| 1. |
- Andrikopoulos, Petros, et al.
(author)
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Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide
- 2023
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In: Nature Communications. - 2041-1723 .- 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
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| 2. |
- Mickael, Michel E., et al.
(author)
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An optimised phylogenetic method sheds more light on the main branching events of rhodopsin-like superfamily
- 2016
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In: Comparative Biochemistry and Physiology - Part D. - : Elsevier BV. - 1744-117X .- 1878-0407. ; 20, s. 85-94
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Journal article (peer-reviewed)abstract
- The comparative genomics between different rhodopsin-like family groups (alpha, beta, gamma and delta) is not well studied. We used a combination of phylogenetic analysis and statistical genomic methods to compare rhodopsin-like family proteins in species likely symbolic of this family's evolutionary progression. For intra-cluster relationships, we applied mathematical optimisation to enhance the tree search produced by the neighbour joining method (NJ) and compared it with maximum likelihood (ML) method. To infer inter-clusters relationships, we used Needleman-Wuns chanalysis (NW), HHsearch, ancestral sequence reconstruction and phylogenetic network analysis. Using this workflow, we were able to identify key evolutionary events in the rhodopsin-like family receptors. We found that a rhodopsin-like group gave rise to the 13 group, while the gamma rhodopsin-like group diverged from the 13 group. We tracked the diversification of every cluster, revealing that fungal opsin is the most ancient member of the a group, while adenosine receptors could be the first member to diverge in the MECA (melanocortin, endothelial differentiation sphingolipid, cannabinoid, and adenosine receptors) subfamily and that histamine receptors could be the parent of the amines receptors, while hypocretin receptors might be the most ancient member of the beta group. SOG (somatostatin, opioid, galanin) receptors formed the most ancient members of the gamma group. Our analysis indicated that basal receptors might be playing a role in early evolution of the nervous system. This is evident in Trichoplax adhaerens genome, where we located histamine receptors and adenosine receptors.
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| 3. |
- Xie, Kan, et al.
(author)
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Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 115:10, s. E2348-E2357
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Journal article (peer-reviewed)abstract
- Advanced age is not only a major risk factor for a range of disorders within an aging individual but may also enhance susceptibility for disease in the next generation. In humans, advanced paternal age has been associated with increased risk for a number of diseases. Experiments in rodent models have provided initial evidence that paternal age can influence behavioral traits in offspring animals, but the overall scope and extent of paternal age effects on health and disease across the life span remain underexplored. Here, we report that old father offspring mice showed a reduced life span and an exacerbated development of aging traits compared with young father offspring mice. Genome-wide epigenetic analyses of sperm from aging males and old father offspring tissue identified differentially methylated promoters, enriched for genes involved in the regulation of evolutionarily conserved longevity pathways. Gene expression analyses, biochemical experiments, and functional studies revealed evidence for an overactive mTORC1 signaling pathway in old father offspring mice. Pharmacological mTOR inhibition during the course of normal aging ameliorated many of the aging traits that were exacerbated in old father offspring mice. These findings raise the possibility that inherited alterations in longevity pathways contribute to intergenerational effects of aging in old father offspring mice.
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