Korenaga M et al. (1995) J Helminthol "Cross-resistance between Strongyloides venezuelensis and S. ratti in mice."

Korenaga M, Hitoshi Y, Tada I, Takatsu K

[J Helminthol, 1995]

Cross-resistance between Strongyloides venezuelensis and S. ratti was tested in mice. The mice were immunized with S. ratti and challenged with infective filariform larvae or larvae recovered from the lungs of mice, of a heterologous species, S. venezuelensis. In this system, cross-resistance was expressed to the intestinal stage but not to the migrating stage of the parasite. Anti-interleukin (IL)-5 monoclonal antibody (mAb) treatment showed that peripheral blood eosinophilia after infection with both species of the genus Strongyloides was dependent on IL-5. Cross-resistance expressed to the intestinal stages was inhibited partially by injection of anti-IL-5 mAb.

Korenaga M et al. (1986) Z Parasitenkd "IgE response in Strongyloides ratti-infected rats with special reference to the life cycle of the parasite."

Nawa Y, Korenaga M, Tada I

[Z Parasitenkd, 1986]

Parasite-specific IgE antibody response was examined in Strongyloides ratti-infected rats. The results showed that the parasite-specific IgE antibody response was generated after a primary infection. However, repeated infections rather depressed the level of parasite-specific IgE antibody in the serum. Immunization limited to specific stages of the parasite revealed that stimulation of parasite-specific IgE antibody was related to the intestinal adult stage. On the other hand, depression of IgE titers was related to the tissue-migrating larval stage. The capacity of the each stage of the parasite to induce specific IgE response may be related to the variable results of the IgE responses in human strongyloidiasis.

Korenaga M et al. (1983) J Parasitol "Effects of preintestinal larval antigenic stimuli on the generation of intestinal immunity in Strongyloides ratti infection in rats."

Tada I, Korenaga M, Mimori T, Nawa Y

[J Parasitol, 1983]

Generation of intestinal immunity by antigenic stimulation with preintestinal, tissue-migrating larvae was investigated in the Strongyloides ratti-rat model. The results of daily fecal egg counts showed that the intestinal immunity against adult worms could be partially generated by priming with preintestinal migrating larvae. A further study demonstrated that this partial reduction of daily fecal egg count was mainly the result of inhibitory effects on the fecundity of the parasitic females, although the expulsion of the parasite from the gut could be advanced by several days. After tertiary immunization with preintestinal larvae, no significant potentiation in the protection was observed when compared with the rats treated by primary immunization alone.

Korenaga M et al. (1983) Exp Parasitol "Strongyloides ratti: the role of enteral antigenic stimuli by adult worms in the generation of protective immunity in rats."

Mimori T, Nawa Y, Korenaga M, Tada I

[Exp Parasitol, 1983]

Immunogenicity of adult Strongyloides ratti was studied in rats. Immunization of rats by intraduodenal implantation of adult worms could completely inhibit the egg production and hasten the expulsion of challenged worms which were developed from subcutaneously inoculated L3 or were implanted intraduodenally as adults. Enteral immunization by intraduodenal implantation of adult worms was, however, not able to affect the esophageal larval output of the challenge infection with L3. In contrast to enteral immunization with adult worms, immunization by full sequence of a primary infection or by a combination of drug-abbreviated infection and adult worm implantation could suppress the esophageal larval output of the challenge infection. The relationship between the host defense mechanism and the life cycle of S. ratti is discussed.

Wypijewska A et al. (2012) Biochemistry "7-methylguanosine diphosphate (m(7)GDP) is not hydrolyzed but strongly bound by decapping scavenger (DcpS) enzymes and potently inhibits their activity."

Wypijewska A, Darzynkiewicz E, Davis RE, Jemielity J, Bojarska E, Lukaszewicz M, Stepinski J

[Biochemistry, 2012]

Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.

O'Connell EM et al. (2015) J Infect Dis "Targeting Filarial Abl-like Kinases: Orally Available, Food and Drug Administration-Approved Tyrosine Kinase Inhibitors Are Microfilaricidal and Macrofilaricidal."

Nutman TB, O'Connell EM, Bennuru S, Steel C, Dolan MA

[J Infect Dis, 2015]

BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.

Nawa Y et al. (1982) J Parasitol "Stage-specific cross-resistance between Nippostrongylus brasiliensis and Strongyloides ratti (Nematoda) in rats."

Tada I, Mimori T, Nawa Y, Korenaga M

[J Parasitol, 1982]

Stage-specificity of cross-resistance between Nippostrongylus brasiliensis and Strongyloides ratti was investigated. Results showed that immunization with tissue-migrating larvae was sufficient to generate cross-resistance and that host defense mechanisms operating in the cross-resistance were directed against tissue-migrating larvae but not against intestinal adult worms. In addition, no significant potentiation of the cross-resistance was observed after multiple immunization. These observations suggest that host defense mechanisms against heterologous challenge infection were qualitatively and/or quantitatively different from those against homologous challenge infection.

Nawa Y et al. (1985) Parasite Immunol "Defective protective capacity of W/Wv mice against Strongyloides ratti infection and its reconstitution with bone marrow cells."

Kotani M, Nawa Y, Kiyota M, Korenaga M

[Parasite Immunol, 1985]

The susceptibility of congenitally anemic, and mast cell deficient W/Wv mice to infection with Strongyloides ratti was examined. After a primary infection, W/Wv mice showed greater and more persistent peak larval counts than did normal littermates. Worm expulsion was also slower in W/Wv mice than in +/+ mice. Furthermore, difference in susceptibility was expressed as early as 24 h after infection, suggesting not only that protective mechanisms of the gut but also of the connective tissue were defective in W/Wv mice. Reconstitution with bone marrow or spleen cells from +/+ mice was effective in restoring the protective response in W/Wv mice, whereas thymocytes or mesenteric lymph nodes had no effect. Both connective tissue and mucosal mast cells were repaired in W/Wv mice after marrow reconstitution and infection. Since relatively long incubation period was required for the expression of such reconstituting activities, bone marrow cells seem to contain precursor cells of the effector and/or regulator cells.

Lemire BD et al. (2009) Mech Ageing Dev "C. elegans longevity pathways converge to decrease mitochondrial membrane potential."

Behrendt M, Decorby A, Lemire BD, Gaskova D

[Mech Ageing Dev, 2009]

Energy production via oxidative phosphorylation generates a mitochondrial membrane potential (DeltaPsi(m)) across the inner membrane. In this work, we show that a lower DeltaPsi(m) is associated with increased lifespan in Caenorhabditis elegans. The long-lived mutants daf-2(e1370), age-1(hx546), clk-1(qm30), isp-1(qm150) and eat-2(ad465) all have a lower DeltaPsi(m) than wild type animals. The lower DeltaPsi(m) of daf-2(e1370) is daf-16 dependent, indicating that the insulin-like signaling pathway not only regulates lifespan but also mitochondrial energetics. RNA interference (RNAi) against 17 genes shown to extend lifespan also decrease DeltaPsi(m). Furthermore, lifespan can be significantly extended with the uncoupler carbonylcyanide-3-chlorophenylhydrazone (CCCP), which dissipates DeltaPsi(m). We conclude that longevity pathways converge on the mitochondria and lead to a decreased DeltaPsi(m). Our results are consistent with the 'uncoupling to survive' hypothesis, which states that dissipation of the DeltaPsi(m) will extend lifespan.

Seo J et al. (2005) Arch Environ Contam Toxicol "Biodegradation of the insecticide N,N-diethyl-m-toluamide by fungi: identification and toxicity of metabolites."

Kim SD, Cha CJ, Hur HG, Lee YG, Seo J, Ahn JH

[Arch Environ Contam Toxicol, 2005]

Fungi (Cunninghamella elegans ATCC 9245, Mucor ramannianus R-56, Aspergillus niger VKMF-1119, and Phanerochaete chrysosporium BKMF-1767) were tested to elucidate the biologic fate of the topical insect repellent N,N-diethyl-m-toluamide (DEET). The elution profile obtained from analysis by high-pressure liquid chromatography equipped with a reverse-phase C-18 column, showed that three peaks occurred after incubation of C. elegans, with which 1 mM DEET was combined as a final concentration. The peaks were not detected in the control experiments with either DEET alone or tested fungus alone. The metabolites produced by C. elegans exhibited a molecular mass of 207 with a fragment ion (m/z) at 135, a molecular mass of 179 with an m/z at 135, and a molecular mass of 163 with an m/z at 119, all of which correspond to N,N-diethyl-m-toluamide-N-oxide, N-ethyl-m-toluamide-N-oxide, and N-ethyl-m-toluamide, respectively. M. ramannianus R-56 also produced N, N-diethyl-m-toluamide-N-oxide and N-ethyl-m-toluamide but did not produce N-ethyl-m-toluamide-N-oxide. For the biologic toxicity test with DEET and its metabolites, the freshwater zooplankton Daphnia magna was used. The biologic sensitivity in decreasing order was DEET > N-ethyl-m-toluamide > N,N-diethyl-m-toluamide-N-oxide. Although DEET and its fungal metabolites showed relatively low mortality compared with other insecticides, the toxicity was increased at longer exposure periods. These are the first reports of the metabolism of DEET by fungi and of the biologic toxicity of DEET and its fungal metabolites to the freshwater zooplankton D. magna.