The low intestinal and hepatic toxicity of hydrolyzed fumonisin B1 correlates with its inability to alter the metabolism of sphingolipids

Fumonisins are mycotoxins frequently found as natural contaminants in maize, where they are produced by the plant pathogen Fusarium verticillioides. They are toxic to animals and exert their effects through mechanisms involving disruption of sphingolipid metabolism.Fumonisin B1 (FB1) is the predominant fumonisins in this family. FB1 is converted to its hydrolyzed analogs HFB1, by alkaline cooking (nixtamalization) or through enzymatic degradation. The toxicity of HFB1 is poorly documented especially at the intestinal level. The objectives of this study were to compare the toxicity of HFB1 and FB1 and to assess the ability of these toxins to disrupt sphingolipids biosynthesis. HFB1 was obtained by a deesterification of FB1, with a carboxylesterase. Piglets, animals highly sensitive to FB1, were exposed by gavage for 2 weeks to 2.8 µmol FB1 or HFB1/kg body weight/day. FB1 induced hepatotoxicity as indicated by the lesion score, the level of several biochemical analytes and the expression of inflammatory cytokines. Similarly, FB1 impaired the morphology of the different section of the small intestine, reduced villi height and modified intestinal cytokine expression. By contrast, HFB1 did not trigger hepatotoxicity, did not impair intestinal morphology and slightly modified the intestinal immune response. This low toxicity of HFB1 correlates with a weak alteration of the sphinganine/sphingosine ratio in the liver and in the plasma. Taken together, these data demonstrate that HFB1 does not cause intestinal or hepatic toxicity in the sensitive pig model, and slightly disrupts sphingolipids metabolism. This finding suggests that conversion to HFB1 could be a good strategy to reduce FB1 exposure

Macrophage metalloelastase (MMP-12) deficiency does not alter bleomycin-induced pulmonary fibrosis in mice

BACKGROUND: Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium resulting in respiratory failure. The role of remodeling mediators such as metalloproteinases (MMPs) and their inhibitors (TIMPs) in the fibrogenic process remains misunderstood. In particular, macrophage metalloelastase, also identified as MMP-12, is known to be involved in remodeling processes under pathological conditions. However, MMP-12 involvement in pulmonary fibrosis is unknown. Here we investigated fibrotic response to bleomycin in MMP-12 deficient mice. MATERIALS AND METHODS: C57BL/6 mice, Balb/c mice and MMP-12 -/- mice with a C57BL/6 background received 0.3 mg bleomycin by intranasal administration. 14 days after, mice were anesthetized and underwent either bronchoalveolear lavage (BAL) or lung removal. Collagen deposition in lung tissue was determined by Sircol™ collagen assay, MMP activity in BAL fluid was analyzed by zymography, and other mediators were quantified in BAL fluid by ELISA. Real time PCR was performed to assess gene expression in lung removed one or 14 days after bleomycin administration. Student t test or Mann & Whitney tests were used when appropriate for statistical analysis. RESULTS: The development of pulmonary fibrosis in "fibrosis prone" (C57BL/6) mice was associated with prominent MMP-12 expression in lung, whereas MMP-12 expression was weak in lung tissue of "fibrosis resistant" (Balb/c) mice. MMP-12 mRNA was not detected in MMP-12 -/- mice, in conformity with their genotype. Bleomycin elicited macrophage accumulation in BAL of MMP-12 -/- and wild type (WT) mice, and MMP-12 deficiency had no significant effect on BAL cells composition. Collagen content of lung was increased similarly in MMP-12 -/- and WT mice 14 days after bleomycin administration. Bleomycin elicit a raise of TGF-β protein, MMP-2 and TIMP-1 protein and mRNA in BAL fluids and lung respectively, and no significant difference was observed between MMP-12 -/- and WT mice considering those parameters. CONCLUSION: The present study shows that MMP-12 deficiency has no significant effect on bleomycin-induced fibrosis

Distribution of miliacin (olean-18-en-3β-ol methyl ether) and related compounds in broomcorn millet (Panicum miliaceum) and other reputed sources: Implications for the use of sedimentary miliacin as a tracer of millet

International audienceUsing sedimentary miliacin (olean-18-en-3β-ol methyl ether) as a molecular tracer of the history of Panicum miliaceum (broomcorn millet) cultivation depends upon broomcorn millet being sedimentary miliacin's dominant source. It also requires knowledge of the variability in miliacin concentration in broomcorn millet. Finally, it is affected by the presence of other pentacyclic triterpene methyl ethers (PTMEs) that may exist in conjunction with miliacin in other sources but not in broomcorn millet. Miliacin biosynthesis has been proposed for other Panicum species, Setaria italica (Italian or foxtail millet), Pennisetum sp., and Chaetomium olivaceum (an olive green mold). We found miliacin concentration in seeds of different varieties of P. miliaceum to be similarly high (with trace amounts of β- and α-amyrin methyl ethers). It was absent from hulls and roots, and nominally present in leaves and stems. The transfer of miliacin from plant to sediments is therefore mostly from seeds. it was abundant (often with larger amounts of β- and α-amyrin methyl ethers) in all other Panicum species studied, but only in some species of the genus Pennisetum and was absent from Setaria italica. Neither C. olivaceum nor its growth medium (rice) showed any trace of miliacin. Our results, with miliacin absent from S. italica and C. olivaceum, its high miliacin in seed of P. miliaceum relative to other PTMEs and to other grasses and, considering the high biomass that cultivated broomcorn millet has relative to other potential plant sources, support the use of sedimentary records of miliacin in some contexts to track past millet agricultural dynamics

Semiabelian varieties over separably closed fields, maximal divisible subgroups, and exact sequences

Given a separably closed field K of positive characteristic and finite degree of imperfection we study the # functor which takes a semiabelian variety G over K to the maximal divisible subgroup #G of G(K). We show that the # functor need not preserve exact sequences. The main result is an example where #G does not have "relative Morley rank", yielding a counterexample to a claim of Hrushovski. The methods involve studying preservation of exact sequences by the # functor as well as issues of descent. We also develop the notion of an iterative D-structure on a group scheme over an iterative Hasse field, as well as giving characteristic 0 versions of our results.Comment: 55 pages In this version 3, some corrections and clarifications are made: in section 2.3 on relative Morley rank. Also in section 5.2 where more explanation is given of D-structures in positive characteristic. In an appendix we give a proof of the exactness of the functor taking a semiabelian variety to its universal vectorial extensio

Inducible chromatin priming is associated with the establishment of immunological memory in T cells

Immunological memory is a defining feature of vertebrate physiology, allowing rapid responses to repeat infections. However, the molecular mechanisms required for its establishment and maintenance remain poorly understood. Here, we demonstrated that the first steps in the acquisition of T-cell memory occurred during the initial activation phase of naïve T cells by an antigenic stimulus. This event initiated extensive chromatin remodeling that reprogrammed immune response genes toward a stably maintained primed state, prior to terminal differentiation. Activation induced the transcription factors NFAT and AP-1 which created thousands of new DNase I-hypersensitive sites (DHSs), enabling ETS-1 and RUNX1 recruitment to previously inaccessible sites. Significantly, these DHSs remained stable long after activation ceased, were preserved following replication, and were maintained in memory-phenotype cells. We show that primed DHSs maintain regions of active chromatin in the vicinity of inducible genes and enhancers that regulate immune responses. We suggest that this priming mechanism may contribute to immunological memory in T cells by facilitating the induction of nearby inducible regulatory elements in previously activated T cells