Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer's-like clinical phenotype.

Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer's disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, "loss-of-function" profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte "loss-of-function" profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.

Functional Food from Endangered Ecosystems: Atriplex portulacoides as a Case Study.

Biodiversity is a reservoir of potential sources of novel food and feed ingredients with suitable compositions for the improvement of the diet and well-being of humans and farmed animals. The halophyte Atriplex portulacoides occurs in habitats that are exposed to seawater inundations, and shows biochemical adaptations to saline and oxidative stresses. Its composition includes long chain lipids, sterols, phenolic compounds, glutathione and carotenoids. These organic compounds and micronutrients, such as Fe, Zn, Co and Cu, make this plant suitable as an optimal functional food that is potentially able to reduce oxidative stress and inflammatory processes in humans and animals. Indeed, many of these compounds have a protective activity in humans against cardiovascular pathologies, cancer, and degenerative processes related to aging. The analysis of its history as food and forage, which dates back thousands of years, attests that it can be safely consumed. Here, the limits of its chemical and microbiological contamination are suggested in order to comply with the European regulations. The productivity of A. portulacoides in natural environments, and its adaptability to non-saline soils, make it a potential crop of high economic interest.

Taxonomic note on Abax contractus (Heer, 1841) and description of A. parallelepipedus ligurinus n. subsp. (Coleoptera, Carabidae, Pterostichini).

The syntype of Pterostichus contractus Heer, 1841 was examined and its taxonomical position was revised accordingly. The historical interpretation of this taxon as a subspecies of Abax parallelepipedus localized in the area between the Maritime-Ligurian Alps and the northern Apennines is rebutted. The taxon is raised to species level under the name Abax contractus (Heer, 1841), as a senior synonym of Abax continuus Ganglbauer, 1891 n. syn. and A. hypocrita Roubal, 1937 n. syn. The subspecies of Abax parallelepipedus previously reported as subsp. contractus Heer, 1841 is re-described under the name Abax parallelepipedus ligurinus n. subsp.

Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins.

The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) alkylation subunit and its isomer 6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one (iso-MeCTI) were found to be 5-6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potency of the corresponding DSA derivatives, consistent with projections made on the basis of the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent as or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC50 = 5 vs 8 pM), and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE2, IC50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents.