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PubMed2003

Parasite mitochondria as drug target: diversity and dynamic changes during the life cycle.

Parasites have developed a wide variety of physiological functions to survive within the specialized environments of the host. Regarding energy metabolism, which represents an essential factor for survival, parasites adapt low oxygen tension in host mammals using metabolic systems that differ substantially from those of the host. Most parasites do not use free oxygen available within the host, but employ systems other than oxidative phosphorylation for ATP synthesis. Furthermore, parasites display marked changes in mitochondrial morphology and components during the life cycle, and these represent very interesting elements of biological processes such as developmental control and environmental adaptation. The enzymes in parasite-specific pathways offer potential targets for chemotherapy. Cyanide-insensitive trypanosome alternative oxidase (TAO) is the terminal oxidase of the respiratory chain of long slender bloodstream forms of the African trypanosome, which causes sleeping sickness. Recently, the most potent inhibitor of TAO to date, ascofuranone, was isolated from the phytopathogenic fungus, Ascochyta visiae. The inhibitory mechanisms of ascofuranone have been revealed using recombinant enzyme. Parasite-specific respiratory systems are also found in helminths. The NADH-fumarate reductase system in mitochondria form a final step in the phosphoenolpyruvate carboxykinase (PEPCK)-succinate pathway, which plays an important role in anaerobic energy metabolism for the Ascaris suum adult. Enzymes in this system, such as NADH-rhodoquinone reductase (complex I) and rhodoquinol-fumarate reductase (complex II), form promising targets for chemotherapy. In fact, a specific inhibitor of nematode complex I, nafuredin, has been found in mass-screening using parasite mitochondria.

Amino Acid Sequence↗
PubMed2004

Complex II from a structural perspective.

The super-macromolecular complex, succinate:quinone oxidoreductase (SQR, Complex II, succinate dehydrogenase) couples the oxidation of succinate in the matrix / cytoplasm to the reduction of quinone in the membrane. This function directly connects the Krebs cycle and the aerobic respiratory chain. Until the recent first report of the structure of SQR from Escherichia coli (E. coli) the structure-function relationships in SQR have been inferred from the structures of the homologous QFR, which catalyses the same reaction in the opposite direction. The structure of SQR from E. coli, analogous to the mitochondrial respiratory Complex II, has provided new insight into SQR's molecular design and mechanism, revealing the electron transport pathway through the enzyme. Comparison of the structures of SQR, QFR and other related flavoproteins shows how common amino acid residues at the interface of two domains facilitate the inter-conversion of succinate and fumarate. Additionally, the structure has provided a possible explanation as to why certain organisms utilise both SQR and QFR despite the fact that both can catalyse the inter-conversion of succinate and fumarate, in vitro and in vivo. Here we review how this structure has advanced our knowledge of this important enzyme and compare the structural information to other members of the Complex II superfamily and related flavoproteins.

Amino Acid Oxidoreductases↗
PubMed2004

The Eker rat: establishing a genetic paradigm linking renal cell carcinoma and uterine leiomyoma.

Renal Cell Carcinoma (RCC) and uterine leiomyoma (often referred to as fibroids) are tumors arising from tubular epithelium and myometrial compartments of the kidney and uterus, respectively. These tumors have a very different clinical presentation, with RCC being one of the less common cancers, having a very poor prognosis, and occurring predominantly in men, whereas uterine leiomyoma are the most common tumor of women and are benign. Although they are distinct histologically, with RCC arising from epithelial cells and leiomyoma arising from smooth muscle cells, they share a common embryological origin. Renal tubular epithelial cells arise during nephrogenesis as a result of the mesenchymal-epithelial transition of condensed mesenchyme induced by the developing ureteric bud, and have a shared mesenchymal lineage with smooth muscle cells of the uterus. In addition to a common embryological origin, RCC and leiomyoma have been demonstrated to share a common genetic etiology. The Eker rat model was the first demonstration of a specific genetic linkage between RCC and uterine leiomyoma. Eker rats carry a germline defect in the rat homologue of the tuberous sclerosis complex 2 (TSC-2) tumor suppressor gene and develop spontaneous RCC and uterine leiomyoma with a high frequency. TSC patients are also at risk for RCC, and sporadic human uterine leiomyomas exhibit loss of function of the TSC-2 gene product, tuberin. Individuals with the inherited cancer syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC) that have germline defects in the fumarate hydratase (FH) gene develop papillary RCC and uterine and skin leiomyomas. Benign cutaneous lesions and uterine leiomyoma also arise in German Shepherd dogs with germline mutations in the Birt-Hogg-Dube (BHD) gene, and these animals develop RCC and uterine leiomyoma with a high frequency. Identification of the tumor suppressor genes involved in these diseases, TSC, FH and BHD, and the elucidation of the function of their protein products, tuberin, fumarate hydratase and folliculin, respectively, opens new avenues for understanding the pathogenesis of both RCC and uterine leiomyoma.

Animals↗
PubMed1998

Manipulation of ruminal fermentation with organic acids: a review.

The dicarboxylic acids aspartate, fumarate, and malate stimulate lactate utilization by the predominant ruminal bacterium, Selenomonas ruminantium. Malate stimulates lactate uptake by S. ruminantium more than does aspartate or fumarate, and it seems that malate and sodium are involved in stimulating lactate utilization by this bacterium. Based on the ability of S. ruminantium to grow on malate in the presence of extracellular hydrogen and produce succinate, malate may be acting as an electron sink for hydrogen in the succinate-propionate pathway used by S. ruminantium. Incorporation of DL-malate into soluble starch and cracked corn fermentations with mixed ruminal microorganisms changed final pH, CH4, and VFA in a manner analogous to ionophore effects. When compared with either dicarboxylic acids or monensin alone, dicarboxylic acid plus monensin addition to cracked corn incubations stimulated the mixed ruminal microorganism fermentation to produce more propionate, less lactate, and increased final pH. Reduced lactate concentrations in dicarboxylic acid- and monensin-treated incubations most likely represents an additive effect of decreased lactate production by monensin-sensitive bacteria (i.e., Streptococcus bovis) and increased lactate utilization by the monensin-resistant S. ruminantium. The inclusion of malate as a feed additive into the diets of ruminants is currently not economically feasible; however, forages rich in organic acids might serve as vehicles for providing malate to ruminants. When five alfalfa varieties and three bermudagrass hay varieties were surveyed for malate content, the concentration of malate in both plant species declined as maturity increased. However, after 42 d of maturity, the concentration of malate in both forages ranged between 1.9 and 4.5% of the DM. These results suggest that the incorporation of forage varieties that are high in malate may include malate economically into the diet and reduce losses associated with ruminal acidosis.

Animals↗
PubMed1995

Inhibition of Fc gamma R- and CR-mediated human neutrophil chemiluminescent responses by anti-allergic and anti-histaminergic drugs.

The effects of ketotifen fumarate (KF) and clemastine fumarate (CF) on neutrophil chemiluminescent (CL) responses to zymosan particles coated with either IgG (IgGZ), C3 (C3Z), or both (IC3Z), were examined in vitro. These opsonized zymosans caused not only detectable neutrophil superoxide anion generation evaluated by an MCLA-dependent CL (MDCL) assay, with the order of light emission being IC3Z > IgGZ > C3Z, but also a transient rise of neutrophil [Ca2+]i measured by an aequorin-dependent CL (ADCL) assay. Both KF and CF could suppress all opsonized zymosan-induced neutrophil MDCL in a dose-dependent fashion, but not all ADCL. Similar inhibitory effects of KF and CF were observed on the phorbol myristate acetate-induced MDCL. However, there was no interference by these two drugs with the measurement of MDCL in the hypoxanthine/xanthine oxidase superoxide anion generation system. These results indicate that the inhibitory effects of both KF and CF on Fc gamma R- and/or CR-mediated neutrophil oxidative potential is attributable to effects on an enzymatic reaction after protein kinase C activation in the oxidative signal transduction pathway.

Clemastine↗
PubMedDate not supplied

Effect of common classes of excipients on extrusion-spheronization.

Different classes of excipients with potential for use in the design of novel pelletized formulations manufactured by extrusion-spheronization were examined using factorial experiments. Among the various silicates examined in a model mix with microcrystalline cellulose and lactose wetted with water, kaolin, talc and Veegum F provided improved plasticity for the formation of spherical pellets. Weak bases such sodium bicarbonate and weak acids such as fumaric acid also aided spheronization. Whereas waxy materials such as hydrogenated castor oil and Precirol ATO5, and wetting agent such as sodium lauryl sulphate improved sphericity, these excipients reduced pellet yield by favouring agglomeration. Other materials promoting unwanted formation of over-size pellets were bentonite, citric acid and tartaric acid. The inclusion of Bentone 27, various hydroxide and carbonate bases, and fumaric acid favoured fines production. Collectively the results showed that within classes of excipients, it was not possible to predict the effect of different materials on pellet yield and sphericity. However, Carr's index and Hausner ratio calculated from density determinations correlated well with sphericity measured by image analysis.

Chemical Phenomena↗
PubMed1976

[A new, sporulating, denitrifying, mesophilic bacterium: Bacillus azotoformans N. SP. (author's transl)].

The described bacterium was isolated by enrichment culture in peptone broth inoculated with garden soil, pasteurized and then put to incubate under N2O at 32 degrees. It is a Gram-negative rod, motile with peritrichous flagella, and producing oval spores without exosporium in swollen sporangia. However, cells have the thick walls, mesosomes and persistant septa characteristic of Gram-positive bacteria. It lacks fermentative activity, does not attack carbohydrates, has complex growth requirements, and will grow anaerobically only if one of the following electron acceptors is present: NO3, NO2, N2O, S4O6, and fumarate. Nitrate, nitrite, and nitrous oxide are denitrified with production of N2. The microorganism is mesophilic, gives a positive oxidase reaction, synthesizes a type of c cytochrome, and does not hydrolyse gelatin, starch nor "Tween 80". The following enzymes are present: nitrate reductase A, respiratory nitrite reductase, tetrathionate and fumarate reductases, L-glutamate dehydrogenase, and superoxide dismutase. The following enzymes are absent: thiosulfate reductase, urease, lecithinase, arginine dihydrolase, L-alanine dehydrogenase, phenylalanine desaminase, and catalase. The GC% of its DNA is 39. The bacterium described can be considered to be a new species. We propose the name Bacillus azotoformans n. sp.

Bacillus↗
PubMed1999

Pathways of glucose catabolism in procyclic Trypanosoma congolense.

Studies of respiration on glucose in procyclic Trypanosoma congolense in the presence of rotenone, antimycin, cyanide, salicylhydroxamic acid and malonate have indicated the presence of NADH dehydrogenase, cytochrome b-c1, cytochrome aa3, trypanosome alternate oxidase and NADH fumarate reductase/succinate dehydrogenase pathway that contributes electrons to coenzyme Q of the respiratory chain. The rotenone sensitive NADH dehydrogenase, the trypanosome alternate oxidase, and cytochrome aa3 accounted for 24.5 +/- 6.5, 36.2 +/- 4.2 and 54.1 +/- 5.5% respectively of the total respiration. Activities of lactate dehydrogenase, NAD(+)-linked malic enzyme and pyruvate kinase were less than 6 nanomoles/min/mg protein suggesting that they play a minor role in energy metabolism of the parasite. Phosphoenolpyruvate carboxykinase, pyruvate dehydrogenase, succinate dehydrogenase, NADP(+)-linked malic enzyme, NADH fumarate reductase, malate dehydrogenase, and alpha-ketoglutarate dehydrogenase and glycerol kinase on the other hand had specific activities greater than 60 nanomoles/min/mg protein. These enzyme activities could account for the production of pyruvate, acetate, succinate and glycerol. The results further show that the amount of glycerol produced was 35-48% of the combined total of pyruvate, acetate and succinate produced. It is apparent that some of the glycerol 3-phosphate produced in glycolysis in the presence of salicylhydroxamic acid is dephosphorylated to form glycerol while the rest is oxidised via cytochrome aa3 to form acetate, succinate and pyruvate.

Animals↗
PubMed2000

New property of vitamin A and beta-carotene on human iron absorption: effect on phytate and polyphenols as inhibitors of iron absorption.

One hundred and seventy four human subjects were studied to find out the interaction of vitamin A or beta-carotene with the inhibitors of iron absorption, from a basal breakfast containing bread from either 100 g of precooked corn flour or 100 g of white wheat flour, 50 g of cheese and 10 g of margarine. Bread was labeled with either 55Fe or 59Fe. This bread was made from commercially flours fortified with iron as ferrous fumarate and vitamins. It was noticed that the percentage of iron absorption from the breakfast prepared with precooked corn flour given alone and with different concentrations of coffee was practically the same, while the iron absorption from the breakfast prepared from wheat flour decreased from 6% when the breakfast was given alone, to less than 2% when it was given with different concentrations of coffee. The only ingredient present in precooked corn flour and not in wheat flour was vitamin A. This difference encouraged the authors to perform further experiments using precooked corn and wheat flours fortified only with ferrous fumarate. These studies demonstrated that vitamin A inhibits the effect of the polyphenol and partially inhibits the effect phytate on iron absorption. HPLC and spectrophotometric studies demonstrated an interaction between vitamin A and iron. Other experiments, which included 100 volunteers, were performed to test the effect of vitamin A and beta-carotene on iron absorption from corn, wheat and rice. The presence of vitamin A increased iron absorption up to 3 times for rice, 2.4 times for wheat and 1.8 times for corn. beta-carotene increased absorption almost 3 times for the three cereals tested, showing that both compounds were capable of preventing the inhibitory effect of phytates on iron absorption. This information suggest that vitamin A and beta-carotene form a complex with iron keeping it soluble in the intestinal lumen and preventing the inhibitory effect of phytates and polyphenols on iron absorption.

Antioxidants↗
PubMed1979

[Carbon assimilation and taxonomic study of Bacillus subtillis and B. licheniformis].

All 14 strains of B. subtilis can use the following 17 sources of carbon and energy: D-glucose, D-mannose, D-glucosamine, salicin, D-ribose, maltose, sucrose, cellobiose, trehalose, arbutin, starch, mannitol, glycerol, glycerate, pyruvate, fumarate, and L-proline. All 15 strains of B. licheniformis can use the following 41 sources of carbon and energy: D-glucose, D-galactose, D-mannose, D-fructose, D-glucosamine, alpha-methyl-D-glucoside, beta-methyl-D-glucoside, salicin, D-gluconate, saccharate, D-xylose, L-arabinose, L-rhamnose, D-ribose, maltose, sucrose, cellobiose, melibiose, trehalose, arbutin, raffinose, starch, inulin, mannitol, D-sorbitol, glycerol, glycerate, citrate, L-malate, D-malate, mucate, pyruvate, fumarate, alpha-L-alanine, alpha-D-alanine, asparagine, L-glutamate, L-arginine, DL-ornithine, L-proline, and 4-amino-n-butyrate. The 29 strains form two distinct groups. Group A includes the 15 strains of B. licheniformis and 2 strains of B. subtilis; group B is formed of 11 strains of B. subtilis; the remaining strain of B. subtilis belongs to neither group. Bacillus licheniformis is a more homogeneous species than B. subtilis. The percentage of guanine + cytosine in the DNA of all 29 strains was determined. In the 14 strains of B. subtilis the average is 46.3% +/- 1.5. In the 15 strains of B. licheniformis the average is 46.4% +/- 0.9.

Bacillus↗
PubMedDate not supplied

[Synthesis of L-aspartic acid by Escherichia coli and Pseudomonas fluorescens as related to the cultivation conditions].

The capacity of the cultures Escherichia coli str. 85, 113, BC, C and K-12 and Pseudomonas fluorescens str. 1 to synthesize L-aspartic acid from fumarate and ammonium ions was studied. E. coli str. 85 was shown to synthesize the largest amounts of aspartic acid. The cultivation conditions which helped to increase the activity several times were selected. The product of fumarate amination by ammonium ions was identified and found to be L-isomer of aspartic acid with an angle of rotation of [alpha] 20/D = +25,5 degrees in 6 N HCl.

Aspartic Acid↗
PubMed2002

Acute iron poisoning.

Intoxications with ferrous compounds are uncommon but ferrous sulphate is most frequently involved. Ferrous fumarate is less toxic than ferrous sulphate. Two cases of ferrous fumarate poisoning that resulted in digestive mucosal lesions are reported.

Acute Disease↗
PubMed2002

Bioavailability of iron from micro-encapsulated iron sprinkle supplement.

To improve the iron status of infants an effort was made to increase the iron content of complementary foods by adding 12.5 mg of elemental iron to the meal in the form of micro-encapsulated ferrous fumarate coated with a lipid. The contents of the packet were sprinkled directly on to infant foods. Relative absorption of iron from this supplement was determined in a prospective randomized study with 39 infants (mean age 33.6 +/- 5.2 weeks) with initial hemoglobin values greater than 100 g/L. They were fed two complementary foods (rice-based and wheat-based) in which the supplement labeled with stable isotopes of iron 57Fe and 58Fe was incorporated. The erythrocyte iron incorporation was measured in the blood by inductively coupled plasma mass spectrophotometry. The incorporation of iron was significantly higher 11.9% p < .001 and 13.3% p < .001 and no difference was observed with the type of cereal in complementary foods. The use of ferrous fumarate sprinkles has proved to be efficacious in increasing the available iron intake of the infants.

Anemia, Iron-Deficiency↗
PubMed2002

Gateways to Clinical Trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil fumarate, testosterone heptanoate, testosterone undecanoate, tipifarnib, tolterodine tartrate, topiramate, troglitazone; Ursodeoxycholic acid; Valdecoxib, valsartan, vardenafil, venlafaxine hydrochloride, VX-745.

Clinical Trials as Topic↗
PubMed1992

Failure of CAPD patients to respond to an oral iron absorption test.

CAPD patients require supplemental iron to maintain a response to erythropoietin. Because of limited availability of parenteral iron dextran, oral iron must be used. However, oral iron may not be effective in most dialysis patients. To determine if oral iron is well absorbed, a modified oral iron absorption or tolerance test was performed in CAPD patients using two oral iron preparations. Serum irons were measured at baseline in a fasting state and repeated two hours after the ingestion of 325 mgs ferrous sulfate in five CAPD patients. In addition, eight patients had serum irons determined before and two hours after taking liquid oral ferrous fumarate in capsule form. Healthy controls were compared with each group. All five patients who received ferrous sulfate had borderline to low normal serum iron and iron stores. Average increase in serum irons was only 19 mcg/dl in patients compared to 52 mcg/dl in controls. Patients receiving ferrous fumarate rose only 14 mcg/dl compared to 60 mcg/dl in controls. We conclude that oral iron is poorly absorbed in most CAPD patients and that the oral iron absorption test may be helpful in identifying patients who are effective iron absorbers. Unfortunately, until parenteral iron dextran is readily available, oral iron therapy is the only alternative for iron supplement. The oral iron absorption test may predict who will respond to oral iron in the long-term.

Administration, Oral↗
PubMed1976

[Experimental studies on anthelmintics (XXVI). Biochemical and pharmacological studies of 4-iodothymol on Ascaris lumbricoides suum].

We have shown previously that 4-iodothymol (IT) produces a contraction in Ascaris muscle, probably due to the myogenic action. In this paper, the effects of IT on the carbohydrate metabolism in Ascaris muscle have been investigated in comparison with those of hexylresorcinol (Hex), santonin (S) and piperazine (Pip). (1) Hex (200 approximately 400 mug/ml) showed a strong nonspecific inhibition on the formation of succinate from fumarate in muscle homogenate, the phosphofructokinase (PFK) activity in cytoplasm, and the electron transfer activity in mitochondria. (2) S(100 approximately 400 mug/ml) and Pip (100 approximately 400 mug/ml) were inneffective on these activities. (3) IT inhibited the formation of succinate from glucose and fumarate in muscle homogenate (100 approximately 400 mug/ml), the PFK activity in cytoplasm (400 mug/ml), and the mitochondrial succinate oxidase system (25 approximately 400 mug/ml). These results suggest that IT elicits the wormcidal action by inhibiting the energy metabolism of Ascaris muscle mitochondria.

Animals↗
PubMedDate not supplied

In vitro evaluation of chemopreventive agents using cultured human prostate epithelial cells.

The effects of nine potential cancer chemopreventive agents on cell growth or clonogenic survival were evaluated in normal human prostate epithelial cells, an immortalized but non-tumorigenic human prostate epithelial cell line (267B1), a human benign prostatic hyperplasia (BPH) cell line (BRF-55T), and a human prostate cancer cell line (267B1/Ki-ras). Of the nine agents tested, 9-cis retinoic acid, liarozole fumarate, phenylenebis(methylene)-selenocyanate (p-XSC), and L-selenomethionine demonstrated much stronger growth inhibitory effects on prostate cancer cells than on the normal prostate epithelial cells, suggesting that these agents may be useful as prostate cancer chemopreventive agents. 9-cis retinoic acid, genistein, liarozole fumarate, p-XSC, L-selenomethionine and vitamin E also showed much stronger growth inhibitory effects on BRF-55T cells than on the normal prostate epithelial cells, indicating that these agents may also be useful for the prevention and treatment of BPH. Difluoromethylornithine (DFMO), DHEA analogue 8354 (fluasterone), and oltipraz did not show strong inhibitory effects on the growth or survival of normal prostate epithelial cells, 267B1 or 267B1/Ki-ras cells, suggesting that these agents may not be effective as prostate cancer preventive or therapeutic agents.

Cell Line, Tumor↗
PubMed1978

K+--induced changes of oxygen uptake by neuronal enriched and glial enriched fractions from mouse brain cortex.

Neuronal and glial enriched fractions were incubated in a medium with 10mM pyruvate, 5mM fumarate and 0.9mM 5'-AMP and the effect of increased external K+ concentrations was studied upon oxygen uptake. A concentration of 65 mM K+ had a different effect on the oxygen consumption of glial and neuronal perikarya. The rate of oxygen uptake by glia was stimulated by 52.81% whilst an insignificant decrease of 15.79% occurred in the neurones. The highest rate of oxygen uptake by incubated cells was estimated in the presence of the substrate system containing pyruvate, fumarate and 5'-AMP. The significance of components in the substrate system for a high rate of oxygen uptake by cells was also tested with 6.2 mM K+ and 65 mM K+.

Animals↗