14 Papers found (0.01 seconds)

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.

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.

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.

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]

Background: 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 5-hydroxymethylcytidine (hm 5C), 5-formylcytidine (f 5C), 2´-O-methyl-5-hydroxymethylcytidine (hm 5Cm) and 2´-O-methyl-5-formylcytidine (f 5Cm). How m 5C, and specially its derivates, contribute to biology mechanistically is poorly understood. We recently showed that m 5C is required for Caenorhabditis elegans 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. Methods: 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 C. elegans. Potential readers were identified using mass spectrometry. The interaction of two of the putative readers with m 5C was validated using immunoblotting. Results: Our mass spectrometry analyses revealed unique binding proteins for each of the modifications. In silico 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 in vitro. 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. Conclusions: 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 C. elegans.

Sun ZW et al. (1999) Genetics "A general requirement for the Sin3-Rpd3 histone deacetylase complex in regulating silencing in Saccharomyces cerevisiae."

Hampsey M, Sun ZW

[

Genetics,

1999]

The Sin3-Rpd3 histone deacetylase complex, conserved between human and yeast, represses transcription when targeted by promoter-specific transcription factors. SIN3 and RPD3 also affect transcriptional silencing at the HM mating loci and at telomeres in yeast. Interestingly, however, deletion of the SIN3 and RPD3 genes enhances silencing, implying that the Sin3-Rpd3 complex functions to counteract, rather than to establish or maintain, silencing. Here we demonstrate that Sin3, Rpd3, and Sap30, a novel component of the Sin3-Rpd3 complex, affect silencing not only at the HMR and telomeric loci, but also at the rDNA locus. The effects on silencing at all three loci are dependent upon the histone deacetylase activity of Rpd3. Enhanced silencing associated with sin3Delta, rpd3Delta, and sap30Delta is differentially dependent upon Sir2 and Sir4 at the telomeric and rDNA loci and is also dependent upon the ubiquitin-conjugating enzyme Rad6 (Ubc2). We also show that the Cac3 subunit of the CAF-I chromatin assembly factor and Sin3-Rpd3 exert antagonistic effects on silencing. Strikingly, deletion of GCN5, which encodes a histone acetyltransferase, enhances silencing in a manner similar to deletion of RPD3. A model that integrates the effects of rpd3Delta, gcn5Delta, and cac3Delta on silencing is proposed.

Sjoberg HT et al. (2019) PLoS Negl Trop Dis "Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models."

[

PLoS Negl Trop Dis,

2019]

The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile.

Huang X et al. (2020) Cell Microbiol "Caenorhabditis elegans mounts a p38 MAPK pathway-mediated defense to Cutibacterium acnes infection."

Zeng K, Pan W, Li S, Kim W, Mylonakis E, Huang X, Li H, Fuchs BB, Lee K, White A

[

Cell Microbiol,

2020]

Cutibacterium acnes is capable of inducing inflammation in acne and can lead to a chronic prostatic infection. The diverse pathogenicity among different strains of C. acnes has been presented, but simple appropriate animal models for the evaluation of this bacterium are lacking. In this study, the nematode Caenorhabditis elegans was used as an invertebrate infection model. We revealed that C. acnes type strain ATCC 6919 caused lethal infections to C. elegans in solid and liquid culture media (p<0.0001). Compared with the strain ATCC 6919, the antibiotic-resistant strain HM-513 was more virulent, resulting in reduced survival (p<0.0001). Four different C. acnes strains killed worms with a p value of less than 0.0001 when provided to C. elegans at 4.8x108 CFU/mL. The infection model was also employed to explore host defense responses. An increase in numerous immune effectors in response to C. acnes was detected. We focused on nine C-type lectins, including: clec-13, clec-17, clec-47, clec-52, clec-60, clec-61, clec-70, clec-71, and clec-227. The induced expression of these C-type lectin genes was down-regulated in mutant worms deficient in the p38 mitogen-activated protein kinase (MAPK) pathway. Meanwhile, PMK-1 (MAPK) was phosphorylated and activated at the onset of C. acnes infection. By monitoring the survival of mutant worms, we found that PMK-1, SEK-1 (MAPKK), and TIR-1 (MAPKKK) were critical in responding to C. acnes infection. C. elegans pmk-1 and tir-1 mutants exhibited higher mortality to C. acnes infection (p<0.0001). In conclusion, C. elegans serves as a simple and valuable model to study C. acnes virulence and facilitates improvements in understanding of host innate immune responses. This article is protected by copyright. All rights reserved.

Monika Jedrusik-Bode et al. (2008) European Worm Meeting "HIS-24, a linker histone variant shows high affinity to subtelomeric regions and specifically binds to the telomere binding protein HRP-1 in C elegans"

Monika Jedrusik-Bode, Jacek R Wisniewski

[

European Worm Meeting,

2008]

Chromatin, histones, telomere, chromatin modification, RNA interference. The most abundant linker histone variant, HIS-24, is essential for a chromatin silencing. process. It is crucial for the proliferation and differentiation of the hermaphrodite germline.. To understand the full spectrum of the HIS-24 functions, we have characterised the HIS-24. interaction partners using (chromatin-)immunoprecipitation follow by high resolution mass. spectrometry in addition to the genetic studies.. We showed that HIS-24 specifically binds to HRP-1 (a human HnRNP A1 homolog),. which was previously implicated in telomere length regulation in C elegans. Using a CHIP. assay, we observed that HIS-24 binds to the subtelomeric regions and minisatellites with. higher affinity as compared to euchromatin regions.. In vivo, his-24-depleted worms show end-to-end chromosome fusions of the intestinal. nuclei similar to the trt-1(Telomerase Reverse Transcriptase) and mrt-2(MoRTal germline). mutants. Interestingly, silent information regulator 2 (sir-2.1), which represses transcription. at subtelomeric and HM loci in yeast and determines the adult life span in worms, increases. the his-24(ok1026) phenotype. Several developmental defects were detectable in the. double mutants of sir-2.1(ok434) his-24(ok1026), such as body morphology defects and. slow growth. A large percentage of these mutants have short germline arms; some. germlines displayed an abnormal germline proliferation (Glp) and masculinization of the. germline (Mog) phenotypes. Additionally, in the double mutants we detected reduced. H3K27-Me3 methylation, which can have an effect on subtelomeric gene repression or. genome-wide expression level in the worm.. In this study, we show the role of HIS-24 in maintenance of an epigenetic status and in. telomere regulation, which provide important new avenues for understanding biological. processes such as development, metabolism and ageing.

Taylor MJ et al. (2019) Sci Transl Med "Preclinical development of an oral anti-Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis."

[

Sci Transl Med,

2019]

There is an urgent global need for a safe macrofilaricide drug to accelerate elimination of the neglected tropical diseases onchocerciasis and lymphatic filariasis. From an anti-infective compound library, the macrolide veterinary antibiotic, tylosin A, was identified as a hit against Wolbachia This bacterial endosymbiont is required for filarial worm viability and fertility and is a validated target for macrofilaricidal drugs. Medicinal chemistry was undertaken to develop tylosin A analogs with improved oral bioavailability. Two analogs, A-1535469 and A-1574083, were selected. Their efficacy was tested against the gold-standard second-generation tetracycline antibiotics, doxycycline and minocycline, in mouse and gerbil infection models of lymphatic filariasis (Brugia malayi and Litomosoides sigmodontis) and onchocerciasis (Onchocerca ochengi). A 1- or 2-week course of oral A-1535469 or A-1574083 provided >90% Wolbachia depletion from nematodes in infected animals, resulting in a block in embryogenesis and depletion of microfilarial worm loads. The two analogs delivered comparative or superior efficacy compared to a 3- to 4-week course of doxycycline or minocycline. A-1574083 (now called ABBV-4083) was selected for further preclinical testing. Cardiovascular studies in dogs and toxicology studies in rats and dogs revealed no adverse effects at doses (50 mg/kg) that achieved plasma concentrations >10-fold above the efficacious concentration. A-1574083 (ABBV-4083) shows potential as an anti-Wolbachia macrolide with an efficacy, pharmacology, and safety profile that is compatible with a short-term oral drug course for treating lymphatic filariasis and onchocerciasis.

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