Parkinson's disease proteins: Novel mitochondrial targets for cardioprotection

Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapeutic targets for protecting the heart against acute ischemia/reperfusion injury (IRI) are required to attenuate cardiomyocyte death, preserve myocardial function, and prevent the onset of heart failure. In this regard, a specific group of mitochondrial proteins, which have been linked to familial forms of Parkinson's disease (PD), may provide novel therapeutic targets for cardioprotection. In dopaminergic neurons of the substantia nigra, these PD proteins, which include Parkin, PINK1, DJ-1, LRRK2, and α-synuclein, play essential roles in preventing cell death-through maintaining normal mitochondrial function, protecting against oxidative stress, mediating mitophagy, and preventing apoptosis. These rare familial forms of PD may therefore provide important insights into the pathophysiology underlying mitochondrial dysfunction and the development of PD. Interestingly, these PD proteins are also present in the heart, but their role in myocardial health and disease is not clear. In this article, we review the role of these PD proteins in the heart and explore their potential as novel mitochondrial targets for cardioprotection

Loss of PINK1 Increases the Heart's Vulnerability to Ischemia-Reperfusion Injury.

Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction

DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury.

Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia-reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1(L166P) and DJ-1(Cys106A) mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection

Co-Localization of the Oncogenic Transcription Factor MYCN and the DNA Methyl Binding Protein MeCP2 at Genomic Sites in Neuroblastoma

MYCN is a transcription factor that is expressed during the development of the neural crest and its dysregulation plays a major role in the pathogenesis of pediatric cancers such as neuroblastoma, medulloblastoma and rhabdomyosarcoma. MeCP2 is a CpG methyl binding protein which has been associated with a number of cancers and developmental disorders, particularly Rett syndrome.Using an integrative global genomics approach involving chromatin immunoprecipitation applied to microarrays, we have determined that MYCN and MeCP2 co-localize to gene promoter regions, as well as inter/intragenic sites, within the neuroblastoma genome (MYCN amplified Kelly cells) at high frequency (70.2% of MYCN sites were also positive for MeCP2). Intriguingly, the frequency of co-localization was significantly less at promoter regions exhibiting substantial hypermethylation (8.7%), as determined by methylated DNA immunoprecipitation (MeDIP) applied to the same microarrays. Co-immunoprecipitation of MYCN using an anti-MeCP2 antibody indicated that a MYCN/MeCP2 interaction occurs at protein level. mRNA expression profiling revealed that the median expression of genes with promoters bound by MYCN was significantly higher than for genes bound by MeCP2, and that genes bound by both proteins had intermediate expression. Pathway analysis was carried out for genes bound by MYCN, MeCP2 or MYCN/MeCP2, revealing higher order functions.Our results indicate that MYCN and MeCP2 protein interact and co-localize to similar genomic sites at very high frequency, and that the patterns of binding of these proteins can be associated with significant differences in transcriptional activity. Although it is not yet known if this interaction contributes to neuroblastoma disease pathogenesis, it is intriguing that the interaction occurs at the promoter regions of several genes important for the development of neuroblastoma, including ALK, AURKA and BDNF

Recommendations for the diagnosis of pediatric tuberculosis

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease

The Role of DJ-1 in Cardioprotection

Background Mutations in the DJ-1 gene in dopaminergic neurones induce mitochondrial dysfunction and a genetic form of Parkinson’s disease (PD). Although DJ-1 is present in the heart its role there is currently unknown. We hypothesised that DJ-1 may be a novel target for cardioprotection. Methods and Results Overexpression of wild-type (WT) DJ-1 in the HL-1 cardiac cell line induced mitochondrial elongation, delayed the opening of the mitochondrial permeability transition pore (mPTP), and reduced cell death following simulated ischaemia-reperfusion injury (s I/R), effects which were absent in non-functional DJ-1 mutants. Adult murine hearts deficient in DJ-1 sustained larger myocardial infarcts following in vivo 45 minutes regional ischaemia and 24 hours reperfusion, and were partially resistant to ischaemic preconditioning (IPC), when compared to WT controls. DJ-1 deficient murine hearts displayed increased mitochondrial fragmentation, although there were no differences in mitochondrial function, myocardial ATP levels, or cardiac dimensions or function. Conclusion DJ-1 is a novel target for cardioprotection

DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury.

10.1038/cddis.2014.41Cell Death and Disease52e108

The protective effect of the Vacha rhizome extract on chronic stress-induced immunodeficiency in rat

Context: Chronic stress is an inevitable factor in the modern day society which affects cell mediated as well as humoral immunity. There is a need to prevent stress effects with traditionally used herbs. Objective: The present study was undertaken to investigate the immunoprotective effect of Vacha (Acorus calamus L. Acoraceae) rhizome under stressful condition. Materials and methods: Soxlet extraction of Vacha rhizome was performed with increasing polarity of solvents, i.e., petroleum ether to ethanol. The extract was concentrated by distilling off the solvent in flash evaporator and dried in desiccators. The benzene extract was found to have anti-stress property in our earlier studies and hence it was used in the present experiment. Extract was administered every day for 4 weeks orally to adult female rats prior to exposure to stress, restraint (1 h) and forced swimming exercise (15 min). Results: Vacha rhizome extract significantly prevented the stress induced reduction in total and differential leukocytes count, immunoglobulin content, bone marrow cellularity and viability, lymphocytes counts in lymphoid organs, islands of white pulp of spleen (ED50 = 10 mg, p < 0.001) and a significant increase in circulating immune complexes and apoptotic index of lymphoid organs (ED50 = 10 mg, p < 0.001) compared to controls. Discussion and conclusion: The present study clearly indicates that Vacha extract not only prevents stress-induced suppression of immunity and structural involution of lymphoid organs, but also boosts immunity in normal rats. Therefore, it is suggested that Vacha extract administration maintains normal immunity despite the body experiencing stress