Vilasboas-Campos D et al. (2020) Free Radic Biol Med "Neurotherapeutic effect of Hyptis spp. leaf extracts in Caenorhabditis elegans models of tauopathy and polyglutamine disease: role of the glutathione redox cycle."

Costa MD, Bessa C, Dias ACP, Vilasboas-Campos D, Rios R, Maciel P, Silva FG, Teixeira-Castro A

[Free Radic Biol Med, 2020]

Hyptis suaveolens (HS), Hyptis pectinata (HP) and Hyptis marrubioides (HM) are plants used in folk medicine for treatment of several diseases. Here, we tested the in vivo antioxidant and neuroprotective potential of methanolic extracts from these plants, containing several rosmarinic acid derivatives and isoquercetin. In C. elegans, HS, HP and HM leaf extracts enhanced the antioxidant responses through the induction of specific antioxidant enzymes and demonstrated neurotherapeutic potential in transgenic models of genetically determined human neurodegenerative diseases - frontotemporal dementia with parkinsonism linked to chromosome 17 and Machado-Joseph disease. Chronic treatment of disease models with HS, HP and HM leaf extracts improved the animals' motor function and increased their tolerance to an oxidative insult. The restorative effect of HM extract in motor performance of both disease models required the presence of glutathione reductase (gsr-1), an enzyme that assures the glutathione redox cycle, highlighting the role of this pathway and unveiling a common candidate therapeutic target for these diseases. Our findings strengthen the relevance of plant-derived bioactive compound discovery for neurodegenerative disorders that remain without effective treatment.

Sterba JP (1976) Worm Breeder's Gazette "News and Technical Notes: Worms Have Turned Into an Expanding, Profitable Business"

Sterba JP

[Worm Breeder's Gazette, 1976]

HOUSTON, July 26--Just as Cervantes and Shakespeare said it would, the once trod-upon worm has turned. Like an underground movie starlet, the worm has been transformed from rural hick into celebrity chic by shrewd promotion, abundant potential and, recently, by famous-name identification.

Wakabayashi T et al. (2020) Biol Trace Elem Res "Multiple Chemosensory Neurons Mediate Avoidance Behavior to Rare Earth Ions in Caenorhabditis elegans."

Wakabayashi T, Nojiri Y, Takahashi-Watanabe M

[Biol Trace Elem Res, 2020]

As rare earth (RE) metals are abundantly present in the soil, in spite of their name, it is conceivable that organisms may encounter and interact with RE ions. In the present study, we demonstrated that the soil nematode Caenorhabditis elegans avoids RE ions, such as yttrium and all examined lanthanide ions, which exhibit toxic effects on nematodes. We also demonstrated that the chemosensory system of this animal mediates avoidance behavior toward RE ions similar to heavy metal (HM) ion avoidance. The C. elegans dyf-11(pe554) mutant is unable to respond to chemosensory cues because it lacks all ciliated endings of the chemosensory neurons required for the detection of environmental chemicals. Cell-specific rescue of the dyf-11 mutant and cell-specific genetic ablation studies revealed that the avoidance behavior toward HM and RE ions was mediated by a partially overlapping but distinct subset of chemosensory neurons (ASH, ADL, ASE, ADF, and ASK). With the help of multiple chemosensory neurons, worms may improve the fidelity of avoidance behavior to evade RE ions. Among the chemosensory neurons in C. elegans, ADF and ASK neurons were involved in RE avoidance, but not in HM avoidance. These results suggested that ADF and ASK neurons in C. elegans have RE-selective mechanisms to mediate the avoidance response.

Balamurugan K et al. (2007) Am J Physiol Cell Physiol "Cloning and functional characterization of a folate transporter from the nematode Caenorhabditis elegans."

Said HM, Balamurugan K, Sze JY, Ashokkumar B, Moussaif M

[Am J Physiol Cell Physiol, 2007]

Two putative orthologs to the human reduced folate carrier (hRFC) folt-1 and folt-2 that share a 40% and 31% identity, respectively, with the hRFC sequence have been identified in the C. elegans genome. Functional characterization of the open reading frame of putative folt-1 and folt-2 showed the folt-1 to be a specific folate transporter. Transport of folate by folt-1 expressed in a heterologous expression system showed an acidic pH-dependence, saturability (apparent Km of 1.23 +/- 0.18 microM), similar degree of inhibition by reduced and substituted folate derivatives, sensitivity to the anti-inflammatory drug sulfasalazine (apparent Ki of 0.13 mM), and inhibition by the anion transport inhibitors, e.g., 4,4''-diisothio-cyanatostilbene-2,2''-disulphonic acid (DIDS). Knocking down or knocking out the folt-1 gene led to a significant inhibition in folate uptake by intact living C. elegans. We also cloned the 5''-regulatory region of folt-1 gene, and confirmed promoter activity of the construct in vivo in living C. elegans. Using the transcriptional fusion construct (i.e., folt-1::GFP), the expression pattern of folt-1 in different tissues of living animal was found to be highest in the pharynx and intestine. Also, folt-1::GFP expression was developmentally and adaptively regulated in vivo. These studies demonstrate for the first time the existence of a specialized folate uptake system in C. elegans that has similar characteristics to that of folate uptake process of the human intestine. Thus, C. elegan provides a genetically tractable model that can be used for integrative aspects of the folate uptake process in the context of the whole animal level. Key words: C. elegans, integrative transport physiology, folate transport, transport regulation.

Biswas A et al. (2013) PLoS One "Identification and functional characterization of the Caenorhabditis elegans riboflavin transporters rft-1 and rft-2."

Biswas A, LaMunyon CW, Rothman J, Elmatari D, Said HM

[PLoS One, 2013]

Two potential orthologs of the human riboflavin transporter 3 (hRFVT3) were identified in the C. elegans genome, Y47D7A.16 and Y47D7A.14, which share 33.7 and 30.5% identity, respectively, with hRFVT3. The genes are tandemly arranged, and we assign them the names rft-1 (for Y47D7A.16) and rft-2 (for Y47D7A.14). Functional characterization of the coding sequences in a heterologous expression system demonstrated that both were specific riboflavin transporters, although the rft-1 encoded protein had greater transport activity. A more detailed examination of rft-1 showed its transport of riboflavin to have an acidic pH dependence, saturability (apparent Km = 1.4 +/- 0.5 M), inhibition by riboflavin analogues, and Na(+) independence. The expression of rft-1 mRNA was relatively higher in young larvae than in adults, and mRNA expression dropped in response to RF supplementation. Knocking down the two transporters individually via RNA interference resulted in a severe loss of fertility that was compounded in a double knockdown. Transcriptional fusions constructed with two fluorophores (rft-1::GFP, and rft-2::mCherry) indicated that rft-1 is expressed in the intestine and a small subset of neuronal support cells along the entire length of the animal. Expression of rft-2 is localized mainly to the intestine and pharynx. We also observed a drop in the expression of the two reporters in animals that were maintained in high riboflavin levels. These results report for the first time the identification of two riboflavin transporters in C. elegans and demonstrate their expression and importance to metabolic function in worms. Absence of transporter function renders worms sterile, making them useful in understanding human disease associated with mutations in hRFVT3.

Fajardo C et al. (2022) Environ Toxicol Pharmacol "Copper and Chrkomium Toxicity is Mediated by Oxidative Stress in Caenorhabditis elegans: The Use of Nanoparticles as an Immobilization Strategy."

Fajardo C, Costa G, Martin C, Martin M, Sanchez-Fortun S, Garrido E, Nande M

[Environ Toxicol Pharmacol, 2022]

Environmental contamination by heavy metals (HMs) has impelled searching for stabilization strategies, where the use of zero-valent iron nanoparticles (nZVI) is considered a promising option. We have evaluated the combined effect of Cu(II)-Cr(VI) on two Caenorhabditis elegans strains (N2 and RB1072 sod-2 mutant) in aqueous solutions and in a standard soil, prior and after treatment with nZVI (5% w/w). The results showed that HMs aqueous solutions had an intense toxic effect on both strains. Production of reactive oxygen species and enhanced expression of the heat shock protein Hsp-16.2 was observed, indicating increased HM-mediated oxidative stress. Toxic effects of HM-polluted soil on worms were higher for sod-2 mutant than for N2 strain. However, nZVI treatment significantly diminished all these effects. Our findings highlighted C. elegans as a sensitive indicator for HMs pollution and its usefulness to assess the efficiency of the nanoremediation strategy to decrease the toxicity of Cu(II)-Cr(VI) polluted environments.

Austin MU et al. (2010) BMC Dev Biol "Knockout of the folate transporter folt-1 causes germline and somatic defects in C. elegans."

Liau WS, LaMunyon CW, Balamurugan K, Ashokkumar B, Austin MU, Said HM

[BMC Dev Biol, 2010]

BACKGROUND: The C. elegans gene folt-1 is an ortholog of the human reduced folate carrier gene. The FOLT-1 protein has been shown to transport folate and to be involved in uptake of exogenous folate by worms. A knockout mutation of the gene, folt-1(ok1460), was shown to cause sterility, and here we investigate the source of the sterility and the effect of the folt-1 knockout on somatic function. RESULTS: Our results show that folt-1(ok1460) knockout hermaphrodites have a substantially reduced germline, generate a small number of functional sperm, and only rarely produce a functional oocyte. We found no evidence of increased apoptosis in the germline of folt-1 knockout mutants, suggesting that germline proliferation is defective. While folt-1 knockout males are fertile, their rate of spermatogenesis was severely diminished, and the males were very poor maters. The mating defect is likely due to compromised metabolism and/or other somatic functions, as folt-1 knockout hermaphrodites displayed a shortened lifespan and elongated defecation intervals. CONCLUSIONS: The FOLT-1 protein function affects both the soma and the germline. folt-1(ok1460) hermaphrodites suffer severely diminished lifespan and germline defects that result in sterility. Germline defects associated with folate deficiency appear widespread in animals, being found in humans, mice, fruit flies, and here, nematodes.

Wakabayashi, Tokumitsu et al. (2013) International Worm Meeting "Caenorhabditis elegans can detect and avoid from rare earth ions, which have toxic effects on the worm locomotion, growth, and development."

Wakabayashi, Tokumitsu, Nakano, Yuta, Tomita, Hiroshi, Nojiri, Yui, Watanabe, Miwa

[International Worm Meeting, 2013]

Rare Earth (REs) are a set of elements including scandium (Sc), yttrium (Y), and fifteen lanthanides. Because of their unique chemical properties, they are used for many High-Tech devises which support our daily life. Despite their name, REs are relatively plentiful in earth crust. Since REs are widely dispersed in soil, organism may encounter these elements during the evolutional history of life. However, effects of REs on biological systems, especially in multicellular organisms, are poorly understood. In this study, we have explored the impact of REs on the behavior, locomotion and growth of organisms by using Caenorhabditis elegans as a model system. To see the effect of REs on the worm growth and development, wild-type eggs were soaked in RE solutions for 24 hr. In the presence of 100 mM RE, a significant part of eggs were unhatched and the large part of larval worms hatched was dead. The effects were observed for all REs except radioactive promethium which we have not tested. MAPK mutants which were hypersensitive to heavy metal (HM) ions such as Cu2+ and Cd2+ showed hypersensitivity to REs in both eggs and adult worm, suggesting that the worm used common signaling pathway for RE- and HM-stress responses. We also tested the behavior of the worm against REs using radial concentration gradient formed on an agar plate. Wild-type worms showed an avoidance behavior against all REs examined. The avoidance behavior was abolished in the chemosensory-defective che-2 mutant worms, indicating that the worm can detect REs via the function of chemosensory neurons. By using cell-specific rescue strain of dyf-11 mutant and cell-specific genetic cell ablation lines, we found that REs were detected by overlapped but distinct subset of sensory neurons that used for HM avoidance.

Navarro IC et al. (2022) Wellcome Open Res "Identification of putative reader proteins of 5-methylcytosine and its derivatives in Caenorhabditis elegans RNA."

Suen KM, Navarro IC, Balasubramanian S, Tanpure A, Lamond A, Miska EA, Bensaddek D

[Wellcome Open Res, 2022]

<b>Background:</b> Methylation of carbon-5 of cytosines (m ⁵C) is a conserved post-transcriptional nucleotide modification of RNA with widespread distribution across organisms. It can be further modified to yield&#xa0;5-hydroxymethylcytidine (hm ⁵C), 5-formylcytidine (f ⁵C), 2&#xb4;-O-methyl-5-hydroxymethylcytidine (hm ⁵Cm) and 2&#xb4;-O-methyl-5-formylcytidine (f ⁵Cm).&#xa0;How m ⁵C, and specially its derivates, contribute to biology mechanistically is poorly understood. We recently showed that m ⁵C is required for <i>Caenorhabditis elegans</i> development and fertility under heat stress. m ⁵C has been shown to participate in mRNA transport and maintain mRNA stability through its recognition by the reader proteins ALYREF and YBX1, respectively. Hence, identifying readers for RNA modifications can enhance our understanding in the biological roles of these modifications. <b>Methods:</b> To contribute to the understanding of how m ⁵C and its oxidative derivatives mediate their functions, we developed RNA baits bearing modified cytosines in diverse structural contexts to pulldown potential readers in <i>C. elegans</i>. Potential readers were identified using mass spectrometry. The interaction of two of the putative readers with m ⁵C was validated using immunoblotting. <b>Results:</b> Our mass spectrometry analyses revealed unique binding proteins for each of the modifications. <i>In silico</i> analysis for phenotype enrichments suggested that hm ⁵Cm unique readers are enriched in proteins involved in RNA processing, while readers for m ⁵C, hm ⁵C and f ⁵C are involved in germline processes. We validated our dataset by demonstrating that the nematode ALYREF homologues ALY-1 and ALY-2 preferentially bind m ⁵C <i>in vitro</i>. Finally, sequence alignment analysis showed that several of the putative m ⁵C readers contain the conserved RNA recognition motif (RRM), including ALY-1 and ALY-2. <b>Conclusions:</b> The dataset presented here serves as an important scientific resource that will support the discovery of new functions of m ⁵C and its derivatives. Furthermore, we demonstrate that ALY-1 and ALY-2 bind to m ⁵C in <i>C. elegans</i>.

Kinchen JM et al. (2005) Curr Top Dev Biol "Tales of cannibalism, suicide, and murder: Programmed cell death in C. elegans."

Hengartner MO, Kinchen JM

[Curr Top Dev Biol, 2005]

"Life is pleasant. Death is peaceful. It''s the transition that''s troublesome," said Isaac Asimov. Indeed, much scientific work over the last hundred years centered around attempts either to stave off or to induce the onset of death, at both the organismal and the cellular levels. In this quest, the nematode C. elegans has proven an invaluable tool, first, in the articulation of the genetic pathway by which programmed cell death proceeds, and also as a continuing source of inspiration. It is our purpose in this Chapter to familiarize the reader with the topic of programmed cell death in C. elegans and its relevance to current research in the fields of apoptosis and cell corpse clearance.