Ecophysiological responses of fishes to increasing ocean acidification and warming

A major goal in conservation biology is to understand the effects of short and long term environmental change on organisms. Fishes are the most valuable marine resource, however very little is known about the synergistic effect of current ocean warming and acidification, and the role of body size and local adaptation on their resilience. There is growing evidence that increased environmental temperature correlates with a reduction in ectotherm body size, suggesting a universal response to warming. To investigate the potential advantage of small body size in fish resilience, I made intra- and inter-specific comparisons of dwarf- and normal-size cleaner gobies of the genus Elacatinus. I first tested the hypothesis that smaller body size would correlate with a wider thermal tolerance by using same-age but different-size gobies reared at 'common garden' conditions. By employing critical thermal methodology, I provided empirical evidence supporting thermal biology theories that predict wider thermal tolerance windows as body size shrinks. These results provided the motivation to examine the effect of body mass on digestive performance, an indicator of fitness. Only smaller fish increased digestive metabolic scope at higher temperatures, thus suggesting that temperature increase caused by global warming will favor smaller individuals. To investigate the role of local adaptation on resilience in climate change, I compared the responses to warming and acidification between latitudinally- and morphologically-distinct populations of the little skate Leucoraja erinacea, by focusing on the most vulnerable life stages, embryos and juveniles. Embryos maintained at common garden conditions showed countergradient variation in performance curves. In juvenile skates, post-exercise metabolic curves shifted performance optima, exhibiting thermal adaptation in the two populations examined. This suggests that as skates hatch and are able to thermoregulate, they can change their temperature optima to exploit local thermal environments. Lastly, temperature and acidification levels predicted by the end of the century may reduce fitness of the northern population of skates, thus increasing vulnerability to local extinction

INSIDIA:a FIJI macro delivering high-throughput and high-content spheroid invasion analysis

Time-series image capture of in vitro 3D spheroidal cancer models embedded within an extracellular matrix affords examination of spheroid growth and cancer cell invasion. However, a customizable, comprehensive and open source solution for the quantitative analysis of such spheroid images is lacking. Here, the authors describe INSIDIA (INvasion SpheroID ImageJ Analysis), an open-source macro implemented as a customizable software algorithm running on the FIJI platform, that enables high-throughput high-content quantitative analysis of spheroid images (both bright-field gray and fluorescent images) with the output of a range of parameters defining the spheroid “tumor” core and its invasive characteristics

Inhibition of Polycomb Repressive Complex2 activity reduces trimethylation of H3K27 and affects development in Arabidopsis seedlings

Background: Polycomb repressive complex 2 (PRC2) is an epigenetic transcriptional repression system, whose catalytic subunit (ENHANCER OF ZESTE HOMOLOG 2, EZH2 in animals) is responsible for trimethylating histone H3 at lysine 27 (H3K27me3). In mammals, gain-of-function mutations as well as overexpression of EZH2 have been associated with several tumors, therefore making this subunit a suitable target for the development of selective inhibitors. Indeed, highly specific small-molecule inhibitors of EZH2 have been reported. In plants, mutations in some PRC2 components lead to embryonic lethality, but no trial with any inhibitor has ever been reported. Results: We show here that the 1,5-bis (3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one compound (RDS 3434), previously reported as an EZH2 inhibitor in human leukemia cells, is active on the Arabidopsis catalytic subunit of PRC2, since treatment with the drug reduces the total amount of H3K27me3 in a dose-dependent fashion. Consistently, we show that the expression level of two PRC2 targets is significantly increased following treatment with the RDS 3434 compound. Finally, we show that impairment of H3K27 trimethylation in Arabidopsis seeds and seedlings affects both seed germination and root growth. Conclusions: Our results provide a useful tool for the plant community in investigating how PRC2 affects transcriptional control in plant development

Design, synthesis and biological evaluation of new pyrimidine derivatives as anticancer agents

BACKGROUND: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent.METHODS: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells.RESULTS: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 muM, 4-13 times more active of hit.CONCLUSIONS: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype

Analytical characterization of an inulin-type fructooligosaccharide from root-tubers of Asphodelus ramosus L

Plant-based systems continue to play a pivotal role in healthcare, and their use has been extensively documented. Asphodelus L. is a genus comprising various herbaceous species, known by the trivial name Asphodelus. These plants have been known since antiquity for both food and therapeutic uses, especially for treating several diseases associated with inflammatory and infectious skin disorders. Phytochemical studies revealed the presence of different constituents, mainly anthraquinones, triterpenoids, phenolic acids, and flavonoids. Although extensive literature has been published on these constituents, a paucity of information has been reported regarding the carbohydrate composition, such as fructans and fructan-like derivatives. The extraction of watersoluble neutral polysaccharides is commonly performed using water extraction, at times assisted by microwaves and ultrasounds. Herein, we reported the investigation of the alkaline extraction of roottubers of Asphodelus ramosus L., analyzing the water-soluble polysaccharides obtained by precipitation from the alkaline extract and its subsequent purification by chromatography. A polysaccharide was isolated by alkaline extraction; the HPTLC study to determine its composition showed fructose as the main monosaccharide. FT-IR analysis showed the presence of an inulin-type structure, and NMR analyses allowed us to conclude that A. ramosus roots contain polysaccharide with an inulin-type fructooligosaccharide with a degree of polymerization of 7-8

Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line

Investigation of Commiphora myrrha (Nees) Engl. oil and its main components for antiviral activity

The resinous exudate produced by Commiphora myrrha (Nees) Engl. is commonly known as true myrrh and has been used since antiquity for several medicinal applications. Hundreds of metabolites have been identified in the volatile component of myrrh so far, mainly sesquiterpenes. Although several efforts have been devoted to identifying these sesquiterpenes, the phytochemical analyses have been performed by gas-chromatography/mass spectrometry (GC–MS) where the high temperature employed can promote degradation of the components. In this work, we report the extraction of C. myrrha by supercritical CO2, an extraction method known for the mild extraction conditions that allow avoiding undesired chemical reactions during the process. In addition, the analyses of myrrh oil and of its metabolites were performed by HPLC and GC–MS. Moreover, we evaluated the antiviral activity against influenza A virus of the myrrh extracts, that was possible to appreciate after the addition of vitamin E acetate (α-tocopheryl acetate) to the extract. Further, the single main bioactive components of the oil of C. myrrha commercially available were tested. Interestingly, we found that both furanodienone and curzerene affect viral replication by acting on different steps of the virus life cycle

Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication

For RNA viruses, RNA helicases have long been recognized to play critical roles during virus replication cycles, facilitating proper folding and replication of viral RNAs, therefore representing an ideal target for drug discovery. SARS-CoV-2 helicase, the non-structural protein 13 (nsp13) is a highly conserved protein among all known coronaviruses, and, at the moment, is one of the most explored viral targets to identify new possible antiviral agents. In the present study, we present six diketo acids (DKAs) as nsp13 inhibitors able to block both SARS-CoV-2 nsp13 enzymatic functions. Among them four compounds were able to inhibit viral replication in the low micromolar range, being active also on other human coronaviruses such as HCoV229E and MERS CoV. The experimental investigation of the binding mode revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding mode that was further supported by molecular modelling calculations predicting the binding into an allosteric conserved site located in the RecA2 domain