Characterization of the xenobiotic response of Caenorhabditis elegans to the anthelmintic drug albendazole and the identification of novel drug glucoside metabolites

2010 ◽  
Vol 432 (3) ◽  
pp. 505-516 ◽  
Author(s):  
Steven T. Laing ◽  
Al Ivens ◽  
Roz Laing ◽  
Sai Ravikumar ◽  
Victoria Butler ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Metabolizing Enzymes ◽  
C Elegans ◽  
Genes Encoding ◽  
Minimal Importance ◽  
Xenobiotic Response ◽  
Novel Drug ◽  
Anthelmintic Drugs

Knowledge of how anthelmintics are metabolized and excreted in nematodes is an integral part of understanding the factors that determine their potency, spectrum of activity and for investigating mechanisms of resistance. Although there is remarkably little information on these processes in nematodes, it is often suggested that they are of minimal importance for the major anthelmintic drugs. Consequently, we have investigated how the model nematode Caenorhabditis elegans responds to and metabolizes albendazole, one of the most important anthelmintic drugs for human and animal use. Using a mutant strain lacking the β-tubulin drug target to minimize generalized stress responses, we show that the transcriptional response is dominated by genes encoding XMEs (xenobiotic-metabolizing enzymes), particularly cytochrome P450s and UGTs (UDP-glucuronosyl transferases). The most highly induced genes are predominantly expressed in the worm intestine, supporting their role in drug metabolism. HPLC-MS/MS revealed the production of two novel glucoside metabolites in C. elegans identifying a major difference in the biotransformation of this drug between nematodes and mammals. This is the first demonstration of metabolism of a therapeutic anthelmintic in C. elegans and provides a framework for its use to functionally investigate nematode anthelmintic metabolism.

Rubidium chloride increases lifespan through an AMPK/FOXO-dependent pathway in Caenorhabditis elegans

2021 ◽  
Author(s):  
Mengjiao Hao ◽  
Zhikang Zhang ◽  
Yijun Guo ◽  
Huihao Zhou ◽  
Qiong Gu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Aging Effect ◽  
Stress Effect ◽  
Neuroprotective Effects ◽  
C Elegans ◽  
Cycle Arrest ◽  
Age Related ◽  
Promising Target ◽  
Amp Activated Protein Kinase

Abstract AMP-activated protein kinase (AMPK) is involved in life span maintenance, stress responses, and germ cell cycle arrest upon dauer entry. AMPK is currently considered a promising target for preventing age-related diseases. Rubidium is one of the trace elements in human body. As early as the 1970s, RbCl has been was reported to have neuroprotective effects. In this work, we report the anti-aging effect of RbCl in Caenorhabditis elegans. Specifically, we reveal that (1) RbCl does increase the lifespan and enhance stress resistance in C. elegans without disturbing their fecundity. (2) RbCl induces superoxide dismutase (SOD) expression, which is essential for its anti-aging and anti-stress effect. (3) AAK-2 and DAF-16 are essential to the anti-aging efficacy of RbCl, and RbCl can promote DAF-16 translocating into the nucleus, suggesting that RbCl delays aging through regulating AMPK/FOXO pathway. RbCl can be a promising agent against aging related diseases.

scholarly journals In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria

2020 ◽  
Vol 21 (21) ◽  
pp. 7813
Author(s):  
Kiho Lee ◽  
Iliana Escobar ◽  
Yeeun Jang ◽  
Wooseong Kim ◽  
Frederick M. Ausubel ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Kinase Gene ◽  
Concentration Dependent Manner ◽  
C Elegans ◽  
Opportunistic Bacteria ◽  
Free Living Nematode

Sphingosine-1-phophate (S1P) is a sphingolipid-derived signaling molecule that controls diverse cellular functions including cell growth, homeostasis, and stress responses. In a variety of metazoans, cytosolic S1P is transported into the extracellular space where it activates S1P receptors in a concentration-dependent manner. In the free-living nematode Caenorhabditis elegans, the spin-2 gene, which encodes a S1P transporter, is activated during Gram-positive or Gram-negative bacterial infection of the intestine. However, the role during infection of spin-2 and three additional genes in the C. elegans genome encoding other putative S1P transporters has not been elucidated. Here, we report an evolutionally conserved function for S1P and a non-canonical role for S1P transporters in the C. elegans immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene (sphk-1) or in the S1P transporter genes spin-2 or spin-3 decreased nematode survival after infection with Pseudomonas aeruginosa or Enterococcus faecalis. In contrast to spin-2 and spin-3, mutating spin-1 leads to an increase in resistance to P. aeruginosa. Consistent with these results, when wild-type C. elegans were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with P. aeruginosa and E. faecalis. In comparison, spin-2 and spin-3 mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the spin-1 mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward P. aeruginosa and Escherichia coli and only minimal activity against E. faecalis MMH594 (40 µM). These data suggest that spin-2 and spin-3, on the one hand, and spin-1, on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in C. eleganssek-1 and pmk-1 mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.

A cilia-mediated environmental input induces solitary behaviour in Caenorhabditis elegans and Pristionchus pacificus nematodes

Nematology ◽  
2018 ◽  
Vol 20 (3) ◽  
pp. 201-209 ◽  
Author(s):  
Eduardo Moreno ◽  
Ralf J. Sommer
Keyword(s):  
Caenorhabditis Elegans ◽  
Social Behaviour ◽  
Intraflagellar Transport ◽  
Large Protein ◽  
Pristionchus Pacificus ◽  
C Elegans ◽  
The Social ◽  
Genes Encoding ◽  
Social Behaviours ◽  
Ciliated Neurons

Nematodes respond to a multitude of environmental cues. For example, the social behaviours clumping and bordering were described as a mechanism of hyperoxia avoidance in Caenorhabditis elegans and Pristionchus pacificus. A recent study in P. pacificus revealed a novel regulatory pathway that inhibits social behaviour in a response to an as yet unknown environmental cue. This environmental signal is recognised by ciliated neurons, as mutants defective in intraflagellar transport (IFT) proteins display social behaviours. The IFT machinery represents a large protein complex and many mutants in genes encoding IFT proteins are available in C. elegans. However, social phenotypes in C. elegans IFT mutants have never been reported. Here, we examined 15 previously isolated C. elegans IFT mutants and found that most of them showed strong social behaviour. These findings indicate conservation in the inhibitory mechanism of social behaviour between P. pacificus and C. elegans.

scholarly journals Mitochondrial Dysfunction Confers Resistance to Multiple Drugs in Caenorhabditis elegans

2010 ◽  
Vol 21 (6) ◽  
pp. 956-969 ◽  
Author(s):  
Iryna O. Zubovych ◽  
Sarah Straud ◽  
Michael G. Roth
Keyword(s):  
Drug Resistance ◽  
Caenorhabditis Elegans ◽  
Mitochondrial Protein ◽  
Drug Resistant ◽  
Wild Type ◽  
C Elegans ◽  
Mitochondrial Inhibitors ◽  
Mitochondrial Superoxide ◽  
Genes Encoding ◽  
Multiple Drugs

In a previous genetic screen for Caenorhabditis elegans mutants that survive in the presence of an antimitotic drug, hemiasterlin, we identified eight strong mutants. Two of these were found to be resistant to multiple toxins, and in one of these we identified a missense mutation in phb-2, which encodes the mitochondrial protein prohibitin 2. Here we identify two additional mutations that confer drug resistance, spg-7 and har-1, also in genes encoding mitochondrial proteins. Other mitochondrial mutants, isp-1, eat-3, and clk-1, were also found to be drug-resistant. Respiratory complex inhibitors, FCCP and oligomycin, and a producer of reactive oxygen species (ROS), paraquat, all rescued wild-type worms from hemiasterlin toxicity. Worms lacking mitochondrial superoxide dismutase (MnSOD) were modestly drug-resistant, and elimination of MnSOD in the phb-2, har-1, and spg-7 mutants enhanced resistance. The antioxidant N-acetyl-l-cysteine prevented mitochondrial inhibitors from rescuing wild-type worms from hemiasterlin and sensitized mutants to the toxin, suggesting that a mechanism sensitive to ROS is necessary to trigger drug resistance in C. elegans. Using genetics, we show that this drug resistance requires pkc-1, the C. elegans ortholog of human PKCε.

scholarly journals Fabrication of sharp silicon arrays to wound Caenorhabditis elegans

2019 ◽  
Author(s):  
Jérôme Belougne ◽  
Igor Ozerov ◽  
Céline Caillard ◽  
Frédéric Bedu ◽  
Jonathan J. Ewbank
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Optical Lithography ◽  
Wet Etching ◽  
C Elegans ◽  
Genes Encoding ◽  
Nematode Cuticle ◽  
Peptide Gene ◽  
Silicon Arrays ◽  
Regular Arrays

ABSTRACTUnderstanding how animals respond to injury and how wounds heal remains a challenge. These questions can be addressed using genetically tractable animals, including the nematode Caenorhabditis elegans. Given its small size, the current methods for inflicting wounds in a controlled manner are demanding. To facilitate and accelerate the procedure, we fabricated regular arrays of pyramidal features (“pins”) sharp enough to pierce the tough nematode cuticle. The pyramids were made from monocrystalline silicon wafers that were micro-structured using optical lithography and alkaline wet etching. The fabrication protocol and the geometry of the pins, determined by electron microscopy, are described in detail. Upon wounding, C. elegans expresses genes encoding antimicrobial peptides. A comparison of the induction of antimicrobial peptide gene expression using traditional needles and the pin arrays demonstrates the utility of this new method.

Analysis of the VPE sequences in the Caenorhabditis elegans vit-2 promoter with extrachromosomal tandem array-containing transgenic strains

1994 ◽  
Vol 14 (1) ◽  
pp. 484-491
Author(s):  
M MacMorris ◽  
J Spieth ◽  
C Madej ◽  
K Lea ◽  
T Blumenthal
Keyword(s):  
Caenorhabditis Elegans ◽  
Fusion Gene ◽  
Caenorhabditis Briggsae ◽  
Unique Role ◽  
Promoter Function ◽  
C Elegans ◽  
Low Copy Number ◽  
Genes Encoding ◽  
Transgenic Lines ◽  
Adult Hermaphrodite

The Caenorhabditis elegans vit genes, encoding vitellogenins, are abundantly expressed in the adult hermaphrodite intestine. Two repeated elements, vit promoter element 1 (VPE1 [TGTCAAT]) and VPE2 (CTGATAA), have been identified in the 5' flanking DNA of each of the vit genes of C. elegans and Caenorhabditis briggsae. These elements have previously been shown to be needed for correctly regulated expression of a vit-2/vit-6 fusion gene in low-copy-number, integrated transgenes. Here we extend the analysis of the function of VPE1 and VPE2 by using transgenic lines carrying large, extrachromosomal arrays of the test genes. The results validate the use of such arrays for transgenic analysis of gene regulation in C. elegans, by confirming previous findings showing that the VPE1 at -45 and both VPE2s are sites of activation. Additional experiments now indicate that when the -45 VPE1 is inverted or replaced by a VPE2, nearly total loss of promoter function results, suggesting that the highly conserved -45 VPE1 plays a unique role in vit-2 promoter function. In contrast, single mutations eliminating the three upstream VPE1s are without effect. However, in combination in double and triple mutants, these upstream VPE1 mutations cause drastic reductions in expression levels. The -150 VPE2 can be replaced by a XhoI site (CTCGAG), and the -90 VPE2 can be eliminated, as long as the overlapping VPE1 is left intact, but when these two replacements are combined, activity is lost. Thus, the promoter must have at least one VPE2 and it must have at least two VPE1s, one at -45 and one additional upstream element.

abf-1 and abf-2, ASABF-type antimicrobial peptide genes in Caenorhabditis elegans

2002 ◽  
Vol 361 (2) ◽  
pp. 221-230 ◽  
Author(s):  
Yusuke KATO ◽  
Tomoyasu AIZAWA ◽  
Hirokazu HOSHINO ◽  
Keiichi KAWANO ◽  
Katsutoshi NITTA ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Antimicrobial Peptide ◽  
Fluorescent Protein ◽  
Fusion Gene ◽  
C Elegans ◽  
Specific Distribution ◽  
Genes Encoding ◽  
Precursor Rna ◽  
Factor Type ◽  
Green Fluorescent

Two genes encoding the ASABF (Ascarissuumantibacterial factor)-type antimicrobial peptide, abf-1 and abf-2, were identified in Caenorhabditis elegans. Recombinant ABF-2 exhibited potent microbicidal activity against Gram-positive and Gram-negative bacteria, and yeasts. The tissue-specific distribution estimated by immunofluorescence staining and transgenic analysis of a gfp fusion gene (where GFP corresponds to green fluorescent protein) suggested that ABF-2 contributes to surface defence in the pharynx. abf-1 contains a single intron at a conserved position, suggesting that asabf and abf originated from a common ancestor. Both transcripts for abf-1 and abf-2 were detected as two distinct forms, i.e. spliced leader (SL)1-trans-spliced with a long 5′-untranslated region (UTR) and SL-less with a short 5′-UTR. A polycistronic precursor RNA encoding ABF-1 and ABF-2 was detected, suggesting that these genes form an operon. An ‘opportunistic operon’ model for regulation of abf genes, including the generation of short SL-less transcripts, is proposed. In conclusion, C. elegans should have an immune defence system due to the antimicrobial peptides. C. elegans can be a novel model for innate immunity. Furthermore, the combination of biochemical identification in Ascaris suum and homologue hunting in C. elegans should be a powerful method of finding rapidly evolved proteins, such as some immune-related molecules in C. elegans.

Molecular characterization of the metabotropic glutamate receptor family in Caenorhabditis elegans

2006 ◽  
Vol 34 (5) ◽  
pp. 942-948 ◽  
Author(s):  
J. Dillon ◽  
N.A. Hopper ◽  
L. Holden-Dye ◽  
V. O'Connor
Keyword(s):  
Caenorhabditis Elegans ◽  
Molecular Characterization ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Model Organism ◽  
Metabotropic Glutamate ◽  
C Elegans ◽  
Genes Encoding ◽  
G Protein Coupled

mGluRs (metabotropic glutamate receptors) are G-protein-coupled receptors that play an important neuromodulatory role in the brain. Glutamatergic transmission itself plays a fundamental role in the simple nervous system of the model organism Caenorhabditis elegans, but little is known about the contribution made by mGluR signalling. The sequenced genome of C. elegans predicts three distinct genes, mgl-1, mgl-2 and mgl-3 (designated Y4C6A.2). We have used in silico and cDNA analyses to investigate the genes encoding mgls. Our results indicate that mgl genes constitute a gene family made up of three distinct subclasses of receptor. Our transcript analysis highlights potential for complex gene regulation with respect to both expression and splicing. Further, we identify that the predicted proteins encoded by mgls harbour structural motifs that are likely to regulate function. Taken together, this molecular characterization provides a platform to further investigate mGluR function in the model organism C. elegans.

scholarly journals Caenorhabditis elegans Teneurin, ten-1, Is Required for Gonadal and Pharyngeal Basement Membrane Integrity and Acts Redundantly with Integrin ina-1 and Dystroglycan dgn-1

2008 ◽  
Vol 19 (9) ◽  
pp. 3898-3908 ◽  
Author(s):  
Agnieszka Trzebiatowska ◽  
Ulrike Topf ◽  
Ursula Sauder ◽  
Krzysztof Drabikowski ◽  
Ruth Chiquet-Ehrismann
Keyword(s):  
Caenorhabditis Elegans ◽  
Basement Membrane ◽  
Membrane Integrity ◽  
Precursor Cells ◽  
Basement Membranes ◽  
Synthetic Lethal ◽  
C Elegans ◽  
Somatic Gonad ◽  
Genes Encoding ◽  
Membrane Components

The Caenorhabditis elegans teneurin ortholog, ten-1, plays an important role in gonad and pharynx development. We found that lack of TEN-1 does not affect germline proliferation but leads to local basement membrane deficiency and early gonad disruption. Teneurin is expressed in the somatic precursor cells of the gonad that appear to be crucial for gonad epithelialization and basement membrane integrity. Ten-1 null mutants also arrest as L1 larvae with malformed pharynges and disorganized pharyngeal basement membranes. The pleiotropic phenotype of ten-1 mutant worms is similar to defects found in basement membrane receptor mutants ina-1 and dgn-1 as well as in the mutants of the extracellular matrix component laminin, epi-1. We show that the ten-1 mutation is synthetic lethal with mutations of genes encoding basement membrane components and receptors due to pharyngeal or hypodermal defects. This indicates that TEN-1 could act redundantly with integrin INA-1, dystroglycan DGN-1, and laminin EPI-1 in C. elegans development. Moreover, ten-1 deletion sensitizes worms to loss of nidogen nid-1 causing a pharynx unattached phenotype in ten-1;nid-1 double mutants. We conclude that TEN-1 is important for basement membrane maintenance and/or adhesion in particular organs and affects the function of somatic gonad precursor cells.

scholarly journals Analysis of the VPE sequences in the Caenorhabditis elegans vit-2 promoter with extrachromosomal tandem array-containing transgenic strains.

1994 ◽  
Vol 14 (1) ◽  
pp. 484-491 ◽  
Author(s):  
M MacMorris ◽  
J Spieth ◽  
C Madej ◽  
K Lea ◽  
T Blumenthal
Keyword(s):  
Caenorhabditis Elegans ◽  
Fusion Gene ◽  
Caenorhabditis Briggsae ◽  
Unique Role ◽  
Promoter Function ◽  
C Elegans ◽  
Low Copy Number ◽  
Genes Encoding ◽  
Transgenic Lines ◽  
Adult Hermaphrodite

The Caenorhabditis elegans vit genes, encoding vitellogenins, are abundantly expressed in the adult hermaphrodite intestine. Two repeated elements, vit promoter element 1 (VPE1 [TGTCAAT]) and VPE2 (CTGATAA), have been identified in the 5' flanking DNA of each of the vit genes of C. elegans and Caenorhabditis briggsae. These elements have previously been shown to be needed for correctly regulated expression of a vit-2/vit-6 fusion gene in low-copy-number, integrated transgenes. Here we extend the analysis of the function of VPE1 and VPE2 by using transgenic lines carrying large, extrachromosomal arrays of the test genes. The results validate the use of such arrays for transgenic analysis of gene regulation in C. elegans, by confirming previous findings showing that the VPE1 at -45 and both VPE2s are sites of activation. Additional experiments now indicate that when the -45 VPE1 is inverted or replaced by a VPE2, nearly total loss of promoter function results, suggesting that the highly conserved -45 VPE1 plays a unique role in vit-2 promoter function. In contrast, single mutations eliminating the three upstream VPE1s are without effect. However, in combination in double and triple mutants, these upstream VPE1 mutations cause drastic reductions in expression levels. The -150 VPE2 can be replaced by a XhoI site (CTCGAG), and the -90 VPE2 can be eliminated, as long as the overlapping VPE1 is left intact, but when these two replacements are combined, activity is lost. Thus, the promoter must have at least one VPE2 and it must have at least two VPE1s, one at -45 and one additional upstream element.

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