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Wang B, Xu W, Xiong Y, Guan KL, Frye S, Ito S, Wang P, Yang C, Yang Y, Kim SH, Liu J, Zhang JY, Jiang WQ, Liu LX, Xiao MT, Zhao SM, Yang H, Zhang Y, Xu YH, Lei QY, Liu Y
[
Cancer Cell,
2011]
IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of alpha-ketoglutarate (alpha-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as alpha-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce alpha-KG and accumulate an alpha-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.
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[
J Med Chem,
1986]
A series of 2,2'-disubstituted 5,5'-dibenzimidazolyl ketones and related compounds have been synthesized of which 2,2'-bis(carbomethoxyamino)-5,5'-dibenzimidazolyl ketone exhibited a broad spectrum of anthelmintic activity in experimental animals. At doses of 10-50 mg/kg given intraperitoneally, 5 killed 100% of the adult worms of Litomosoides carinii, Dipetalonema viteae, and Brugia malayi. By the oral route the macrofilaricidal efficacy of 5 was 97-100% at 100-200 mg/kg X 5 days. The treated animals showed gradual disappearance of microfilariae and before autopsy they became amicrofilariaemic. Some of the compounds also showed 100% efficacy against the human hookworms and tapeworm, Ancylostoma ceylanicum in hamsters, and Hymenolepis nana in rats at a single oral dose of 50-250 mg/kg. Compound 5 was also effective against Syphacia obvelata in mice at a single oral dose of 100 mg/kg and was found to be well tolerated by mice up to an oral dose of 2500 mg/kg.
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[
Int J Parasitol,
2001]
PF 1022A, a novel anthelmintically active cyclodepsipeptide, and Bay 44-4400, a semisynthetic derivative of PF 1022A were tested for filaricidal efficacy in Mastomys coucha infected with Litomosoides sigmodontis, Acanthocheilonema viteae and Brugia malayi. The parent compound PF 1022A showed limited anti-filarial efficacy in L. sigmodontis and B. malayi infected animals. Oral doses of 5 x 100 mg/kg on consecutive days caused only a temporary decrease of microfilariaemia levels. By contrast, Bay 44-4400 was highly effective against microfilariae of all three species in single oral, subcutaneous and cutaneously applied (spot on) doses. Minimum effective doses (MED, reducing parasitaemia density by > or =95%) determined 3 and 7 days after treatment were 3.125-6.25 and 6.25-12.5mg/kg, respectively. Using the spot on formulation, doses of 6.25mg/kg (L. sigmodontis), 12.5mg/kg (A. viteae) and 25mg/kg (B. malayi) were required to cause reductions of microfilaraemia levels by > or =95% until day 56. Adulticidal effects, determined as minimum curative doses (MCD, eliminating adult parasites within 56 days by >95%) after single dose treatment were limited to A. viteae (MCD, 100mg/kg independent of the route of administration). Repeated oral treatment (100mg/kg on 5 consecutive days) killed all adult L. sigmodontis but did not affect B. malayi. However, single doses of 6.25 and 25mg/kg resulted in severe pathological alterations of intrauterine stages of L. sigmodontis and B. malayi, respectively. These alterations may be responsible for long-lasting reductions of microfilaraemia even when curative effects could not be achieved.
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[
Trans R Soc Trop Med Hyg
]
Ivermectin, at the standard dose of 150 micrograms/kg bodyweight, does not kill the adult worms of Onchocerca volvulus and does not disrupt embryogenesis or spermatogenesis. Repeated standard doses, if maintained, arrest microfilarial production but result in only a mild-to-modest macrofilaricidal effect. We investigated whether high doses would effectively kill the adult worms, and whether cessation of microfilarial production could be reproduced by an equivalent, single, high dose. One hundred men participated in a double-blind placebo-controlled trial and received increasing doses of ivermectin from 150 micrograms/kg to 1600 micrograms/kg bodyweight. Nodules were excised at day 180 and examined by histopathology. Total doses of ivermectin up to 1600 micrograms/kg were not significantly more effective than 150 micrograms/kg. Moreover, they did not reproduce the marked inhibitory effects of the repeat standard-dose regimens on embryogenesis, nor the modest effect on adult worm viability, at comparable total doses. These effects may be functions of multiplicities of dosages rather than of the total dose. Our findings also suggest that repeated high-dose regimens are unlikely to be more effective than a similar number of 150 micrograms/kg doses. This deficiency of ivermectin requires that the search for macrofilaricides remains a top priority.
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Jung ME, Vergnes L, Deng G, Monsalve GC, Meli VS, Huang J, Faull KF, Quach A, Reue K, Fu X, Saghatelian A, Trauger SA, Pai MY, Christofk HR, Lomenick B, Wang JX, Diep S, Hwang H, Frand AR, Teitell MA, Chang HR, Chin RM, Petrascheck M, Solis GM, Jiang M, Hu E, Clarke CF, Godwin HA, Whelan SA, Fazlollahi F, Jung G, Krall AS, Braas D, Guo F, Kaweeteerawat C, Nili M
[
Nature,
2014]
Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that -ketoglutarate (-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit is identified as a novel binding protein of -KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that -KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by -KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by -KG requires ATP synthase subunit and is dependent on target of rapamycin (TOR) downstream. Endogenous -KG levels are increased on starvation and -KG does not extend the lifespan of dietary-restricted animals, indicating that -KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.
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[
Environ Pollut,
2006]
The toxicity of linear alkylbenzene sulphonates (LAS), to freshwater benthic organisms was assessed during exposure to spiked sediment. Lethal and sub-lethal end-points were monitored for two organisms (oligochaete Lumbriculus variegatus and nematode Caenorhabditis elegans). Results demonstrated relatively low toxicity (LOECs >100mg/kg dry weight). No observed effect concentrations (NOECs) of 81mg/kg dw (Lumbriculus) and 100mg/kg dw (Caenorhabditis) were determined. For the oligochaete, no specific endpoint was particularly sensitive to LAS. For the nematode, egg production was the most sensitive endpoint. Significant degradation was measured over the 28-day duration of the Lumbriculus study, equating to a half-life of 20days in sediment.
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[
Acta Pharmacol Toxicol (Copenh),
1981]
Metrifonate has been studied in the treatment of infections with Onchocerca volvulus in West Africa. In doses of 10 mg/kg daily for six days, metrifonate was effective against the microfilariae but produced unpleasant reactions due both to the death of the microfilariae and to the muscarinic effects of the drug. In a comparison of 10 mg/kg metrifonate, for 3 doses at 10 day intervals, with diethylcarbamazine (D.E.C.) in a total dose of 6.6 g, metrifonate was significantly less effective than D.E.C. in killing microfilariae but produced significantly fewer adverse effects. In a final study comparing metrifonate 10 mg/kg/day given for 3 or for 6 days there was little difference in their therapeutic effect. However, metrifonate 10 mg/kg given for 6 days produced more severe adverse reactions due largely to the muscarinic and nicotinic effects of acetylcholine and these effects were not prevented by the administration of belladonna alkaloids. Metrifonate 10 mg/kg given for 3 doses at 10 day intervals is effective in the treatment of onchocerciasis but is unlikely to replace diethylcarbamazine. Metrifonate has no action on the adult worms.
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Fazlollahi F, Clarke SG, Huang J, Graeber TG, Braas D, Fu X, Hwang H, Teitell MA, Ta L, Chin RM, Cloughesy TF, Faull KF, Deng G, Vergnes L, Reue K, Lai A, Nathanson DA, Jung ME, Christofk HR, Prins RM, Jiang M, Xing Y, Li S, Chen C, Pai MY
[
Cell Metab,
2015]
We discovered recently that the central metabolite -ketoglutarate (-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various -KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like -KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or -KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.
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[
PLoS Negl Trop Dis,
2011]
BACKGROUND: Few effective drugs are available for soil-transmitted helminthiases and drug resistance is of concern. In the present work, we tested the efficacy of the veterinary drug monepantel, a potential drug development candidate compared to standard drugs in vitro and in parasite-rodent models of relevance to human soil-transmitted helminthiases. METHODOLOGY: A motility assay was used to assess the efficacy of monepantel, albendazole, levamisole, and pyrantel pamoate in vitro on third-stage larvae (L3) and adult worms of Ancylostoma ceylanicum, Necator americanus and Trichuris muris. Ancylostoma ceylanicum- or N. americanus-infected hamsters, T. muris- or Ascaris suum-infected mice, and Strongyloides ratti-infected rats were treated with single oral doses of monepantel or with one of the reference drugs. PRINCIPAL FINDINGS: Monepantel showed excellent activity on A. ceylanicum adults (IC(50)=1.7 g/ml), a moderate effect on T. muris L3 (IC(50)=78.7 g/ml), whereas no effect was observed on A. ceylanicum L3, T. muris adults, and both stages of N. americanus. Of the standard drugs, levamisole showed the highest potency in vitro (IC(50)=1.6 and 33.1 g/ml on A. ceylanicum and T. muris L3, respectively). Complete elimination of worms was observed with monepantel (10 mg/kg) and albendazole (2.5 mg/kg) in A. ceylanicum-infected hamsters. In the N. americanus hamster model single 10 mg/kg oral doses of monepantel and albendazole resulted in worm burden reductions of 58.3% and 100%, respectively. Trichuris muris, S. ratti and A. suum were not affected by treatment with monepantel in vivo (following doses of 600 mg/kg, 32 mg/kg and 600 mg/kg, respectively). In contrast, worm burden reductions of 95.9% and 76.6% were observed following treatment of T. muris- and A. suum infected mice with levamisole (200 mg/kg) and albendazole (600 mg/kg), respectively. CONCLUSIONS/SIGNIFICANCE: Monepantel reveals low or no activities against N. americanus, T. muris, S. ratti and A. suum in vivo, hence does not qualify as drug development candidate for human soil-transmitted helminthiases.
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[
Ann Trop Med Parasitol,
1983]
The efficacy of the avermectin compound 22, 23-dihydroavermectin B1 against murine strongyloidiasis has been examined. A daily dose of 4 micrograms (200 micrograms kg-1) totally suppressed excretion of Strongyloides ratti larvae in the faeces. A similar marked suppression was seen when 10 micrograms (500 micrograms kg-1) of the drug was given on two days during the phase of larval migration or during the intestinal phase. Avermectin did not affect larval numbers in the skin but reduced larval numbers in the lungs by 91%. Administration of avermectin during the phase of larval migration completely prevented the subsequent appearance of adult worms in the gut. A single dose of 50 micrograms (2.5 mg kg-1) eradicated intestinal adult worms. Some variability was noted in dose-response studies, but the drug was very potent and a dose of 50 micrograms (2.5 mg kg-1) always eradicated the worms. Avermectin greatly reduced the numbers of S. stercoralis larvae in the muscles, whether it was given early or late in the infection. Eradication of S. stercoralis larvae from muscle followed a single dose of 100 micrograms (5 mg kg-1). It is concluded that this avermectin could be valuable in the treatment of human strongyloidiasis.