Ng HWY et al. (2021) Dis Model Mech "Genetically altered animal models for ATP1A3-related disorders."

Clapcote SJ, Ng HWY, Ogbeta JA

[Dis Model Mech, 2021]

Within the past 20 years, particularly with the advent of exome sequencing technologies, autosomal dominant and de novo mutations in the gene encoding the neurone-specific alpha3 subunit of the Na+,K+-ATPase (NKA alpha3) pump, ATP1A3, have been identified as the cause of a phenotypic continuum of rare neurological disorders. These allelic disorders of ATP1A3 include (in approximate order of severity/disability and onset in childhood development): polymicrogyria; alternating hemiplegia of childhood; cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss syndrome; relapsing encephalopathy with cerebellar ataxia; and rapid-onset dystonia-parkinsonism. Some patients present intermediate, atypical or combined phenotypes. As these disorders are currently difficult to treat, there is an unmet need for more effective therapies. The molecular mechanisms through which mutations in ATP1A3 result in a broad range of neurological symptoms are poorly understood. However, in vivo comparative studies using genetically altered model organisms can provide insight into the biological consequences of the disease-causing mutations in NKA alpha3. Herein, we review the existing mouse, zebrafish, Drosophila and Caenorhabditis elegans models used to study ATP1A3-related disorders, and discuss their potential contribution towards the understanding of disease mechanisms and development of novel therapeutics.

Oh WS et al. (2009) PLoS One "Identification and characterization of a dual-acting antinematodal agent against the pinewood nematode, Bursaphelenchus xylophilus."

Joo HJ, Moon YS, Lee YU, Paik YK, Kim JH, Lee JE, Jeong PY, Cheon HM, Shim YH, Oh WS

[PLoS One, 2009]

The pinewood nematode (PWN), Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS) method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride), a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca(2+) channel blockers suggested that HWY-4213 targets the calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound.

Zain MM et al. (2016) Trop Life Sci Res "The Effect of Macrocyclic Lactones-Ivermectin Exposure on Egg Hatching and Larval Development of Caenorhabditis elegans."

Zain MM, Him NA, Yahaya ZS

[Trop Life Sci Res, 2016]

To date, the ivermectin resistance in nematode parasites has been reported and many studies are carried out to determine the causes of this problem. A free-living Caenorhabditis elegans is used as a model system for this study to investigate the response of C. elegans to ivermectin exposure by using larval development assay. Worms were exposed to ivermectin at concentration from 1 ng/mL to 10 ng/mL and dimethyl sulphoxide (DMSO) as a control. The developments of the worms were monitored for 24, 48, 72, and 96 hours until the worms become adults. Results indicated that worms' growth began to be affected by ivermectin at a concentration of 5 ng/mL, while at the concentration of 6, 7, 8, 9, and 10 ng/mL, the growth of worms were inhibited compared to control worms. Further study of the protein expression in C. elegans should be done to investigate the up-regulated and down-regulated proteins involve in ivermectin resistance.

Hussain R et al. (1981) J Immunol "IgE responses in human filariasis. I. Quantitation of filaria-specific IgE."

Ottesen EA, Hussain R, Hamilton RG, Adkinson NF, Kumaraswami V

[J Immunol, 1981]

We have developed a noncompetitive solid phase radioimmunoassay to quantitate human IgE antibodies against soluble adult antigens of Brugia malayi (B.m.), a filarial parasite, in sera of patients with various forms of clinical filariasis in Madras, India. A single reference serum was shown to contain 23 micrograms/ml of B.m.-specific IgE by depletion analysis and was used as a standard serum throughout the study. The levels of specific IgE ranged in the patients sera from 2 to 23,000 ng/ml. When these individuals were divided into clinical groups, the individuals with tropical pulmonary eosinophilia had the highest levels (mean = 8630 ng/ml) and were significantly higher than all the other groups (p less than 0.001). The lowest levels were seen in patients with circulating microfilariae (mean = 30.5 ng/ml). Patients exhibiting lymphatic obstruction (i.e., chronic pathology group) had levels slightly higher than microfilaremics (mean = 68 ng/ml) but were not significantly different (p less than 0.1). Surprisingly, individuals living in endemic areas but who had no clinical signs of filariasis also showed appreciable levels of B.m.-specific IgE (mean = 55 ng/ml). The B.m.-specific IgE represented 0.1 to 48% of the total IgE. High percentages of specific IgE may be responsible for evoking allergic symptomatology in patients with tropical pulmonary eosinophilia.

Haldimann P et al. (2011) J Biol Chem "The novel hydroxylamine derivative NG-094 suppresses polyglutamine protein toxicity in Caenorhabditis elegans."

Goloubinoff P, Muriset M, Vigh L, Haldimann P

[J Biol Chem, 2011]

Aggregation-prone polyglutamine (polyQ) expansion proteins cause several neurodegenerative disorders, including Huntington disease. The pharmacological activation of cellular stress responses could be a new strategy to combat protein conformational diseases. Hydroxylamine derivatives act as co-inducers of heat-shock proteins (HSPs) and can enhance HSP expression in diseased cells, without significant adverse effects. Here, we used Caenorhabditis elegans expressing polyQ expansions with 35 glutamines fused to the yellow fluorescent protein (Q35-YFP) in body wall muscle cells as a model system to investigate the effects of treatment with a novel hydroxylamine derivative, NG-094, on the progression of polyQ diseases. NG-094 significantly ameliorated polyQ-mediated animal paralysis, reduced the number of Q35-YFP aggregates and delayed polyQ-dependent acceleration of aging. Micromolar concentrations of NG-094 in animal tissues with only marginal effects on the nematode fitness sufficed to confer protection against polyQ proteotoxicity, even when the drug was administered after disease onset. NG-094 did not reduce insulin/insulin-like growth factor 1-like signaling, but conferred cytoprotection by a mechanism involving the heat-shock transcription factor HSF-1 that potentiated the expression of stress-inducible HSPs. NG-094 is thus a promising candidate for tests on mammalian models of polyQ and other protein conformational diseases.

Lobos E et al. (2003) Infect Immun "Elevated immunoglobulin E against recombinant Brugia malayi gamma-glutamyl transpeptidase in patients with bancroftian filariasis: association with tropical pulmonary eosinophilia or putative immunity."

Nutman TB, Hothersall JS, Moncada S, Lobos E

[Infect Immun, 2003]

A major allergen of the lymphatic filarial nematode Brugia malayi, a homologue of gamma-glutamyl transpeptidase (gamma-GT), is involved in the pathology of tropical pulmonary eosinophilia (TPE) through its potent allergenicity and the induction of antibodies against the host pulmonary epithelium. To investigate the immunoglobulin G (IgG) subclass and IgE responses to recombinant B. malayi gamma-GT, we analyzed the results obtained from 51 patients with differing clinical manifestations of bancroftian filariasis. gamma-GT-specific IgG1, rather than IgG4, was the predominant IgG subclass, particularly in patients with TPE (geomean, 6,321 ng/ml; range, 78 to 354,867 ng/ml) and was 75 times higher than in patients with elephantiasis (CP) (P < 0.003) and 185 times higher than in endemic normal individuals (ENL) (P < 0.010). IgG2 responses were low and IgG3 was almost absent, with no significant differences among the groups. gamma-GT-specific IgG4 responses were significantly elevated in those with subclinical microfilaremia (MF) compared to the CP and ENL groups and correlated with the presence of circulating filarial antigen (CAg). More significantly, gamma-GT-specific IgE antibody levels were strikingly elevated in patients with TPE (geomean, 681 ng/ml; range, 61 to 23,841 ng/ml) and in the ENL group (geomean, 106 ng/ml; range, 13 to 1,405 ng/ml) whereas the gamma-GT-specific IgE level was 44 and 61 times lower in those with MF and CP, respectively (P < 0.001). Elevated gamma-GT-specific IgE/IgG4 ratios were demonstrated in patients with TPE (ratio, 45) and ENL (ratio, 107). Because expression of gamma-GT in Brugia infective third-stage larvae (L3) was demonstrated by immunoblot analysis, the elevated gamma-GT-specific IgE antibodies appear to be associated not only with pulmonary pathology but also with possible resistance to infection in lymphatic filariasis.

Merris M et al. (2003) J Lipid Res "Sterol effects and sites of sterol accumulation in Caenorhabditis elegans: developmental requirement for 4alpha-methyl sterols."

Khamrai U, Merris M, Chitwood DJ, Lenard J, Bittman R, Wadsworth WG

[J Lipid Res, 2003]

Caenorhabditis elegans requires sterol, usually supplied as cholesterol, but this is enzymatically modified, and different sterols can substitute. Sterol deprivation decreased brood size and adult growth in the first generation, and completely, reversibly, arrested growth as larvae in the second. After one generation of sterol deprivation, 10 ng/ml cholesterol allowed delayed laying of a few eggs, but full growth required 300 ng/ml. C. elegans synthesizes two unusual 4alpha-methyl sterols (4MSs), but each 4MS supported only limited growth as the sole sterol. However, addition of only 10 ng of cholesterol to 1,000 ng of 4MS restored full growth and egg-laying, suggesting that both a 4MS and an unmethylated sterol are required for development. Filipin stained sterols in only a few specific cells: the excretory gland cell, two amphid socket cells, two phasmid socket cells and, in males, spicule socket cells. Sterols were also present in the pharynx and in the intestine of feeding animals in a proximal-to-distal gradient. This non-random sterol distribution, the low concentration requirements, and the effects of 4MSs argues that sterols are unlikely to be used for bulk structural modification of cell membranes, but may be required as hormone precursors and/or developmental effectors.

Pertel R et al. (1974) Comp Gen Pharmacol "Histamine content of the nematode, Caenorhabditis elegans."

Pertel R, Wilson SH

[Comp Gen Pharmacol, 1974]

1. The histamine contect in axenically grown nematodes was found to be 350 ng. per g. wet weight. 2. Histamine content was determined in extracts from the free-living nematode, Caenorhabditis elegans var. Bristol (strain B1-Pl) by an isotope dilution procedure which obviated error encountered in a conventional fluorescence assay. 3. This is the first report of histamine in the Nematoda.

Shu EN et al. (2000) Acta Trop "Ivermectin: concentration-dependent effects on adenosine triphosphatases in adult worms of Onchocerca volvulus."

Okonkwo PO, Onyeanusi J, Shu EN, Batey WO

[Acta Trop, 2000]

The effect of increasing concentrations of ivermectin on adenosine triphosphatase (ATPase) activity was investigated in adult worms of Onchocerca volvulus. Mean Mg- and Na,K-ATPase activities decreased significantly (F ratio = 29.82, P &lt; 0.01 and F ratio = 28.54, P &lt; 0.01, respectively) with increasing concentrations of ivermectin (0-100 ng/ml) in the female worms. When male and female worms were mixed with equal amounts of proteins from each, only the Na,K-ATPase activity was significantly decreased (F ratio = 56.61, P &lt; 0.01) over a similar range of ivermectin concentrations. Since ivermectin exhibits concentration-dependent effects on both ATPases in female adult worms, this might provide an insight into other effects of the drug. However, the adjustment of the dose of ivermectin to obtain a nodular concentration of at least 40 ng/ml is therefore recommended in the complete chemotherapy of onchocerciasis.

Ju J et al. (2023) Aquat Toxicol "The growth toxicity and neurotoxicity mechanism of waterborne TBOEP to nematodes: Insights from transcriptomic and metabolomic profiles."

Wu X, Zhu Y, Wang Y, Ma S, Ju J, Zhang C, Ge W, Mao W

[Aquat Toxicol, 2023]

Tris(2-butoxy) ethyl phosphate (TBOEP) is a typical organophosphorus flame retardant (OPFR), which has been detected in natural water bodies and drinking water and has reached a certain concentration. As a new type of organic pollutant, the environmental health risk of TBOEP needs to be assessed urgently. Here, Caenorhabditis elegans were exposed to 0, 50, 500, and 5000&#xa0;ng/L TBOEP in water for 72&#xa0;h. The results showed that TBOEP exposure caused concentration-dependent inhibition to the growth of nematodes, while exposure to 5000&#xa0;ng/L TBOEP significantly inhibited the locomotor behavior of nematodes. Transcriptomic and metabolomic analysis showed that the disturbances in neurotransmitter transmission and amino acid, carbohydrate, and lipid metabolism were the reason for the neurotoxicity and growth toxicity of TBOEP to nematodes. These results provide basic data and a theoretical basis for evaluating the environmental health risks of organophosphorus flame retardants.