Leishmania donovani in hamsters: stimulation of non-specific resistance by some novel glycopeptides and impact on therapeutic efficacy

Several glycopeptides structurally related to muramyl dipeptide (MDP) have been synthesized and evaluated for their ability to stimulate the non-specific resistance of hamsters against L. donovani infection. These compounds have been named CDRI compounds. The synthetic procedure used for compounds 86/448 and 84/212 is described. MDP and its synthetic congeners were administered as immunostimulants at a prophylactic dose of 3 mg/kg at two weeks interval. The challenge infection (1 x 10(7) amastigotes i.c./hamster) was given in between two doses of the compounds. One of the glycopeptides, CDRI comp. 86/448, has been found to be significantly more potent than MDP, effecting 92% inhibition of the challenge dose, whereas MDP produced only 26.5% inhibition. The effect of comp. 86/448 lasted until day 7 of challenge. The efficacy of sodium stibogluconate was appreciably improved in hamsters treated with comp. 86/448.     

Leishmania donovani in hamsters: Stimulation of non-specific resistance by novel lipopeptides and their effect in antileishmanial therapy

Several novel type of lipopeptides were synthesized and evaluated for their ability to stimulate non-specific resistance againstLeishmania donovani infection. Peritoneal macrophages isolated from young male hamsters treated with muramyl dipeptide (MDP) and various synthetic lipopeptides (6 mg/kg i.p.) 7 days earlier, were cultured in vitro and challenged 24 h later withL. donovani promastigotes. One lipopeptide, Central Drug Research Institute (CDRI) compound 86/450, exhibited significantly higher immunostimulatory activity than MDP. Its prophylactic activity was further confirmed in hamsters by giving 2 split doses of 3 mg/kg of the compound spaced at 2 weeks, i.e. on day –7 and +7 of challenge withL. donovani amastigotes. The prophylactic effect lasted for 7 days following the last treatment with compound 86/450. The antileishmanial action of sodium stibogluconate (SAG) was also found to be enhanced by 16% in hamsters primed with compound 86/450.CDRI Communication No. 5034.     

Increase in the non-specific resistance to infection in mice after oral administration of 2 synthetic glycopeptides with adjuvant activity]

Two synthetic glycopeptides (MurNAc-L-Ala-D-isoGln and MurNAc-L-Ala-D-Glu), having adjuvant activity, were shown to enhance non-specific resistance to infection against K. pneumoniae. These compounds were active by various routes including oral administration and even if administered after the challenge. Two steroisomers lacking adjuvant activity did not protect the infected Mice.     

Effect of actinomycin D onTrypanosoma cruzi

Summary Viable metacyclic forms ofT. cruzi, Y strain, treated with an adequate dose of actinomycin D (50 g Act-D/ml/10⁷ parasites/ml for 72 h at 28° C) showed the following properties: 1) they lost their ability to replicate in culture medium, in blood and in tissues of normal mice and were no longer able to incorporate tritiated thymidine; 2) they could no penetrate into Vero cells and could not replicate inside normal macrophages; 3) they retained their immunogenicity and the ability to protect mice against a virulent infection; 4) they did not induce histological lesions as described in chronic experimental Chagas' disease.     

Propriétés antiacétylcholinestérasiques du diiodométhylate debis-(diméthylamino-3-phénoxy)-1-3 propane,de ses dérivés phénoliques et des esters carbamiques correspondants

Summary Thein vitro anti-acetylcholinesterase properties ofbis-(dimethylamino-3-phenoxy)-1-3 propane dimethiodide (2842 CT) of two phenolics derivatives (3443 CT and 3116 CT) and of the two corresponding carbamic esters (3152 CT et 3113 CT) have been compared using human red blood corpuscles as enzyme source; under specified conditions, the Cl-50 are respectively 8 × 10^–7 M for 2842 CT, 3.5 × 10^–9 for the two phenolic compounds, and 1.5 × 10^–9 for the carbamic esters. The potencies of these phenols are very close to those of the carbamates, being a bit higher or lower depending on the concentration of the inhibitor and on the time of the readingThe two phenolic compounds, like 2842 CT, react readily with the enzyme contrarily to the carbamic esters which combine slowly. On the other hand the inhibition by the phenolic derivatives is as stable against washing as that by the carbamates. The carbamates, but not the phenols, show the slow displacement phenomenon.Some of these characteristics are compatible with the hypothesis that carbamic compounds could act through liberated phenolic functions but others indicate that carbamic groups have a role of their own.     

Transgenic and mutant animal models to study mechanism of protection of red cell genetic defects against malaria

Malaria, caused by members of the genusPlasmodia, is still the most prevalent parasitic disease in the world. In an attempt to understand genetic factors conferring resistance to malaria, mouse models of thalassemia, sickle trait, and ankyrin and spectrin deficiency were studied during infection with species of malaria infectious to rodents. Although growth ofP. falciparum is not inhibited in thalassemic erythrocytes in culture, mice carrying a -thalassemia mutation were protected fromPlasmodium chabaudi adami, supporting epidemiologic findings. Transgenic mice expressing ^s hemoglobin were also significantly protected from two species of rodent malaria. Importantly, a significant role for the spleen in protection in the ^s transgenic mice was found. Finally, mice deficient in spectrin and ankyrin were studied with respect to their ability to support the growth of malaria. It was found that spectrin deficient mice were almost completely refractory toP. chabaudi adami andP. berghei. These models will allow further study of host factors in resistance to malaria.     

GABA transporter lysine 448: a key residue for tricyclic antidepressants interaction

The effects of three tricyclic antidepressants (TCAs) and two serotonin selective reuptake inhibitors (SSRIs) have been studied with an electrophysiological approach on Xenopus laevis oocytes expressing the rat GABA (γ-Aminobutyric-acid) transporter rGAT1. All tested TCAs and SSRIs inhibit the GABA-associated current in a dose-dependent way with low but comparable efficacy. The pre-steady-state and uncoupled currents appear substantially unaffected. The efficacy of desipramine, but not of the other drugs, is strongly increased in the lysine-glutamate or -aspartate mutants K448E and K448D. Comparison of I _max and K _0.5GABA in the absence and presence of desipramine showed that both parameters are reduced by the drug in the wild-type and in the K448E mutant. This suggests an uncompetitive inhibition, in which the drug can bind only after the substrate, an explanation in agreement with the lack of effects on the pre-steady-state and leak currents, and with the known structural data.     

New C26 δ-lactones from the Dufour's gland of the urticating antTetramorium aculeatum

(6R^*)-{(2S^*)-2-hydroxyheneicos-12-enyl}-5,6-dihydro-2H-pyran-2-one (1)^o is the major constituent of the secretion of freshly dissected Dufour's gland of the urticating antTetramorium aculeatum. In solution, compound 1 is slowly transformed into (1S^*, 5R^*, 7S^*)-7-(nonadec-10-enyl)-2,6-dioxabicyclo[3.3.1]nonan-3-one (2)^o on standing. The structures of compounds 1 and 2 have been established on the basis of their spectral and chemical properties. Compound 1 could be responsible for the urticating properties of the ant.^o IUPAC numbering.     

Allozyme polymorphism and linkage disequilibrium ofAdh and α-Gpdh loci in wine cellar and field populations ofDrosophila melanogaster

Summary Over three years, theAdh and -Gpdh loci have been studied in two cellar populations ofDrosophila melanogaster and in two field populations which were each near to one of the cellars. Analyses of gene frequencies indicate that the divergence among subpopulations is greater in theAdh locus than in the -Gpdh locus. Selection for or againstAdh ^S allele acting on theIn(2L)t inversion influences of the -Gpdh alleles. This phenomenon may contribute to explain the maintenance of theAdh and -Gpdh polymorphism and of theIn(2L)t inversion.     

Glycine absorption from the small intestines of rats after secondary infections withEimeria nieschulzi

Summary A second (challenge) infection ofEimeria nieschulzi in clinically immune rats did not produce weight gain depression but caused a decrease in the absorption of glycine from the ileum. The malabsorption due to challenge was equivalent to that caused by the primary infection which did cause weight loss.     

Utilization of phosphate compounds for growth ofTetrahymena

Summary Taking advantage of a synthetic nutrient medium, we have studied which compounds phosphate-starvedTetrahymena thermophila can use as phosphate sources for growth and cell multiplication. Ortho-, trimeta- and -glycero-phosphate are good sources for both the wild type and a food-vacuoleless mutant; phosphorylcholine is used only by the wild type, and 2-aminoethyl phosphonic acid fails to serve as a phosphate source. Since at least two phosphatases are found in the extracellular fluid these results indicate thatTetrahymena can make use of extracellular digestion of nutrients.     

Cytogenetic effects of delta-9-tetrahydrocannabinol (Δ 9-THC) on hamster bone marrow

Summary Single s.c. injections of 10 or 1000 mg/kg of ⁹-THC did not induce discernable chromosomal damage but caused significant mitotic inhibition in the bone marrow of Syrian hamsters.Acknowledgments. The authors which to thank Mr R.H. Graham, Department of National Health and Welfare, Health Protection Branch, for the generous supply of ⁹-THC. This research was supported by a grant to Dr M.G. Joneja from the Department of National Health and Welfare.     

Phosphoramidon enhances allatostatin-mediated inhibition of juvenile hormone biosynthesis in the corpora allta of the cockroach,Diploptera punctata

Use of the enkephalinase inhibitor phosphoramidon in the in vitro radiochemical assay for juvenile hormone biosynthesis enhanced allatostatin-mediated inhibition of hormone production by corpora allata of the cockroach,Diploptera punctata. Significant increases in inhibition in day 2 virgin female CA by AST 1 (at 10^–7 M) and AST 4 (10^–8–10^–7 M) were observed in the presence of phosphoramidon (10^–5M or greater). No significant increases in inhibition were seen in CA from day 6 mated females with AST 4 (10^–9–10^–7M) and phosphoramidon combined. Phosphoramidon alone had no effect on JH biosynthesis. Analysis of allatostatin content of the CA, as determined by ELISA, revealed that addition of phosphoramidon to the medium increased the endogenous allatostatin conten in CA of virgin and mated females. The similarity in primary structure between allatostatins and enkephalin-like peptides and their similar distribution makes it probable that phosphoramidon acts by preventing breakdown of allatostatins within the CA.     

Effect of tingenone,a quinonoid triterpene,on growth and macromolecule biosynthesis inTrypanosoma cruzi

Summary Tingenone and horminone, two natural quinonoid substances, inhibited the in vitro growth ofTrypanosoma cruzi, 30 M drug concentration producing total inhibition of growth. Tingenone inhibited total uptake and incorporation of [³H]thymidine, [³H]uridine, L-[³H]leucine into parasite macromolecules. Other quinonoids assayed were either less effective (abruquinone A) or even quite inactive (visminone B and ferruginin B). Investigation of several mechanisms for the cytotoxic action of tingenone pointed to the interaction with DNA as the most likely factor involved. Tingenone also inhibited the growth ofCrithidia fasciculata, but the drug was significantly less active on this organism than onT. cruzi.This work was supported by grants of UNDP/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases, Organization of American States (Multinational Programme of Biochemistry) and Programa Nacional de Enfermedades Endémicas (SECYT), República Argentina. A preliminary account was given at the Workshop on Oxidative Damage and Related Enzymes, Frascatti (Italy), 1983.     

Antidesmanol-a new pentacyclic triterpenoid fromAntidesma menasu Miq. ex. Tul.

Summary Antidesmanol (1), a new pentacyclic triterpenoid, has been isolated along with n-tritriacontane, friedelin, canophyllal and canophyllol from the aerial parts ofAntidesma menasu. Based on chemical and spectroscopic evidence, its structure has been established as 3-keto-16-hydroxyfriedelane. n-Tritriacontane and friedelin have shown antiinflammatory and diuretic activities respectively in experimental animals.CDRI Communication No. 2536.     

Strong mutagenic action of a bipyridylium herbicide in a N2-fixing blue-green alga

Summary The herbicide paraquat (1,1-dimethyl-4,4-bipyridylium ion) has been found to exert a growth inhibitory effect on the N₂-fixing blue-green algaNostoc muscorum in nitrogen-free (N₂) and NO ₃ ^– media, without any apparent inhibitory or stimulatory effect on the heterocyst-forming capacity of the organism. With a dose of paraquat permitting about 20 and 50% survival of this alga a reverse mutation (fromhet ⁺ nif ^– auxotrophy tohet ⁺ nif ⁺ prototrophy), a forward mutation (for L-methionine-DL-sulfoximine [MSO]-resistance), and an auxotrophic mutation (for carbon-auxotrophy through methylamine [MA]-resistance) have been obtained. The toxic and mutagenic effects of this agrochemical have been compared with those of the well known mutagen MNNG (N-methyl-N-nitro-N-nitrosoguanidine) and found to be stronger than those of the latter in each case.The author wishes to thank Mr Girish Nath, Lakshami Chemicals Pvt. Ltd., Phatuha (Patna), India, for providing pure samples of the herbicide for the present investigation. The receipt of financial assistance for this work in the form of a Higher Research Associateship Award to the author from the University Grants Commission, Govt. of India, New Delhi-110002 (Grant No. F/16-51/83), is thankfully acknowledged.     

The pleiotropic functions of aspirin: mechanisms of action

Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores, increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding κB site (NF-κB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy. Received 1 February 1999; received after revision 1 April 1999; accepted 7 May 1999     

Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product Calcipressin 1 (or RCAN1) in disease

The DSCR1 (Adapt78) gene¹ is transiently induced by stresses to temporarily protect cells against further potentially lethal challenges. However, chronic expression of the DSCR1 (Adapt78) gene has now been implicated in several pathological conditions including Alzheimer’s disease, Down syndrome and cardiac hypertrophy. Calcipressin 1 has been shown to function through direct binding and inhibition of the serine threonine protein phosphatase Calcineurin. Pharmacological inhibition of calcineurin, by the immunosuppressive drugs cyclosporin A and FK506, affects a wide variety of diseases. It is, therefore, likely that this endogenous calcineurin inhibitor, calcipressin 1, may also play a role in a variety of human diseases. ¹Please note that the mammalian DSCR1 gene is also called Adapt78 or RCAN1, and its protein products have been named Calcipressin1, MCIP1 and RCAN1. A proposal to adopt a single gene name of RCAN1 and a protein name RCAN1 (for Regulator of Calcineurin) has been endorsed by the HUGO Gene Nomenclature Committee, but final approval must await agreement from a majority of researchers in the field. Received 2 March 2005; received after revision 27 May 2005; accepted 19 July 2005     

BlaB,a protein involved in the regulation of <Emphasis Type="Italic">Streptomyces cacaoi</Emphasis> β-lactamases,is a penicillin-binding protein

Streptomyces cacaoi -lactamase genes are controlled by two regulators named blaA and blaB. Whereas BlaA has been identified as a LysR-type activator, the function of BlaB is still unknown. Its primary structure is similar to that of the serine penicillin-recognizing enzymes (PREs). Indeed, the SXXK and KTG motifs are perfectly conserved in BlaB, whereas the common SXN element found in PREs is replaced by a SDG motif. Site-directed mutations were introduced in these motifs and they all disturb -lactamase regulation. A water-soluble form of BlaB was also overexpressed in the Streptomyces lividans TK24 cytoplasm and purified. To elucidate the activity of BlaB, several compounds recognized by PREs were tested. BlaB could be acylated by some of them, and it can therefore be considered as a penicillin-binding protein. BlaB is devoid of -lactamase, D-aminopeptidase, DD-carboxypeptidase or thiolesterase activity.Received 13 January 2003; received after revision 9 April 2003; accepted 11 April 2003     

A reinvestigation of the chemistry of the Dufours gland of the formicine ant,Anoplolepis custodiens

The components of individual Dufours glands excised fromAnoplolepis custodiens workers were analysed by GC-MS. In addition to then-alkanes andn-alkenes previously reported² in these glands, primary alcohols (C₁₉-C₂₂), secondary alcohols (C₂₀-C₂₃), 2-ketones (C₂₀-C₂₃) and possibly carboxylate ethyl esters (C₁₉ and C₂₁) were identified as components of these glands. It seems possible that these high-boiling compounds are used by the workers in laying trails on the hot sandy surfaces of their characteristic habitat and in lining of the inner walls of nests, but no standard compounds have been available to us for any behavioral studies.