[Stimulating Type I interferon response with small molecules: revival of an old idea]. / Stimuler la réponse interféron de type I avec des petites molécules : le renouveau d'une vieille idée.

Type I interferons play a central role in the establishment of an innate immune response against viral infections and tumor cells. Shortly after their discovery in 1957, several groups have looked for small molecules capable of inducing the expression of these cytokines with therapeutic applications in mind. A set of active compounds in mice were identified, but because of their relative inefficiency in humans for reasons not understood at the time, these studies fell into oblivion. In recent years, the characterization of pathogen recognition receptors and the signaling pathways they activate, together with the discovery of plasmacytoid dendritic cells, have revolutionized our understanding of innate immunity. These discoveries and the popularization of high-throughput screening technologies have renewed the interest for small molecules that can induce type I interferons. Proofs about their therapeutic potency in humans are expected very soon.

Phenolic Compounds from the Roots of Rhodiola crenulata and Their Antioxidant and Inducing IFN-γ Production Activities.

In the present study, two new phenolic compounds 1 and 11, a pair of lignan isomers 12 and 13 with their absolute configurations established for the first time, were isolated from the ethanol extract of the roots of Rhodiola crenulata, together with 13 known phenolic compounds, and their structures were elucidated via NMR, HRESIMS, UV, IR and CD analyses. All the isolated compounds were evaluated for their in vitro antioxidant activities using the 2,2-diphenyl-1-picryhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays. Ten of them exhibited significant antioxidant activities compared to ascorbic acid. Furthermore, the inducibilities of the isolated compounds to IFN-γ production were also assessed. Compounds 1, 8, 9, 12, 13, 14 and 15 could moderately stimulate IFN-γ expression.

Designing improved poly lactic-co-glycolic acid microspheres for a malarial vaccine: incorporation of alginate and polyinosinic-polycytidilic acid.

Vaccination using proteins and peptides is currently gaining importance. One of the major drawbacks of this approach is the lack of an efficient immune response when the antigens are administered without adjuvants. In this study, we have taken the advantage of a combined adjuvant system in order to improve the immunogenicity of the SPf66 malarial antigen. For that purpose, we have combined poly (lactic-co-glycolic) acid microspheres, alginate, and polyinosinic polycytidilic acid. Our results show that microspheres can enhance the IgG production obtained with Freund's complete adjuvant. We have attributed this improvement to the presence of polyinosinic polycytidilic acid, since formulations comprising this adjuvant overcame the immune response from the others. In addition, our microspheres produced both IgG1 and IgG2a, leading to mixed Th1/Th2 activation, optimal for malaria vaccination. In conclusion, we have designed a preliminary formulation with a high potential for the treatment of malaria.

Discovery of a highly potent series of TLR7 agonists.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.

Quantitative determination of the composition of multi-shell calcium phosphate-oligonucleotide nanoparticles and their application for the activation of dendritic cells.

Biodegradable calcium phosphate nanoparticles as carriers for the immunoactive toll-like receptor ligands CpG and polyinosinic-polycytidylic acid for the activation of dendritic cells (DC) combined with the viral antigen hemagglutinin (HA) were prepared. A purification method based on ultracentrifugation and ultrasonication was developed to separate the nanoparticles from dissolved biomolecules. The number of biomolecules, i.e., oligonucleotides and peptide, incorporated into the nanoparticles was quantitatively determined by UV-spectroscopy, using fluorescent derivatives of the biomolecules. The immunostimulatory effects of purified calcium phosphate nanoparticles on DC were studied, i.e., cytokine production and activation of the cells in terms of the upregulation of surface molecules. Purified calcium phosphate nanoparticles, i.e., without dissolved biomolecules, are capable of inducing adaptive immunity by activation of DC. Immunostimulatory effects of purified calcium phosphate nanoparticles on DC were demonstrated by increased expression of co-stimulatory molecules and MHC II and by cytokine secretion. In addition, DC treated with purified functionalized calcium phosphate nanoparticles induced an antigen-specific T-cell response in vitro.

Germane facts about germanium sesquioxide: I. Chemistry and anticancer properties.

This paper reviews the history, chemistry, safety, toxicity, and anticancer effects of the organogermanium compound bis (2-carboxyethylgermanium) sesquioxide (CEGS). A companion review follows, discussing the inaccuracies in the scientific record that have prematurely terminated research on clinical uses of CEGS. CEGS is a unique organogermanium compound first made by Mironov and coworkers in Russia and, shortly thereafter, popularized by Asai and his colleagues in Japan. Low concentrations of germanium occur in nearly all soils, plants and animal life; natural occurrence of the CEGS form is postulated but not yet demonstrated. The literature demonstrating its anticancer effect is particularly strong: CEGS induces interferon-gamma (IFN-gamma), enhances natural killer cell activity, and inhibits tumor and metastatic growth--effects often detectable after a single oral dose. In addition, oral consumption of CEGS is readily assimilated and rapidly cleared from the body without evidence of toxicity. Given these findings, the absence of human clinical trials of CEGS is unexpected. Possible explanations of why the convincing findings from animal research have not been used to support clinical trials are discussed. Clinical trials on CEGS are recommended.

A novel mode of carbohydrate recognition in jacalin, a Moraceae plant lectin with a beta-prism fold.

Jacalin, a tetrameric two-chain lectin (66,000 Mr) from jackfruit seeds, is highly specific for the tumour associated T-antigenic disaccharide. The crystal structure of jacalin with methyl-alpha-D-galactose reveals that each subunit has a three-fold symmetric beta-prism fold made up of three four-stranded beta-sheets. The lectin exhibits a novel carbohydrate-binding site involving the N terminus of the alpha-chain which is generated through a post-translational modification involving proteolysis, the first known instance where such a modification has been used to confer carbohydrate specificity. This new lectin fold may be characteristic of the Moraceae plant family. The structure provides an explanation for the relative affinities of the lectin for galactose derivatives and provides insights into the structural basis of its T-antigen specificity.