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[
Environ Int,
2019]
Telomeres (TLs) play major roles in stabilizing the genome and are usually shortened with ageing. The maintenance of TLs is ensured by two mechanisms involving telomerase (TA) enzyme and alternative lengthening telomeres (ALT). TL shortening and/or TA inhibition have been related to health effects on organisms (leading to reduced reproductive lifespan and survival), suggesting that they could be key processes in toxicity mechanisms (at molecular and cellular levels) and relevant as an early warning of exposure and effect of chemicals on human health and animal population dynamics. Consequently, a critical analysis of knowledge about relationships between TL dynamic and environmental pollution is essential to highlight the relevance of TL measurement in environmental toxicology. The first objective of this review is to provide a survey on the basic knowledge about TL structure, roles, maintenance mechanisms and causes of shortening in both vertebrates (including humans) and invertebrates. Overall, TL length decreases with ageing but some unexpected exceptions are reported (e.g., in species with different lifespans, such as the nematode Caenorhabditis elegans or the crustacean Homarus americanus). Inconsistent results reported in various biological groups or even between species of the same genus (e.g., the microcrustacean Daphnia sp.) indicate that the relation usually proposed between TL shortening and a decrease in TA activity cannot be generalized and depends on the species, stage of development or lifespan. Although the scientific literature provides evidence of the effect of ageing on TL shortening, much less information on the relationships between shortening, maintenance of TLs, influence of other endogenous and environmental drivers, including exposure to chemical pollutants, is available, especially in invertebrates. The second objective of this review is to connect knowledge on TL dynamic and exposure to contaminants. Most of the studies published on humans rely on correlative epidemiological approaches and few in vitro experiments. They have shown TL attrition when exposed to contaminants, such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), pesticides and metallic elements (ME). In other vertebrates, the studies we found deals mainly with birds and, overall, report a disturbance of TL dynamic consecutively to exposure to chemicals, including metals and organic compounds. In invertebrates, no data are available and the potential of TL dynamic in environmental risk assessment remains to be explored. On the basis of the main gaps identified some research perspectives (e.g., impact of endogenous and environmental drivers, dose response effects, link between TL length, TA activity, longevity and ageing) are proposed to better understand the potential of TL and TA measurements in humans and animals in environmental toxicology.
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Nat Rev Mol Cell Biol,
2014]
Many organs contain networks of epithelial tubes that transport gases or fluids. A lumen can be generated by tissue that enwraps a pre-existing extracellular space or it can arise de novo either between cells or within a single cell in a position where there was no space previously. Apparently distinct mechanisms of de novo lumen formation observed in vitro - in three-dimensional cultures of endothelial and Madin-Darby canine kidney (MDCK) cells - and in vivo - in zebrafish vasculature, Caenorhabditis elegans excretory cells and the Drosophila melanogaster trachea - in fact share many common features. In all systems, lumen formation involves the structured expansion of the apical plasma membrane through general mechanisms of vesicle transport and of microtubule and actin cytoskeleton regulation.
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[
Hermann, Editeurs des Sciences et des Arts. Paris, France.,
2002]
L'espce Caenorhabditis elegans fut dcrite en 1900 Alger par E. Maupas, qui s'intressait son mode de reproduction hermaphrodite. Plus tard, vers le milieu du vingtime sicle, V. Nigon et ses collaboratuers Lyon tudirent les reorganizations cellulaires accompagnant la fecundation et les premiers clivages. J. Brun isola les preiers mutants morpholgiques.
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Trends Genet,
1997]
The 100 Mb sequence of the nematode Caenorhabditis elegans genome will be completed in 1998. More than 10,000 predicted genes have been identified to date, so it should come as no surprise to find a C. elegans homologue of your favourite gene in current databases. For some investigators, the discovery of a C. elegans homologue represents a unique opportunity to adopt a genetic approach and to take advantage of the extensive repertoire of C. elegans gene characterization and manipulation tools. RNA injection provides a quick and efficient method for obtaining clues about wild-type gene function. Reverse genetic approaches also make it feasible to screen de novo for mutations in specific gene sequences. This review highlights the resources available for analysing a C. elegans homologue, starting from the gene sequence and proceeding to the biological function.
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[
Cell,
1998]
Since the rise of the field of sociobiology, the study of the biological basis of social behavior, scientists have striven to assign genetic origins for a variety of social behaviors. There have been a number of highly publicized and often controversial studies of the basis of human social behavoirs such as sexual orientation and religion. Less trumpeted by the popular press, there have been a number of more credible advances in the genetic analysis of complex behavioral traits. Two papers in the past year, one in this issue of Cell (de Bono and Bargmann, 1998), have established two interesting cases of a molecular basis for complex behaviors that are arguably relevant to social interactions in natural populations. Both have to do with food foraging strategies, one in Drosophila and one in C.
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Exp Neurol,
2019]
Non-mammalian models of CIPN remain relatively sparse, but the knowledge gained from the few published studies suggest that these species have great potential to serve as a discovery platform for new pathways and underlying genetic mechanisms of CIPN. These models permit large-scale genetic and pharmacological screening, and they are highly suitable for in vivo imaging. CIPN phenotypes described in rodents have been confirmed in those models, and conversely, genetic players leading to axon de- and regeneration under conditions of chemotherapy treatment identified in these non-mammalian species have been validated in rodents. Given the need for non-traditional approaches with which to identify new CIPN mechanisms, these models bear a strong potential due to the conservation of basic mechanisms by which chemotherapeutic agents induce neurotoxicity.
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[
Neuron,
1998]
The question of how genes contribute to normal individual differences in behavior has captured our imagination for more than a century. Several fundamental questions come to mind. How do genes and their proteins act in the nervous system and in response to the environment in order to cause individual differences in behavior? Do genetic differences between natural variants arise from alterations in the structural or regulatory region of a gene? Can we predict which genes for behavior, identified by mutant analysis in the laboratory, will have natural allelic variation? Three groundbreaking studies (Osborne et al., 1997; Sawyer et al., 1997; de Bono and Bargmann, 1998) published in the past year demonstrate that we now have the knowledge and technological capability to address these questions empirically. Each study has successfully identified a single major gene for a given behavior and, with the aid of transgenic animals, shown that its gene product is responsible for naturally occurring individual differences
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Qi Y, Cui J, Wang R, Tang C, Shan K, Feng N, Cui G, Chen YQ, Qu H, Fu G, Li J
[
Eur J Med Chem,
2021]
Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is an attractive therapeutic target for diseases characterized by excessive lipid accumulation. Many FASN inhibitors have failed in the clinical trial phase, largely because of poor solubility and safety. In this study, we generated a novel small-molecule FASN inhibitor by structure-based virtual screening. PFI09, the lead compound, is easy to synthesize, and inhibits the lipid synthesis in OP9 mammalian cell line and Caenorhabditis elegans as well as the proliferation of several cancer cell lines via the blockade of FASN. Mechanistic investigations show that PFI09 induces S-phase arrest, cell division reduction and apoptosis. We also develop a chemically stable analog of PFI09, MFI03, which reduces the proliferation of PC3 tumor cells both invitro and invivo, without toxicity to mice. In summary, our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.
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Biochem J,
2001]
Protein phosphatase 2A (PP2A) comprises a family of serine/threonine phosphatases, minimally containing a well conserved catalytic subunit, the activity of which is highly regulated. Regulation is accomplished mainly by members of a family of regulatory subunits, which determine the substrate specificity, (sub)cellular localization and catalytic activity of the PP2A holoenzymes. Moreover, the catalytic subunit is subject to two types of post-translational modification, phosphorylation and methylation, which are also thought to be important regulatory devices. The regulatory ability of PTPA (PTPase activator), originally identified as a protein stimulating the phosphotyrosine phosphatase activity of PP2A, will also be discussed, alongside the other regulatory inputs. The use of specific PP2A inhibitors and molecular genetics in yeast, Drosophila and mice has revealed roles for PP2A in cell cycle regulation, cell morphology and development. PP2A also plays a prominent role in the regulation of specific signal transduction cascades, as witnessed by its presence in a number of macromolecular signalling modules, where it is often found in association with other phosphatases and kinases. Additionally, PP2A interacts with a substantial number of other cellular and viral proteins, which are PP2A substrates, target PP2A to different subcellular compartments or affect enzyme activity. Finally, the de-regulation of PP2A in some specific pathologies will be touched upon.
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Journal of Cell Science,
2004]
How do cells regulate centrosome number? A canonical duplication cycle generates two centrosomes from one in most proliferating cells. Centrioles are key to this process, and molecules such as centrins, SAS-4 and ZYG-1 govern daughter centriole formation. Cdk2 activity probably couples centrosome duplication with the S phase, and a licensing mechanism appears to limit centrosome duplication to once per cell cycle. However, such mechanisms must be altered in some cells - for example, spermatocytes - in which centrosome duplication and DNA replication are uncoupled. There are also alternative pathways of centrosome biogenesis. For example, one centrosome is reconstituted from two gametes at fertilization; in this case, the most common strategy involves differential contributions of centrioles and pericentriolar material (PCM) from each gamete. Furthermore, centrioles can sometimes form de novo from no apparent template. This occurs, for instance, in the early mouse embryo and in parthenogenetic species and might rely on a pre-existing seed that resides within PCM but is not visible by