Curcumin-Based β-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer

The influence of physical activity performed at 20-40 years of age on cardiovascular outcomes in medical patients aged 65-75

Summary Introduction Several studies show that physical activity can reduce the risk of cardiovascular disease, but the vast majority of these focus on the short- to intermediate-term benefits or refer to very specific populations. This observational study was conducted to determine whether physical activity performed during the third or fourth decade of life influences the occurrence of cardiovascular events in patients aged 65-75 years. Materials and methods We studied a cohort of 2191 unselected patients admitted to Internal Medicine Departments. Data were collected on the patients' medical history and their physical activity level when they were 20 to 40 years old. For the latter purpose, we used a specific questionnaire to assess the levels of physical activity related to the patients' job, daily life, leisure time, and sports. Results Almost half (44.2%) of the patients we evaluated reported moderate-intense physical activity when they were 20-40 years old. Around one third (35.8%) of the patients had experienced at least one major cardiovascular event, and there was a slight trend towards fewer cardiovascular events in patients with histories of physical activity (mean risk reduction: 4%, multivariate analysis). More evident benefits were observed in the subgroup of patients with diabetes, where cardiovascular outcomes were much better in patients who had been physically active than in those with sedentary life-styles (mean risk reduction: 24%). Conclusions Given its design, our study may have underestimated the cardiovascular benefits of physical activity. Nonetheless, our results suggest that moderate-intense exercise during young adulthood may have limited beneficial effects on cardiovascular disease in old age, except in specific high-risk populations (diabetic patients). More evident benefits are probably associated with regular physical activity throughout life

Contaminants from dredged sediments alter the transcriptome of Manila clam and induce shifts in microbiota composition

Background The reuse of dredged sediments in ports and lagoons is a big issue as it should not affect the quality and the equilibrium of ecosystems. In the lagoon of Venice, sediment management is of crucial importance as sediments are often utilized to built-up structures necessary to limit erosion. However, the impact of sediment reuse on organisms inhabiting this delicate area is poorly known. The Manila clam is a filter-feeding species of high economic and ecological value for the Venice lagoon experiencing a drastic decline in the last decades. In order to define the molecular mechanisms behind sediment toxicity, we exposed clams to sediments sampled from different sites within one of the Venice lagoon navigable canals close to the industrial area. Moreover, we investigated the impacts of dredged sediments on clam’s microbial communities. Results Concentrations of the trace elements and organic chemicals showed increasing concentrations from the city of Venice to sites close to the industrial area of Porto Marghera, where PCDD/Fs and PCBs concentrations were up to 120 times higher than the southern lagoon. While bioaccumulation of organic contaminants of industrial origin reflected sediments’ chemical concentrations, metal bioaccumulation was not consistent with metal concentrations measured in sediments probably due to the activation of ABC transporters. At the transcriptional level, we found a persistent activation of the mTORC1 signalling pathway, which is central in the coordination of cellular responses to chemical stress. Microbiota characterization showed the over-representation of potential opportunistic pathogens following exposure to the most contaminated sediments, leading to host immune response activation. Despite the limited acquisition of new microbial species from sediments, the latter play an important role in shaping Manila clam microbial communities. Conclusions Sediment management in the Venice lagoon will increase in the next years to maintain and create new canals as well as to allow the operation of the new mobile gates at the three Venice lagoon inlets. Our data reveal important transcriptional and microbial changes of Manila clams after exposure to sediments, therefore reuse of dredged sediments represents a potential risk for the conservation of this species and possibly for other organisms inhabiting the Venice lagoon

Molecular regulation of nitrate and ammonium response in maize roots

Nitrogen (N) is fundamental for plant growth and development, since it represents an essential component of DNA, RNA, proteins and other metabolic components. Thus, nitrogen can be considered the most requested mineral nutrient in plants. Soil does not have sufficient N in available forms to support production levels, for this reason the application of nitrogen fertilization plays a key role in crop productivity. Only about 50% of the total N is harvested in the grain, and the remainder is lost from the plant-soil system, causing adverse impacts on environment and human health. Therefore, in order to increase the sustainability of agriculture and to reduce the environmental damage, improving nitrogen use efficiency (NUE) of crops represents a crucial point for reducing the N fertilizer application by ensuring high yields. However, the NUE molecular pathway components that act in plant response to nitrogen availability are still only partially characterized. The nitrogen uptake and assimilation by plants can essentially occur in two forms: nitrate (NO3-) and ammonium (NH4+). Concerning nitrate, besides its role as a nutrient, it acts also as a signalling molecule since it is involved in the modulation of expression of several genes linked to plant development. The understanding of the molecular mechanisms at the base of root architecture adjustment in response to N fluctuations in soil seems to be necessary to enhance the ability of plants to capture the applied N fertilizer. In the present study, in order to discriminate between the specific effects of nitrate from those more generally attributed to nitrogen, root morphology and gene expression analyses 6 were conducted, particularly on 2 days-old maize seedlings growth for 24 hours in a N deprived solution and then transferred for additional 24 hours to nitrate or ammonium supplied medium

Deepening the Whole Transcriptomics of Bovine Liver Cells Exposed to AFB1: A Spotlight on Toll-like Receptor 2

Aflatoxin B1 (AFB1) is a food contaminant metabolized mostly in the liver and leading to hepatic damage. Livestock species are differently susceptible to AFB1, but the underlying mechanisms of toxicity have not yet been fully investigated, especially in ruminants. Thus, the aim of the present study was to better characterize the molecular mechanism by which AFB1 exerts hepatotoxicity in cattle. The bovine fetal hepatocyte cell line (BFH12) was exposed for 48 h to three different AFB1 concentrations (0.9 µM, 1.8 µM and 3.6 µM). Whole-transcriptomic changes were measured by RNA-seq analysis, showing significant differences in the expression of genes mainly involved in inflammatory response, oxidative stress, drug metabolism, apoptosis and cancer. As a confirmatory step, post-translational investigations on genes of interest were implemented. Cell death associated with necrosis rather than apoptosis events was noted. As far as the toxicity mechanism is concerned, a molecular pathway linking inflammatory response and oxidative stress was postulated. Toll-Like Receptor 2 (TLR2) activation, consequent to AFB1 exposure, triggers an intracellular signaling cascade involving a kinase (p38β MAPK), which in turn allows the nuclear translocation of the activator protein-1 (AP-1) and NF-κB, finally leading to the release of pro-inflammatory cytokines. Furthermore, a p38β MAPK negative role in cytoprotective genes regulation was postulated. Overall, our investigations improved the actual knowledge on the molecular effects of this worldwide relevant natural toxin in cattle