motor symptoms rarely appear individually and occur simultaneously with motor deficits or independently. However, a comprehensive research on the non-motor symptoms using an experimental model of PD remains poorly understood. The aim of the current study is to establish a chronic mouse model of PD mimicking the comprehensive non-motor symptoms of human PD by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid (MPTP/p). The non-motor and motor symptoms were evaluated by performing buried food, short-term olfactory memory, hot plate, open field, tail suspension, Y maze, novel object recognition, bead expulsion, one-h stool collection, rotarod, rearing, catalepsy, and akinesia tests after 10 injections of MPTP/p into mice. The expression levels of α-synuclein, glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) or DJ-1 were analyzed by Western blotting or immunostaining. MPTP/p-treated mice achieved to reproduce the key features of non-motor symptoms including olfactory deficit, thermal hyperalgesia, anxiety, depression, cognitive decline, and gastrointestinal dysfunction in addition to motor deficits. The MPTP/p-treated mice also showed the high levels of α-synuclein and low levels of TH and DJ-1 in striatum, substantia nigra, olfactory bulb, hippocampus, amygdala, prefrontal cortex, locus coeruleus, or colon. In addition, the expression levels of phosphorylated-α-synuclein and GFAP were elevated in the striatum and substantia nigra in the MPTP/p-treated mice. Taken together, our study clarifies that the chronic MPTP/p-treated mice have a variety of non-motor dysfunctions as well as motor abnormalities by α-synuclein overexpression and dopaminergic depletion. Therefore, the study of comprehensive phenotypes of non-motor symptoms in one PD model would advance in-depth understandings of neuropathological alternations and contribute to future strategies for PD treatment.

Effects of Dietary Pomegranate Peel on Antioxidant Gene Expression and DJ-1 Protein Abundance in Ram Testes.

Background:Pomegranate is an ancient fruit containing Punicalagin, which has known as an effective antioxidant. Pomegranate peel was recognized as a phenol and tannin source, and pomegranate seed contains unique fatty acid (Punicic acid). Limited information exists about the influences of pomegranate peel and seed on antioxidant enzymes and proteins in the male reproduction system. This study was performed to determine the pomegranate peel and seed effects on the expression of antioxidant genes and DJ-1 protein in ram’s testis.Materials and Methods: In this experimental study, twenty-one mature Iranian rams were randomly divided into three groups (n=7 in each group), and fed experimental diets consisted of a control diet (C), a diet containing dry pomegranate seed pulp (S), and a diet containing pomegranate peel (P) for 80 days. All rams were offered isoenergetic and isonitrogenous rations. Testicular tissue samples were collected, and expression of Gpx1, Gpx4, Prdx4, Prdx5, and Sod2 genes was quantified by real-time polymerase chain reaction (RT-PCR). In addition, western blotting was used to evaluate DJ-1 expression at the protein level.Results:Gpx1 and Sod2 mRNA levels in the peel group were significantly (P<0.05) higher than control. Prdx5 mRNA level was increased (P<0.05) in the seeds group than in the control group. Gpx4 and Prdx4 expression were statistically not affected significantly by the experimental diet. Data analysis showed a significant (P<0.05) increase (1.5-fold) in the expression level of DJ-1 in peel groups than in control.Conclusion:The expression of antioxidant genes and DJ-1 protein in ram testes are more influenced by pomegranate peel than seed.

Correlations among Pulmonary DJ-1, VDR and Nrf-2 in patients with Chronic Obstructive Pulmonary Disease: A Case-control Study.

Parkinson protein 7 (PARK7)/DJ-1 (DJ-1) is a redox sensitive molecular and stabilizer of nuclear factor erythroid 2-related factor 2 (Nrf-2). Nrf-2 regulates the downstream antioxidant defense system and exerts a significant function in patients with chronic obstructive pulmonary disease (COPD). Vitamin D receptor (VDR) is the nuclear receptor that regulates the downstream target genes. This study aimed to analyze the associations among pulmonary function, DJ-1, VDR and Nrf-2 in COPD patients. Serum was collected from 180 COPD patients and control subjects. Thirty-five lung tissues were obtained. DJ-1 was measured using ELISA and western blotting. Nrf-2 and VDR were detected by immunohistochemistry. Serum and pulmonary DJ-1 levels were lower in COPD patients than those in control subjects. Pulmonary VDR-positive nuclei were reduced in COPD patients. Nrf-2-positive nuclei were reduced in lung tissues of COPD patients. On the contrary, Nrf-2-related downstream target proteins were elevated in COPD patients. Further correlation analysis indicated that forced expiratory volume in 1 second (FEV1) was positively associated with pulmonary DJ-1, VDR and Nrf-2 in patients with COPD. In addition, there were positive correlations among DJ-1, VDR and Nrf-2 in lung tissues of COPD patients. In conclusion, DJ-1, VDR and Nrf-2 were decreased in COPD patients compared with control subjects. The reduction of DJ-1 and VDR associating with Nrf-2 downregulation may be involved in the process of COPD.

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

To study the role of changes in the expression of human Parkinson's disease protein 7 (PARK7/DJ-1) in preeclampsia. 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. 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. 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.

Antioxidative effects of uridine in a neonatal rat model of hyperoxic brain injury

Premature birth is a major problem that results in an increased risk of mortality and morbidity. The management of such infants consists of supraphysiological oxygen therapy, which affects brain development due, in part, to the deterioration caused by reactive oxygen species (ROS). We showed previously that exogenously administered uridine provides neuroprotection in a neonatal rat model of hyperoxic brain injury. Hence, the aim of the present study was to investigate the effects of uridine on ROS in the same setting. Hyperoxic brain injury was induced by subjecting a total of 53 six-day-old rat pups to 80% oxygen (the hyperoxia group) for a period of 48 h. The pups in the normoxia group continued breathing room air (21% oxygen). Normoxia + saline or hyperoxia + saline or hyperoxia + uridine 100 mg/kg or hyperoxia + uridine 300 mg/kg or hyperoxia + uridine 500 mg/kg was injected intraperitoneally (i. p.) 15 min prior to the hyperoxia procedure. The pups were decapitated and the brains were homogenized to analyze superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), myeloperoxidase (MPO), and malondialdehyde (MDA) enzymes as well as DJ-1 (protein deglycase DJ-1) — an oxidative stress-sensitive protein. Hyperoxia-induced may cause overproduction of oxygen radicals and the oxidant/antioxidant balance may be disturbed in the brain. Brain MPO and MDA levels were significantly increased in saline-receiving pups exposed to hyperoxia. Brain SOD and GSH-Px levels were significantly decreased in saline-receiving pups exposed to hyperoxia. Our results showed that uridine administration prevented the hyperoxia-induced decrease in SOD and GSH-Px while counteracting the hyperoxia-induced increase in MPO and MDA in a dose-dependent manner. Uridine also increased the DJ-1 levels in brains of rat pups subjected to hyperoxia. These data suggest that uridine exhibits antioxidative properties which may mediate the protective effects of uridine in a neonatal rat model of hyperoxic brain injury.

Resveratrol Reduces Cardiomyocyte Apoptosis Induced by I-R Injury Through Upregulating DJ-1

The NF-E2 related factor 2 (Nrf2) involves in anti-oxidative stress. DJ-1 is a multifunctional protein widely distributed in various tissues that plays a role in enhancing Nrf2 stability and promoting Nrf2 protein expression. Resveratrol (Res) is an important polyphenolic substance with various pharmacological effects, such as anti-oxidation and protection of cardiovascular and cerebrovascular. Our study intends to assess Resveratrol?s role in regulating DJ-1/Nrf2 pathway activity and alleviating rat cardiomyocyte I-R injury. Rat cardiomyocyte I-R injury model was established to detect DJ-1 and Nrf2 expressions, caspase-3 activity, malondialdehyde (MDA), and superoxide dismutase (SOD). The I-R rats were assigned into I-R group, I-R+Res 20 (20 mg/Kg) group, and I-R+Res 40 (20 mg/Kg) group. Rat H9C2 cells were assigned into control group, I-R group, and I-R+Res group followed by analysis of cell apoptosis and reactive oxygen species (ROS) by flow cytometry. The MDA content and caspase-3 activity were significantly elevated, while the SOD activity was obviously reduced in the cardiomyocyte of the I-R model rats. DJ-1 and Nrf2 expressions were apparently upregulated in I-R model. MDA content and caspase-3 activity were significantly decreased, whereas SOD activity, DJ-1, and Nrf2 expression levels were obviously elevated in Res treatment group with dose dependence. I-R treatment induced H9C2 cell apoptosis and intracellular ROS production, and upregulated DJ-1 and Nrf2 expressions. Res treatment further enhanced DJ-1 and Nrf2 levels, attenuated ROS production, and reduced apoptotic rate in H9C2 cells under I-R treatment. Res attenuates brain cell apoptosis and neuronal damage after I-R by increasing DJ-1 level, enhancing DJ-1/Nrf2 pathway, and elevating the anti-oxidation level.

Abstract 13548: Dicarbonyl Stress, Mitochondrial Impairments, and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Introduction: Right ventricular dysfunction (RVD) is the leading cause of mortality in pulmonary arterial hypertension (PAH), but the molecular mediators of RVD are incompletely understood. In PAH, RV glucose uptake is inversely proportional to RV function, which is a consequence of increased glycolytic flux due to mitochondrial dysfunction. Methylglyoxal (MG) is a highly reactive dicarbonyl that is generated during glycolysis. MG can deleteriously modulate protein function via post-translational modifications. MG is metabolized by two key enzymes: glyoxalase (Glo) 1 and 2. Finally, DJ-1 is a deglycase enzyme that reverses protein-glycation. The regulation of protein-glycation, the glyoxalase system, and DJ-1 in RVD due to PAH are unexplored. Methods: We analyzed protein-glycation, Glo-1/2, and DJ-1 expression in RV extracts from control, monocrotaline (MCT), and pulmonary artery banded (PAB) rats. The effects of protein-glycation on mitochondrial function in H9c2 cardiomyocytes were probed using Seahorse analysis. Finally, we examined the link between protein-glycation and RV function in PAH patients using hemoglobin-A1C as a surrogate measure of protein-glycation. Results: In MCT RVs, protein-glycation was increased (3.2±0.9-fold), Glo-1 (48±7%) was decreased, while Glo-2 (1.4±0.1-fold) and DJ-1 (1.5±0.4-fold) were increased. Conversely, in PAB rats, protein-glycation (1.4±0.3-fold) was not as drastically elevated. Moreover, Glo-1 (1.7±0.3-fold), Glo-2 (1.6±0.2-fold change), and DJ-1 (2.3±0.3-fold) levels were all increased. In H9c2 cardiomyocytes, MG treatment induced protein-glycation and impaired mitochondrial function. Finally, hemoglobin-A1C levels were inversely associated with RV contractility in PAH patients. Conclusions: Increased protein-glycation results in impaired mitochondrial function in vitro and is associated with more severe RV dysfunction in rodent and human PAH.

AITC induces MRP1 expression by protecting against CS/CSE-mediated DJ-1 protein degradation via activation of the DJ-1/Nrf2 axis.

The present study aimed to examine the effect of allyl isothiocyanate (AITC) on chronic obstructive pulmonary disease and to investigate whether upregulation of multidrug resistance-associated protein 1 (MRP1) associated with the activation of the PARK7 (DJ-1)/nuclear factor erythroid 2-related factor 2 (Nrf2) axis. Lung function indexes and histopathological changes in mice were assessed by lung function detection and H&E staining. The expression levels of Nrf2, MRP1, heme oxygenase-1 (HO-1), and DJ-1 were determined by immunohistochemistry, Western blotting and reverse transcription-quantitative polymerase chain reaction. Next, the expression of DJ-1 in human bronchial epithelial (16HBE) cells was silenced by siRNA, and the effect of DJ-1 expression level on cigarette smoke extract (CSE)-stimulated protein degradation and AITC-induced protein expression was examined. The expression of DJ-1, Nrf2, HO-1, and MRP1 was significantly decreased in the wild type model group, while the expression of each protein was significantly increased after administration of AITC. Silencing the expression of DJ-1 in 16HBE cells accelerated CSE-induced protein degradation, and significantly attenuated the AITC-induced mRNA and protein expression of Nrf2 and MRP1. The present study describes a novel mechanism by which AITC induces MRP1 expression by protecting against CS/CSE-mediated DJ-1 protein degradation via activation of the DJ-1/Nrf2 axis.

DJ-1 deficiency causes metabolic abnormality in ornidazole-induced asthenozoospermia.

Asthenozoospermia (AS), defined as low-motility spermatozoa in the ejaculate, is a frequent cause of human male infertility. DJ-1 (also known as PARK7), a protein highly associated with male sterility, binds to the mitochondrial complex I subunit to protect mitochondrial function. However, its involvement in spermatogenesis has not been fully elucidated. Previously, the levels of DJ-1 were shown to be significantly decreased in testicular tissues of rats with ornidazole (ORN)-induced AS. Here, we used a rat model to investigate the localization and expression levels of DJ-1 and its interacting NDUFS3 and NDUFA4 mitochondrial complex I subunits, as well as AS-induced metabolic alterations in testicular tissues. ORN significantly reduced the levels of DJ-1 in the nucleus of secondary spermatocytes, while increasing the expression of NDUFS3 in the cytoplasm of primary spermatocytes. Further, NDUFA4 showed higher expression after treatment with ORN. The principal ORN-induced changes in metabolic small molecules related to the accumulation of glucose, glutamine, and N-acetyl aspartate, enhancement of purine pathway, increase of the phosphatidic acid (PA) (18:0/18:1), phosphatidylethanolamine (PE) (16:0/18:1), and PA (18:0/20:4) lipid metabolites, and imbalance in the concentrations of Na+ and K+. However, we did not observe any abnormalities of certain small metabolic molecules and metal ions in semen samples from patients with AS. In conclusion, these results suggest that DJ-1 deficiency in testicular tissues might be closely related to the localization of NDUFS3 and content of NDUFA4, thus causing abnormalities in the mitochondrial energy metabolism and multiple other metabolic pathways.

Overexpression of DJ-1 alleviates autosomal dominant polycystic kidney disease by regulating cell proliferation, apoptosis, and mitochondrial metabolism in vitro and in vivo.

BackgroundDJ-1 is critical for the mitochondrial function associated with autosomal dominant polycystic kidney disease (ADPKD). We aimed to investigate DJ-1’s function in the pathogenesis of ADPKD.MethodsDJ-1 was knocked-down in IMCD3 cells to evaluate the effects of DJ-1 on cell phenotype and mitochondrial function in vitro. Furthermore, we generated three groups of mice with different expression levels of DJ-1 within an established ADPKD model: ADPKD, ADPKDpcDNA, and ADPKDpcDNA-DJ-1.ResultsDJ-1 knock-down significantly increased oxidative stress as well as the proliferation and apoptosis rate of IMCD3 cells, along with Bcl-2 down-regulation and the up-regulation of Ki67, PCNA, Bax, cleaved caspase-3, and cleaved caspase-9. DJ-1 knock-down suppressed the cellular respiration, Ca2+ absorption, and mitochondrial complex I activity in mitochondria. In vivo, we verified that DJ-1 was down-regulated in ADPKD models, and its overexpression attenuated the renal dysfunction in ADPKD models. The transgenic mice had a significantly smaller renal cyst and less interstitial fibrosis than control, accompanied byα-SMA, fibronectin, and TGF-β1 up-regulation. Moreover, in vivo results confirmed DJ-1 overexpression inhibited the proliferation and apoptosis of tubular epithelial cells along with down-regulation of Ki67, PCNA, p53, intracellular Cyt c, cleaved caspase-3, and cleaved caspase-9 and the up-regulation of Bcl-2.ConclusionsDJ-1 was down-regulated in ADPKD models, and its overexpression may attenuate the renal dysfunction and pathological damage by regulating the proliferation, apoptosis, oxidative stress and mitochondrial metabolism, which may be mediated by the p53 signaling pathway.

Mechanism of N-acetylcysteine in alleviating diabetic myocardial ischemia reperfusion injury by regulating PTEN/Akt pathway through promoting DJ-1.

Ischemic heart disease is the main cardiovascular complication of diabetes patients which is mainly caused by oxidative stress. DJ-1 is the key regulator for myocardial protection through inhibiting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activating Akt (also known as PKB or protein kinase B). This research is to investigate whether the antioxidant N-acetylcysteine (NAC) could alleviate diabetic myocardial ischemia/reperfusion (I/R) injury by the protective molecule DJ-1. DJ-1 in rat myocardial H9c2 cells and cardiac tissue was respectively knocked down by siRNA and adeno-associated virus (AAV). From the present study, it could be found that compared with high glucose (HG)-normal (N)/DM group, hypoxia/reoxygenation (H/R) or I/R injury can aggravate oxidative stress injury and apoptosis rate of myocardial cells, inhibit the expression of Bcl-2, activate the BAX and cleaved caspase-3 (c-caspase-3) protein and PTEN/Akt pathway. However, in the groups of HG-N, DM, HG-N+I/R and DM+I/R, NAC can significantly reduce oxidative stress injury and apoptosis rate of myocytes, promote the Bcl-2 and DJ-1 molecules, inhibit BAX and c-caspase-3 protein and PTEN/Akt pathway. Compared with HG-N+I/R+NAC and DM+I/R+NAC groups, the oxidative stress injury, apoptosis rate of myocardial cells and heart tissues increased after the knockdown of DJ-1, the expression of Bcl-2 and DJ-1 were inhibited, the BAX and c-caspase-3 expression was increased, and PTEN/Akt pathway was activated. Taken together, the findings suggest that NAC can reduce I/R injury in diabetic myocardium by up-regulating the PTEN/Akt pathway through the level of DJ-1.