Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.
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PMID:Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum. 1143 7

The molecular mechanisms regulating cell proliferation and development during the life cycle of malaria parasites remain to be elucidated. The peculiarities of the cell cycle organization during Plasmodium falciparum schizogony suggest that the modalities of cell cycle control in this organism may differ from those in other eukaryotes. Indeed, existing data concerning Plasmodium cell cycle regulators such as cyclin-dependent kinases reveal structural and functional properties that are divergent from those of their homologues in other systems. The work presented here lies in the context of the exploitation of the recently available P. falciparum genome sequence toward the characterization of putative cell cycle regulators. We describe the in silico identification of three open reading frames encoding proteins with maximal homology to various members of the cyclin family and demonstrate that the corresponding polypeptides are expressed in the erythrocytic stages of the infection. We present evidence that these proteins possess cyclin activity by demonstrating either their association with histone H1 kinase activity in parasite extracts or their ability to activate PfPK5, a P. falciparum cyclin-dependent kinase homologue, in vitro. Furthermore, we show that RINGO, a protein with no sequence homology to cyclins but that is nevertheless a strong activator of mammalian CDK1/2, is also a strong activator of PfPK5 in vitro. This raises the possibility that "cryptic" cell cycle regulators may be found among the 50% of the open reading frames in the P. falciparum genome that display no homology to any known proteins.
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PMID:Identification and initial characterization of three novel cyclin-related proteins of the human malaria parasite Plasmodium falciparum. 1286 62

Cyclin dependent protein kinases (CDKs) have become attractive drug targets in an effort to identify effective inhibitors of the parasite Plasmodium falciparum, the causative agent of the most severe form of human malaria. We tested known CDK inhibitors for their ability to inhibit two malarial CDKs: Pfmrk and PfPK5. Many broad spectrum CDK inhibitors failed to inhibit Pfmrk suggesting that the active site differs from other CDKs in important ways. By screening compounds in the Walter Reed chemical database, we identified oxindole-based compounds as effective inhibitors of Pfmrk (IC(50) = 1.5 microM). These compounds have low cross-reactivity against PfPK5 and human CDK1 demonstrating selectivity for Pfmrk. Amino acid comparison of the active sites of Pfmrk and PfPK5 identified unique amino acid differences that may explain this selectivity and be exploited for further drug development efforts.
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PMID:Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. 1293 Jan 49

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for ~80% of all lung cancer cases. The aim of the present study was to identify key genes and pathways in NSCLC, in order to improve understanding of the mechanism of lung cancer. The GSE33532 gene expression dataset, containing 20 normal and 80 NSCLC samples, was used. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to obtain the enrichment data of differently expressed genes (DEGs). Disease modules within NSCLC were constructed by Cytoscape, using protein-protein interaction (PPI) from the Search Tool for the Retrieval of Interacting Genes database. In addition, the Kaplan Meier plotter KMplot was used to assess the top hub genes in the PPI network. As a result, 1,795 genes were identified in NSCLC; 729 were upregulated and 1,066 were downregulated. The results of the GO analysis indicated that the upregulated DEGs were significantly enriched in 'biological processes' (BP), including 'cell cycle and nuclear division'; the downregulated DEGs were also significantly enriched in BP, including 'response to wounding', 'anatomical structure morphogenesis' and 'response to stimulus'. Upregulated DEGs were also enriched in 'cell cycle', 'DNA replication' and the 'tumor protein 53 signaling pathway', while the downregulated DEGs were also enriched in 'complement and coagulation cascades', 'malaria' and 'cell adhesion molecules'. The top 9 hub genes were cyclin-dependent kinase 9 (CDK1), polo-like kinase 1, aurora kinase B, cell division cycle 20, baculoviral initiator of apoptosis repeat containing 5, mitotic checkpoint serine/threonine kinase B, proliferating cell nuclear antigen (PCNA), centromere protein A and MAD2 mitotic arrest deficient-like 1, and the KMplot results revealed that the high expression levels of these genes resulted in significantly low survival rates, compared with low expression samples (P<0.05), with the exception of PCNA and CDK1. In the pathway crosstalk analysis, 26 nodes and 41 interactions were divided into two groups: One module of the two groups primarily included 'metabolism of amino acid' and the other primarily contained 'tumor necrosis signaling' pathways. In conclusion, the present study assisted in improving the understanding of the molecular mechanisms underlying NSCLC development, and the results may help the understanding of the biological mechanism of NSCLC.
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PMID:Hub genes and key pathways of non-small lung cancer identified using bioinformatics. 3000 38

Lung cancer is the world's most common malignancies and ranks first among all cancer-related deaths. Lung adenocarcinoma (LUAD) is the most frequent histological type in lung cancer. Its pathogenesis has not yet been fully elucidated, so it is of great significance to explore related genes for elucidating the molecular mechanism involved in occurrence and development of LUAD.To explore the crucial genes associated with LUAD development and progression, microarray datasets GSE7670, GSE10072, and GSE31547 were acquired from the Gene Expression Omnibus (GEO) database. R language Limma package was adopted to screen the differentially expressed genes (DEGs). The clusterProfiler package was used for enrichment analysis and annotation of the Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways for DEGs. The Search Tool for the Retrieval of Interacting Genes database (STRING) was used to construct the protein interaction network for DEGs, while Cytoscape was adopted to visualize it. The functional module was screened with Cytoscape's MCODE (The Molecular Complex Detection) plugin. The crucial genes associated with LUAD were identified by cytoHubba plugin. Kaplan-Meier plotter online tool was used to perform survival analysis of the hub gene.Three hundred twenty-one DEGs in total were screened, of which 105 were upregulated and 216 were downregulated. It was found that some GO terms and pathways (e.g., collagen trimer, extracellular structure organization, heparin binding, complement and coagulation cascades, malaria, protein digestion and absorption, and PPAR signaling pathway) were considerably enriched in DEGs. UBE2C, TOP2A, RRM2, CDC20, CCNB2, KIAA0101, BUB1B, TPX2, PRC1, and CDK1 were identified as crucial genes. Survival analysis showed that the overexpression of UBE2C, TOP2A, RRM2, CDC20, CCNB2, KIAA0101, BUB1B, TPX2, and PRC1 significantly reduced the overall survival of LUAD patients. One of the crucial genes: UBE2C was validated by immunohistochemistry to be upregulated in LUAD tissues.This study screened out potential biomarkers of LUAD, providing a theoretical basis for elucidating the pathogenesis and evaluating the prognosis of LUAD.
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PMID:Identification of crucial genes associated with lung adenocarcinoma by bioinformatic analysis. 3312 97