l-Arabinose Inhibits Colitis by Modulating Gut Microbiota in Mice.

l-Arabinose is a monosaccharide extracted from plants or fibers, which is known to have a variety of functional properties. In this study, we aim to investigate whether l-arabinose could inhibit colitis by modulating gut microbiota. l-Arabinose was administered in mice daily in a dextran sodium sulfate (DSS)-induced colitis model. The histological analysis, disease index, and the expression of inflammatory genes were measured. 16S-rRNA sequence analysis was performed to investigate gut microbiota. Intriguingly, we found that l-arabinose could repress DSS-induced colitis and inhibit p38-/p65-dependent inflammation activation. Besides that, our data revealed that l-arabinose-modulated DSS-induced gut microbiota were disturbed. Additionally, the perturbed gut microbiota was responsible for the suppressive effects of l-arabinose on DSS-induced colitis treated with antibiotics. Lastly, Caco-2 cells were used to confirm the protective effects of l-arabinose in colitis or inflammatory bowel disease. As expected, the protein expression levels in Caco-2 cells of pro-inflammatory genes, which were treated with l-arabinose and incubated with or without tumor necrosis factor alpha. Our work suggested that l-arabinose exerts anti-inflammation effects in DSS-induced colitis. These beneficial effects have correlations with the composition, diversity, and abundance of the gut microbiota regulated by l-arabinose. l-Arabinose could be a remarkable candidate as a functional food or novel therapeutic strategy for intestinal health.

Pentoses Used in Cultures of Synechococcus nidulans and Spirulina paracas: Evaluation of Effects in Growth and in Content of Proteins and Carbohydrates

Abstract The biological assimilation of the sugars present in lignocellulosic residues has gained prominence since these residues are the most abundant and economic residues in nature. Thus, the objective of this work was to determine whether the use of D-xylose and L-arabinose as sources of carbon in Synechococcus nidulans and Spirulina paracas cultures affects the growth and production of proteins and carbohydrates. Kinetic growth parameters, pentose consumption, protein content and carbohydrates were evaluated. Synechococcus nidulans and Spirulina paracas consumed all concentrations of pentose used. The highest cellular concentration (1.37 g.L-1) and the highest protein productivity (54 mg.L-1.d-1) were obtained for Spirulina paracas, which was submitted to the addition of 38.33 mg.L-1 D-xylose and 1.79 mg.L-1 L-arabinose. The use of pentose promoted the accumulation of proteins for the studied microalgae. This is one of the first works to report protein bioaccumulation as a result of pentose addition.

Drug-inducible remote control of gene expression by probiotic Escherichia coli Nissle 1917 in intestine, tumor and gall bladder of mice.

The probiotic bacterium Escherichia coli Nissle 1917 (EcN) constitutes a prospective vector for delivering heterologous therapeutic molecules to treat several human disorders. To add versatility to this carrier system, bacteria should be equipped with expression modules that can be regulated deliberately in a temporal and quantitative manner. This approach is called in vivo remote control (IVRC) of bacterial vectors. Here, we have evaluated promoters P(araBAD), P(rhaBAD) and P(tet), which can be induced with L-arabinose, L-rhamnose or anhydrotetracycline, respectively. EcN harboring promoter constructs with luciferase as reporter gene were administered either orally to healthy mice or intravenously to tumor bearing animals. Subsequent to bacterial colonization of tissues, inducer substances were administered via the oral or systemic route. By use of in vivo bioluminescence imaging, the time course of reporter gene expression was analyzed. Each promoter displayed a specific in vivo induction profile depending on the niche of bacterial residence and the route of inducer administration. Importantly, we also observed colonization of gall bladders of mice when EcN was administered systemically at high doses. Bacteria in this anatomical compartment remained accessible to remote control of bacterial gene expression.

Remote control of tumour-targeted Salmonella enterica serovar Typhimurium by the use of L-arabinose as inducer of bacterial gene expression in vivo.

We have used Salmonella enterica serovar Typhimurium (S. typhimurium) which are able to colonize tumours besides spleen and liver. Bacteria were equipped with constructs encoding green fluorescent protein or luciferase as reporters under control of the promoter PBAD that is inducible with L-arabinose. Reporter genes could be induced in culture but also when the bacteria resided within the mouse macrophages J774A.1. More important, strong expression of reporters by the bacteria could be detected in mice after administration of L-arabinose. This was especially pronounced in bacteria colonizing tumours. Histology demonstrated that the bacteria had accumulated in and close to necrotic areas of tumours. Bacterial gene induction was observed in both regions. PBAD is tightly controlled also in vivo because gene E of bacteriophage PhiX174 could be introduced as inducible suicide gene. The possibility to deliberately induce genes in bacterial carriers within the host should render them extremely powerful tools for tumour therapy.

Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications.

1. Osmotic opening of the blood-brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 A. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton. 2. The marked increase in apparent blood-brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min. 3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity.

Cerebral interferon entry in mice after osmotic alteration of blood-brain barrier.

Systemically administered interferon (IFN) is not readily detected in the central nervous system (CNS) due to the presence of the blood-brain barrier (BBB). A method of osmotic BBB alteration in a mouse model was established in this laboratory. IFN's entry into the normal and osmotically altered brain after its intracarotid injection was investigated. Significant IFN levels (100-1,000 units) in the brain can be achieved by this method. The highest IFN activity was found in the brain hemisphere ipsilateral to the injection site within 20 min to 1 h after injection. IFN activity in the brain was detectable up to 4 h. Animals injected in this manner with murine IFN-alpha/beta (MuIFN-alpha/beta) and observed for a 6-month time interval showed no signs of neurological dysfunctions and resumed their normal activities. The therapeutic value of this method will be tested in a murine model of malignant glioma.

Central nervous system involvement at presentation in acute granulocytic leukemia. A prospective cytocentrifuge study.

We have undertaken a perspective study of the prevelance of the central nervous disease in acute granulocytic leukemia (AGL). Thirty-nine newly diagnosed patients with AGL underwent cytocentrifuge examination of cerebral spinal fluid. Seven of the 39 patients had blast cells in their cerebral spinal fluid. All seven of these patients had acute myelomonocytic leukemia (AMML). No patients with other variants of AGL demonstrated blast cells in their cerebral spinal fluid. Other high risk factors associated with meningeal infiltration were elevated serum lysozyme levels, high peripheral white blood cell count, low age, splemomegaly and the presence of infiltration in other organs. The admission rates for patients with meningeal leukemia were lower and the survival time was shorter than in both the 32 noninvolved patients and the noninvolved patients with AMML. We believe that a lumbar puncture is indicated in all patients with newly diagnosed AMML.

Experiments to increase the selectivity of tumor chemotherapy by means of in vivo activation of transport forms of cancerostatics by exogenous enzymes.

A significant tumor damaging effect (growth inhibition) on transplanted syngeneic sarcoma in mouse was obtained by means of pH-dependent activation of a transport form of a cancerostatic drug by an enzyme foreign to the organism. This effect was achieved by combined administration of 8-0-(alpha-L-arabinofuranosyl)beta-peltatin-A as a transport form of beta-peltatin-A and the exogenous enzyme alpha-L-arabinofuranosidase from Aspergillus niger and additional increase of the acidity of the tumor by injection of glucose. The combined application of the transport form plus enzyme showed a more favorable effect on selectivity than free peltatin when a quantitative comparison was made between the tumor growth inhibition and the damage to the blood picture.