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

Jule is the second complete long-terminal-repeat (LTR) Ty3/Gypsy retrotransposon identified to date in vertebrates. Jule, first isolated from the poeciliid fish Xiphophorus maculatus, is 4.8 kb in length, is flanked by two 202-bp LTRs, and encodes Gag (structural core protein) and Pol (protease, reverse transcriptase, RNase H, and integrase, in that order) but no envelope. There are three to four copies of Jule per haploid genome in X. maculatus. Two of them are located in a subtelomeric region of the sex chromosomes, where they are associated with the Xmrk receptor tyrosine kinase genes, of which oncogenic versions are responsible for the formation of hereditary melanoma in Xiphophorus. One almost intact copy of Jule was found in the first intron of the X-chromosomal allele of the Xmrk proto-oncogene, and a second, more corrupted copy is present only 56 nt downstream of the polyadenylation signal of the Xmrk oncogene. Jule-related elements were detected by Southern blot hybridization with less than 10 copies per haploid genome in numerous other poeciliids, as well as in more divergent fishes, including the medakafish Oryzias latipes and the tilapia Oreochromis niloticus. Database searches also identified Jule-related sequences in the zebrafish Danio rerio and in both genome project pufferfishes, Fugu rubripes and Tetraodon nigroviridis. Phylogenetic analysis revealed that Jule is the first member of the Mag family of Ty3/Gypsy retrotransposons described to date in vertebrates. This family includes the silkworm Mag and sea urchin SURL retrotransposons, as well as sequences from the nematode Caenorhabditis elegans. Additional related elements were identified in the genomes of the malaria mosquito Anopheles gambiae and the nematode Ascaris lumbricoides. Phylogeny of Mag-related elements suggested that the Mag family of retrotransposons is polyphyletic and is constituted of several ancient lineages that diverged before their host genomes more than 600 MYA.
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PMID:Jule from the fish Xiphophorus is the first complete vertebrate Ty3/Gypsy retrotransposon from the Mag family. 1115 69

Testosterone (T) is known to induce persistent susceptibility to blood-stage malaria of Plasmodium chabaudi in otherwise resistant female C57BL/6 mice, which is associated with permanent changes in mRNA expression of the liver. Here, we investigate the spleen as the major effector against blood-stage malaria for any possible T-induced long-term effects on lincRNA and mRNA expression. Female C57BL/6 mice were treated with T for 3 weeks, then T was withdrawn for 12 weeks before challenging with P. chabaudi. LincRNA and mRNA expression was examined after 12 weeks of T-withdrawal and after subsequent infections using Agilent whole mouse genome oligo microarrays. Our data show for the first time long-term effects of T on lincRNA expression evidenced directly as persistent changes after T-withdrawal for 12 weeks and indirectly as altered responsiveness of expression to P. chabaudi infections. There are 3 lincRNA-species upregulated and 10 lincRNAs downregulated by more than 2-fold (p<0.01). In addition, 11 and 10 mRNAs are persistently up- and downregulated by T, respectively. These changes remain not sustained during infections at peak parasitemia, when 15 other lincRNAs and 9 other mRNAs exhibit an altered expression. The only exception is the Tnk1-mRNA encoding the non-receptor tyrosine kinase 1 that is persistently downregulated by 0.34-fold after T-withdrawal and that becomes upregulated by 5.9-fold upon infection at peak parasitemia, suggesting an involvement of tyrosine phosphorylation by Tnk1 in mediating long-term effects of T in the spleen. The T-induced changes in splenic mRNA expression are totally different to those previously observed in the liver. Collectively, our data support the view that T induces long-term organ-specific changes in both lincRNA and mRNA expression, that presumably contribute to organ-specific dysfunctions upon infection with blood-stage malaria of P. chabaudi.
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PMID:Testosterone-induced persistent susceptibility to Plasmodium chabaudi malaria: long-term changes of lincRNA and mRNA expression in the spleen. 2312 41

Malaria is a severe disease and kills over 400,000 people each year. Malarial complications are the main cause of death and include cerebral malaria and malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite antimalarial treatment, lethality rates of MA-ARDS are still between 20 and 80%. Patients develop pulmonary edema with hemorrhages and leukocyte extravasation in the lungs. The vascular endothelial growth factor-A (VEGF-A) and the placental growth factor (PlGF) are vascular permeability factors and may be involved in the disruption of the alveolar-capillary membrane, leading to alveolar edema. We demonstrated increased pulmonary VEGF-A and PlGF levels in lungs of mice with experimental MA-ARDS. Depletion of pathogenic CD8+ T cells blocked pulmonary edema and abolished the increase of VEGF-A and PlGF. However, neutralization of VEGF receptor-2 (VEGFR-2) with the monoclonal antibody clone DC101 did not decrease pulmonary pathology. The broader spectrum receptor tyrosine kinase inhibitor sunitinib even increased lung pathology. These data suggest that the increase in alveolar VEGF-A and PlGF is not a cause but rather a consequence of the pulmonary pathology in experimental MA-ARDS and that therapeutic inhibition of VEGF receptors is not effective and even contra-indicated.
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PMID:Pathogenic CD8+ T Cells Cause Increased Levels of VEGF-A in Experimental Malaria-Associated Acute Respiratory Distress Syndrome, but Therapeutic VEGFR Inhibition Is Not Effective. 2903 14

Macroautophagy (hereafter referred to as autophagy) is a highly conserved, intracellular degradation process characterised by de novo formation of autophagosomes. These double membraned organelles engulf and deliver cargo, for example damaged organelles and protein aggregates, to lysosomes for degradation and recycling. Autophagy is primarily a stress response mechanism activated to survive unfavourable conditions such as starvation or hypoxia. In addition, autophagy functions in differentiation, immune responses against invading microorganisms and tissue remodelling in mammalian cells. Besides its cytoprotective nature, and depending on the context, autophagy can as well support cell death. Based on autophagy&rsquo;s cytoprotective, cytotoxic and developmental influences, it does not come as a surprise that this mechanism is involved in tumourigenesis, tumour development and the response to anticancer therapies. HER2 is a receptor tyrosine kinase that activates downstream signalling pathways involved in cellular survival, growth and proliferation. Amplification of the gene and subsequent overexpression of the HER2 protein lead to increased activation of downstream signalling and are implicated in several cancer types. HER2-targeted therapies are valuable treatment options for HER2 amplified cancers. However, pre-existing and acquired resistance remain a clinical challenge. Autophagy has been discussed in several scenarios in HER2 amplified cancers. Generally, HER2+ tumours have been shown to exhibit low levels of proteins essential for autophagy. Moreover, a protein involved in autophagy activation, Beclin-1, was shown to interact directly with HER2 at the cellular membrane. The signalling cascade activated by HER2 also activates mTOR, a negative regulator of autophagy. In the context of resistance formation against HER2-targeting treatment, autophagy has often been reported to be upregulated, and resistance has been shown to be abrogated through autophagy inhibition. Since the autophagy inhibitors chloroquine and hydroxychloroquine are approved drugs for the treatment of malaria, autophagy inhibition is discussed as an option to enhance the effect of certain anticancer treatments or to overcome resistance against cancer therapies. In this review we focus on autophagy and its role in the response to HER2-targeted therapies for breast and gastrointestinal tumours.
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PMID:The role of autophagy in HER2-targeted therapy. 3165 36

Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.
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PMID:EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria. 3199 7