Assessment of the safety of Levilactobacillus brevis CNCM I-5321, a probiotic candidate strain isolated from pulque with anti-proliferative activities.

Gut dysbiosis has been strongly correlated with colorectal cancer (CRC) development and the use of probiotics to modulate this imbalance represents a potential and promising therapy to prevent and treat CRC. For this reason, the identification of novel probiotic strains from diverse origins has widely increased in recent years, including traditional fermented foods. In this work we describe a new strain previously isolated from pulque (a traditional Mexican beverage), Levilactobacillus brevis CNCM I-5321, which may represent an interesting probiotic candidate to prevent and treat cancer. Indeed, our results show that CNCM I-5321 displays significant and specific antiproliferative capacities in human intestinal cancer cell lines (HT-29, HTC-116 and Caco-2 cells), but not in normal cells (FH cells). In addition, CNCM I-5321 is able to induce: (1) a pro-inflammatory immune response through stimulation of interleukin (IL)-2, IL-6, IL-12 and IL-17 cytokines and (2) apoptosis via activation of caspase 8. On the other hand, a minimum inhibitory concentration (MIC) assay revealed phenotypic resistance of this strain to ampicillin and chloramphenicol. However, no known transferable determinants were found in the genome of CNCM I-5321, thus this probiotic candidate presents no risk of horizontal transfer to the intestinal bacterial population. Finally, the safety status of CNCM I-5321 was evaluated using an innovative model of chicken embryo chorioallantoic membrane (CAM) to assess undesirable and/or toxic effects. Overall, our results support that CNCM I-5321 strain is non-pathogenic and safe for potential use as an anti-cancer candidate in human and animal medicine.

Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines.

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.

Asymmetrically substituted ethylenediamine platinum(II) complexes as antitumor agents: synthesis and structure-activity relationships.

A series of platinum dichloroethylenediamine complexes [PtCl2(R-en)] bearing a side chain on one carbon atom of the ethylenediamine ligand, with or without a functional group on the side chain, have been prepared and investigated for antitumor activity against L1210 leukemia. They were tested both in vitro, with cisplatin-sensitive and resistant cell lines, and in vivo, with cisplatin-sensitive and resistant tumors grafted i.p. in B6D2F1 mice. The rationale for this study was to test how charge, polarity and shape of the R side chain influence antitumor activity. Complexes carrying one or more ammonium groups on the side chain were all inactive. Derivatives with a carbamate function attached by the nitrogen atom, via a methylene group, to the ethylenediamine moiety ('N-bound' carbamate) were highly active in vitro and in vivo. The best results were obtained with these carbamates bearing hydrophobic substituents of intermediate size. Replacement of N-bound by O-bound carbamate or by urea groups led to decreased in vivo activity. Sulfonamide derivatives were all inactive. Good to excellent activities were also recorded for complexes bearing bulky bicycloalkyl substituents, without any functional group, attached to one ethylenediamine carbon atom. Thus, it is the steric features of the side chain rather than its polarity that appear to favor the antitumor activity of the complex. Compared to cisplatin and oxaliplatin, the present complexes do not exhibit advantages in terms of experimental antitumor activities in solid tumor models.