Antimalarial activity of axidjiferosides, new ß-galactosylceramides from the African sponge Axinyssa djiferi.

The marine sponge, Axinyssa djiferi, collected on mangrove tree roots in Senegal, was investigated for glycolipids. A mixture containing new glycosphingolipids, named axidjiferoside-A, -B and -C, accounted for 0.07% of sponge biomass (dry weight) and for 2.16% of total lipids. It showed a significant antimalarial activity, with a 50% inhibitory concentration (IC50) of 0.53 ± 0.2 µM against a chloroquine-resistant strain of Plasmodium falciparum. They were identified as homologous ß-galactopyranosylceramides composed of 2-amino-(6E)-octadec-6-en-1,3,4-triol, and the major one, axidjiferoside-A (around 60%), contained 2-hydroxytetracosanoic acid. Cytotoxicity was studied in vitro on human cancer cell lines (multiple myeloma, colorectal adenocarcinoma, glioblastoma and two lung cancer NSCLC-N6 and A549). Results of this investigation showed that axidjiferosides are of interest, because they proved a good antiplasmodial activity, with only a low cytotoxicity against various human cell lines and no significant antitrypanosomal and antileishmanial activity. Thus, it seems that galactosylceramides with a ß anomeric configuration may be suitable in searching for new antimalarial drugs.

Monocyte cytokine and costimulatory molecule expression in patients infected with Leishmania mexicana.

Leishmania mexicana causes localized and diffuse cutaneous leishmaniasis. Patients with localized cutaneous leishmaniasis (LCL) develop a benign disease, whereas patients with diffuse cutaneous leishmaniasis (DCL) suffer from a progressive disease associated with anergy of the cellular response towards Leishmania antigens. We evaluated the production of the interleukins (IL) IL-12, IL-15, IL-18 and tumour necrosis factor-alpha (TNF-alpha) and the expression of the costimulatory molecules CD40, B7-1 and B7-2 in monocytes from LCL and DCL patients, stimulated in vitro with Leishmania mexicana lipophosphoglycan (LPG) for 18 h. LCL monocytes significantly increased TNF-alpha, IL-15 and IL-18 production, and this increase was associated with reduced amounts of IL-12. DCL monocytes produced no IL-15 or IL-18 and showed a decreasing tendency of TNF-alpha and IL-12 production as the severity of the disease increased. No difference was observed in the expression of CD40 and B7-1 between both groups of patients, yet B7-2 expression was significantly augmented in DCL patients. It remains to be established if this elevated B7-2 expression in DCL patients is cause or consequence of the Th2-type immune response that characterizes these patients. These data suggest that the diminished ability of the monocytes from DCL patients to produce cell-activating innate proinflammatory cytokines when stimulated with LPG is a possible cause for disease progression.

Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1, 2-dimethylhydrazine-treated CF1 mice.

Dietary sphingomyelin (SM) inhibits early stages of colon cancer (appearance of aberrant crypt foci, ACF) and decreases the proportion of adenocarcinomas vs. adenomas in 1,2-dimethylhydrazine (DMH)-treated CF1 mice. To elucidate the structural specificity of this inhibition, the effects of the other major sphingolipids in milk (glycosphingolipids) were determined. Glucosylceramide (GluCer), lactosylceramide (LacCer) and ganglioside G(D3) were fed individually to DMH-treated (six doses of 30 mg/kg body weight) female CF1 mice at 0.025 or 0.1 g/100 g of the diet for 4 wk. All reduced the number of ACF by > 40% (P < 0.001), which is comparable to the reduction by SM in earlier studies. Immunohistochemical analysis of the colons revealed that sphingolipid feeding also reduced proliferation, with the most profound effect (up to 80%; P < 0.001) in the upper half of the crypts. Since the bioactive backbones of the glycosphingolipids (i.e., ceramide and other metabolites) are the likely mediators of these effects, the susceptibility of these complex sphingolipids to digestion in the colon was examined by incubating 500 microgram of each sphingolipid with colonic segments from mice and analysis of substrate disappearance and product formation by tandem mass spectrometry. All of the sphingolipids (including SM) disappeared over time with a substantial portion appearing as ceramide. Partially hydrolyzed intermediates (such as GluCer from LacCer or G(D3)) were not detected, which suggests that the cleavage involves colonic (or microflora) endoglycosidases. In summary, consumption of dairy SM and glycosphingolipids suppresses colonic cell proliferation and ACF formation in DMH-treated mice; hence, many categories of sphingolipids affect these key events in colon carcinogenesis.