P-glycoprotein (P-gp) is a membrane protein associated with multidrug resistance (MDR) due to its key role in mediating the traffic of chemotherapeutic drugs outside cancer cells, leading to a cellular response that hinders efforts toward successful therapy. With the aim of finding agents that circumvent the MDR phenotype mediated by P-gp, 15 compounds isolated from native and naturalized plants of Argentina were screened. Among these, the non-cytotoxic lignan (±) pinoresinol successfully restored sensitivity to doxorubicin from 7 μM in the P-gp overexpressed human myelogenous leukemia cells, Lucena 1. This resistance-reversing effect was confirmed by competitively increasing the intracellular doxorubicin accumulation and by significantly inhibiting the efflux of doxorubicin and, to a lesser extent, that of rhodamine 123. The activity obtained was similar to that observed with verapamil. No such results were observed in the sensitive parental K562 cell line. To gain deeper insight into the mode of action of pinoresinol, its effect on P-gp function and expression was examined. The lignan bound to P-gp at the apex of the V-shaped transmembrane cavity, involving transmembrane helices 4, 5 and 6, and partially overlapped the binding region of tariquidar, which was used as a positive control. These results would shed some light on the nature of its interaction with P-gp at molecular level and merit further mechanistic and kinetic studies. In addition, it showed a maximum 29% activation of ATP hydrolysis and antagonized verapamil-stimulated ATPase activity with an IC50 of 20.9 μM. On the other hand, pinoresinol decreased the presence of P-gp in the cell surface. Derivatives of pinoresinol with improved activity were identified by docking studies. The most promising one, the non-cytotoxic 1-acetoxypinoresinol, caused a reversion of doxorubicin resistance from 0.11 μM and thus higher activity than the lead compound. It also caused a significant increase in doxorubicin accumulation. Results were similar to those observed with verapamil. The results obtained positioned these compounds as potential candidates for effective agents to overcome P-gp-mediated MDR, leading to better outcomes for leukemia chemotherapy.

To ensure soil quality and soil health, it is necessary to improve fertilization practices while minimizing environmental impacts. The aim of this study was to record the state of the art on soil fertility related to fertilization management (organic and/or mineral) and to detect environmental challenges in highly productive fields. A soil survey was set up in a new irrigated area (c. 20 years old), in the north-eastern part of Spain, which is mainly devoted to double annual crop rotations of cereals and maize. The area also supports an important animal rearing activity. The survey covered 733 ha of calcareous soils, owned by 35 farmers. At each farm, fertilization management was recorded, and soil was analyzed for nutrients and heavy metals. Multivariate analyses were performed. Total N, P, Cu and Zn, and available P, Cu, Zn and Mn soil concentrations were associated to the use of organic amendments. Heavy metals concentrations were below established thresholds. Available P (Olsen-P) was identified as an indicator of the previously adopted fertilization management and of the potential of P leaching towards deeper soil layers. Regression analyses were performed. A displacement of available P from the uppermost layer (0–0.3 m) occurs in the breakpoint of 86 mg P kg⁻¹ soil. Preventative actions might be established from 53 mg P kg⁻¹ soil due to the slowdown in P immobilization. Our results reinforce the importance of setting up P threshold soil levels for best practices of fertilization, as a basis for sustainable agriculture intensification.

Organic fertilization is a key issue in European Union (EU) regulations, particularly in the context of promoting a circular nutrient economy, maintaining soil quality, and sequestering carbon to face climate change. In a rainfed system in Northeastern Spain, an experiment was set up (split-plot design). It included five pre-sowing N fertilization treatments: control, mineral, pig slurry, and composted sewage sludge (two rates). The average N rates were 0, 30, 141, 176, and 351 kg N ha⁻¹, respectively. They were combined with mineral N topdressings (0, 50, and 100 kg N ha⁻¹). Three crops were grown: barley (nine years), wheat (three years), and rapeseed (one year). In the driest years (c. 350 mm rainfall), the yields averaged 2.5, 2.0, and 1.9 Mg ha⁻¹, respectively. The maximum yields were for barley (6.5 Mg ha⁻¹) and wheat (5.5 Mg ha⁻¹). The avoidance of a significant increase in soil residual NO₃⁻-N, plus the control of soil build up of available P, micronutrients, and Cd, defines the fertilization strategies. (i) With a previous spring drought season, no fertilization is needed in the following year, if devoted to winter cereals. (ii) In rainier seasons, pig slurry or composted sewage sludge (lowest rate) applied at sowing is sufficient; however, 50 kg of mineral-N ha⁻¹ at the topdressing can be applied. The study found that pig slurry favors K, Mg, Cu, and Zn availability, while composted sewage sludge enhances Fe availability. Although it is possible to reduce N inputs from organic fertilizers, organic C build-up will be constrained.