Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain
- Preston, Sarah, Korhonen, Pasi, Mouchiroud, Laurent, Cornaglia, Matteo, McGee, Sean, Young, Neil, Davis, Rohan, Crawford, Simon, Nowell, Cameron, Ansell, Brendan, Fisher, Gillian, Andrews, Katherine, Chang, Bill, Gijs, Martin, Sternberg, Paul, Auwerx, Johan, Baell, Jonathan, Hofmann, Andreas, Jabbar, Abdul, Gasser, Robin
- Authors: Preston, Sarah , Korhonen, Pasi , Mouchiroud, Laurent , Cornaglia, Matteo , McGee, Sean , Young, Neil , Davis, Rohan , Crawford, Simon , Nowell, Cameron , Ansell, Brendan , Fisher, Gillian , Andrews, Katherine , Chang, Bill , Gijs, Martin , Sternberg, Paul , Auwerx, Johan , Baell, Jonathan , Hofmann, Andreas , Jabbar, Abdul , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: FASEB Journal Vol. 31, no. 10 (2017), p. 4515-4532
- Full Text: false
- Reviewed:
- Description: As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation. © FASEB.
A perspective on genomic-guided anthelmintic discovery and repurposing using Haemonchus contortus
- Preston, Sarah, Jabbar, Abdul, Gasser, Robin
- Authors: Preston, Sarah , Jabbar, Abdul , Gasser, Robin
- Date: 2016
- Type: Text , Journal article
- Relation: Infection, Genetics and Evolution Vol. 40, no. (2016), p. 368-373
- Full Text: false
- Reviewed:
- Description: High-throughput molecular and computer technologies have become instrumental for systems biological explorations of parasites. Investigating the genomes and transcriptomes of different developmental stages of parasitic nematodes can provide insights into gene expression, regulation and function in the parasite, which is a significant step toward understanding their biology as well as host interactions and disease. This article covers aspects of a talk given at the MEEGID XII conference in Thailand in 2014. Here, we refer to recent studies of the genomes and transcriptomes of socioeconomically important parasitic nematodes of animals; provide an account of the barber's pole worm (Haemonchus contortus) and emerging drug resistance problems in this and related worms; we also propose a genomic-guided drug discovery and repurposing approach, involving the prediction of the druggable genome, prioritization of drug targets, screening of compound libraries against H. contortus and, briefly, a hit-to-lead optimization approach. We conclude by indicating prospects that molecular tool kits for nematodes provide to the scientific community for future comparative genomic, genetic, proteomic, metabolomic, evolutionary, biological, ecological and epidemiological investigations, and as a basis for biotechnological outcomes and translation. © 2015 Elsevier B.V.
Genetic and epigenetic changes associated with polygenic left ventricular hypertrophy
- Authors: Prestes, Priscilla
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.
- Description: Doctor of Philosophy
- Authors: Prestes, Priscilla
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: Cardiac hypertrophy (CH) is the thickening of heart muscles reducing functionality and increasing risk of cardiac disease. Commonly, pathological CH is presented as left ventricular hypertrophy (LVH) and genetic factors are known to be involved but their contribution is still poorly understood. I used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of LVH, and its control strain, the normal heart rat (NHR) to investigate genetic and epigenetic contributions to LVH independent of high blood pressure. To address this study, I used a systematic approach. Firstly, I sequenced the whole genome of HHR and NHR to identify genes related to LVH, focusing on quantitative trait locus Cm22. I found the gene for tripartite motif-containing 55 (Trim55) was significantly downregulated and also presented decreased protein expression with the presence of one exonic missense mutation that altered the protein structure. Interestingly, Trim55 mRNA expression was reduced in idiopathic dilated cardiomyopathic hearts. Secondly, I selected 42 genes previously described in monogenic forms of human cardiomyopathies and studied DNA variants, mRNA and micro RNA (miRNA) expression to determine their involvement in this polygenic model of LVH at five ages. This comprehensive approach identified the differential expression of 29 genes in at least one age group and two miRNAs in validated miRNA-mRNA interactions. These two miRNAs have binding sites for five of the genes studied. Lastly, I found circular RNA (circRNA) Hrcr was upregulated in the hypertrophic heart. I then silenced Hrcr expression in human primary cardiomyocytes to investigate its miRNA downstream targets and elucidate possible regulatory mechanisms. I described four miRNAs (miR-1-3p, miR-330, miR-27a-5p, miR-299-5p) as novel targets for HRCR and predicted 359 mRNA targets in the circRNA-miRNA-mRNA regulatory axis. In silico analysis identified 206 enriched gene ontology based on the predicted mRNA target list, including cardiomyocyte differentiation and ventricular cardiac muscle cell differentiation. The findings in this thesis suggest that 1) Trim55 is a novel functional candidate gene for polygenic LVH; 2) genes implicated in monogenic forms of cardiomyopathy may be involved in this condition and 3) circRNA expression is associated with changes in hypertrophic hearts and deserve further attention.
- Description: Doctor of Philosophy
An examination of peripheral blood to reflect transcriptomic adaptation to physical exercise training in sedentary men compared with sex-matched athletic phenotypes
- Authors: Marin, Sergio
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: There is renewed interest in exercise genomics that peripheral blood RNA expression may be important to understand exercise mediated adaptations to exercise. However, there is little direct supporting evidence. Therefore, this thesis involved two studies to examine the relationship between RNA expression and exercise, and two experimental studies to examine relationships and adaptive response of peripheral blood RNA in sedentary compared with athletic phenotypes. In the first two studies, we conducted both meta-analysis and network meta-analysis to examine current randomised controlled trial (RCT) evidence to determine current best evidence on the link between RNA expression and athletic phenotype in addition to head-to-head comparison of different exercise types to induce differential expression of RNA transcripts in sedentary compared with athletic phenotypes. We observed that current available body of RCTs in peripheral blood exercise genomics presents too large heterogeneity in study design, methodological and data reporting aspects. Thus, we concluded that peripheral blood cannot be established as a valid source for identifying, neither the effect of physical exercise training on transcriptomic markers nor the distinction of divergent transcriptomic profiles in response to different exercise modalities. In the third and fourth studies, we aimed to determine whether peripheral blood RNA and circular RNA (circRNA) expression was different between sedentary and athletic phenotypes, and whether these transcripts were consistent in response to exercise training in exercise-naïve men. To achieve this, we conducted two STROBE compliant observational experiments of n=71 participants with distinct athletic phenotypes. We concluded that peripheral blood transcriptome expression might allow for identification of divergent athletic phenotypes, although this is not supported by further examination of peripheral blood RNA expression levels in response to an exercise training intervention. The sum of works presented in this thesis does not agree with many propositions relating to the strength of evidence in peripheral blood transcriptomics literature. This is principally due to the heterogeneity and lack of consistency of research in this field which is currently insufficient to provide any strong conclusions. In conclusion, peripheral blood RNA and circRNA do not yet offer useful avenues to predict the adaptive response to different exercise types in athletic and non-athletic men.
- Description: Doctor of Philosophy
- Authors: Marin, Sergio
- Date: 2021
- Type: Text , Thesis , PhD
- Full Text:
- Description: There is renewed interest in exercise genomics that peripheral blood RNA expression may be important to understand exercise mediated adaptations to exercise. However, there is little direct supporting evidence. Therefore, this thesis involved two studies to examine the relationship between RNA expression and exercise, and two experimental studies to examine relationships and adaptive response of peripheral blood RNA in sedentary compared with athletic phenotypes. In the first two studies, we conducted both meta-analysis and network meta-analysis to examine current randomised controlled trial (RCT) evidence to determine current best evidence on the link between RNA expression and athletic phenotype in addition to head-to-head comparison of different exercise types to induce differential expression of RNA transcripts in sedentary compared with athletic phenotypes. We observed that current available body of RCTs in peripheral blood exercise genomics presents too large heterogeneity in study design, methodological and data reporting aspects. Thus, we concluded that peripheral blood cannot be established as a valid source for identifying, neither the effect of physical exercise training on transcriptomic markers nor the distinction of divergent transcriptomic profiles in response to different exercise modalities. In the third and fourth studies, we aimed to determine whether peripheral blood RNA and circular RNA (circRNA) expression was different between sedentary and athletic phenotypes, and whether these transcripts were consistent in response to exercise training in exercise-naïve men. To achieve this, we conducted two STROBE compliant observational experiments of n=71 participants with distinct athletic phenotypes. We concluded that peripheral blood transcriptome expression might allow for identification of divergent athletic phenotypes, although this is not supported by further examination of peripheral blood RNA expression levels in response to an exercise training intervention. The sum of works presented in this thesis does not agree with many propositions relating to the strength of evidence in peripheral blood transcriptomics literature. This is principally due to the heterogeneity and lack of consistency of research in this field which is currently insufficient to provide any strong conclusions. In conclusion, peripheral blood RNA and circRNA do not yet offer useful avenues to predict the adaptive response to different exercise types in athletic and non-athletic men.
- Description: Doctor of Philosophy
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