Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bis-indole derivatives including 1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane (DIM-C-pPhCl) and substituted quinolines such as chloroquine (CQ) and amodiaquine (AQ) are nuclear receptor 4A2 (NR4A2, Nurr1) ligands, and they exhibit anti-inflammatory activities in mouse and rat models of Parkinson's disease, respectively. However, computational modeling demonstrates that the quinoline derivatives interact with the ligand-binding domain, whereas the bis-indoles preferentially interact with a C-terminal cofactor binding site of NR4A2. In this study, the effects of DIM-C-pPhCl and related analogs were compared with CQ/AQ as inducers of NR4A2-responsive genes including vasoactive intestinal peptide, osteopontin, proopiomelanocortin, and neuropilin 1 in Panc1 and Panc28 pancreatic cancer cells. The results demonstrate that, among the bis-indole analogs, their relative potencies as inducers were structure-gene- and cell context dependent. In contrast, CQ and AQ were significantly less potent than the bis-indole derivatives and, for some of the NR4A2-regulated genes, CQ and AQ were inactive as inducers. These results demonstrate that although bis-indole and quinoline derivatives have been characterized as activators of NR4A2-dependent gene expression, these two classes of compounds exhibit different activities, indicating that they are selective NR4A2 modulators.
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PMID:Structure-dependent activation of gene expression by bis-indole and quinoline-derived activators of nuclear receptor 4A2. 3110 70

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the ventral midbrain dopaminergic neurons, resulting in motor defects mainly tremor, rigidity, and bradykinesia along with a wide array of non-motor symptoms. The current study is focused on determining the potential druggable targets of PD by consolidating gene expression profiling and network methodology. Initially, the differentially expressed genes were established from which the central network was constructed by assimilating the interacting partners. Investigating the topological parameters of the network, the genes SYT1, CXCR4, CDC42, KIT, RET, DRD2, NTN1, PRKACB, KDR, NR4A2, SLC18A2, CCK, TH, KCNJ6, and TAC1 were identified as the hub genes and can be explored as potential candidate genes for PD therapeutics. Gene ontology and cluster analysis of the hub genes has provided further insights about the pathophysiology of the disease. Among the hub genes, PRKACB is observed in relatively all the enriched pathways which are modulated by G protein-coupled receptors through protein kinases. Further, we noticed SYT1 as a novel biomarker for PD. Moreover, the regulatory network was constructed with the hub genes as seed nodes with associated transcription factors (TFs) and microRNA (miRNAs). In this analysis, we identified MYC as the major TF and the miRNAs miR-21, miR-155, miR-7, and miR26A1 have a significant role in modulating the hub genes. Briefly, these significant hub genes and their enriched pathways, TFs, and miRNAs have aided in the better understanding of molecular mechanisms underlying PD and its potential core target genes.
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PMID:Integrative Analysis of Gene Expression and Regulatory Network Interaction Data Reveals the Protein Kinase C Family of Serine/Threonine Receptors as a Significant Druggable Target for Parkinson's Disease. 3272 98

Infantile- and childhood-onset parkinsonism is mainly due to genetic alterations and is an exceedingly rare condition, unlike Parkinson's disease (PD), which is one of the most common neurologic disorders in adulthood. The clinical characterization of parkinsonism during early stages of neuromotor development is controversial due to the lack of consensus regarding the clinical criteria of PD or parkinsonism in the immature brain. The classification here proposed is based on a review of conditions that emerge during infancy and childhood, with key symptoms evocative of adult parkinsonism. The proposed nosography is based on age at presentation, clinical features, outcome, and etiological background. It includes developmental parkinsonism, infantile degenerative parkinsonism, parkinsonism in the setting of neurodevelopmental disorders, parkinsonism in the setting of multisystem brain diseases, juvenile parkinsonism and dystonia-parkinsonism, and acquired parkinsonism. The subgroups denoting peculiar clinical presentations as a consequence of disease impact on the immature brain are developmental parkinsonism due to monoamine metabolic disorders and infantile degenerative parkinsonism caused by DAT and WASR2 defects. More tardive parkinsonisms occur in genetic conditions that cause a generalized derangement of neurodevelopmental processes, such as those due to MECP2, NR4A2, SCN1A, and RAB39B. Some conditions presenting with neurodevelopmental disorder can progress later, disclosing their neurodegenerative nature (i.e. WDR45 and KCND3). Finally, new emerging conditions with childhood-onset parkinsonism arise from the cumulative effect of multiple genetic lesions.
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PMID:Parkinsonism in children: Clinical classification and etiological spectrum. 3310 74


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