Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters.

Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodiumfalciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance

Critical Zone Services: Expanding Context, Constraints, and Currency beyond Ecosystem Services

Processes within the critical zone—spanning groundwater to the top of the vegetation canopy—have important societal relevance and operate over broad spatial and temporal scales that often are not included in existing frameworks for ecosystem services evaluation. Here we expand the scope of ecosystem services by specifying how critical zone processes extend context both spatially and temporally, determine constraints that limit provision of services, and offer a potentially powerful currency for evaluation. Context: A critical zone perspective extends the context of ecosystem services by expressly addressing how the physical structure of the terrestrial Earth surface (e.g., parent material, topography, and orography) provides a broader spatial and temporal template determining the coevolution of physical and biological systems that result in societal beneits. Constraints: The rates at which many ecosystem services are provided are fundamentally constrained by rate-limited critical zone processes, a phenomenon that we describe as a conceptual “supply chain” that accounts for rate-limiting soil formation, hydrologic partitioning, and streamlow generation. Currency: One of the major challenges in assessing ecosystem services is the evaluation of their importance by linking ecological processes to societal beneits through market and nonmarket valuation. We propose that critical zone processes be integrated into an evaluation currency, useful for valuation, by quantifying the energy lux available to do thermodynamic work on the critical zone. In short, characterization of critical zone processes expands the scope of ecosystem services by providing context, constraints, and currency that enable more effective management needed to respond to impacts of changing climate and disturbances

Coevolution of Nonlinear trends in Vegetation, Soils, and Topography with Elevation and Slope Aspect: A Case Study in the Sky Islands of Southern Arizona

Feedbacks among vegetation dynamics, pedogenesis, and topographic development affect the “critical zone”—the living filter for Earth’s hydrologic, biogeochemical, and rock/sediment cycles. Assessing the importance of such feedbacks, which may be particularly pronounced in water-limited systems, remains a fundamental interdisciplinary challenge. The sky islands of southern Arizona offer an unusually well-defined natural experiment involving such feedbacks because mean annual precipitation varies by a factor of five over distances of approximately 10 km in areas of similar rock type (granite) and tectonic history. Here we compile high-resolution, spatially distributed data for Effective Energy and Mass Transfer (EEMT: the energy available to drive bedrock weathering), above-ground biomass, soil thickness, hillslope-scale topographic relief, and drainage density in two such mountain ranges (Santa Catalina: SCM; Pinaleño: PM). Strong correlations exist among vegetation-soil-topography variables, which vary nonlinearly with elevation, such that warm, dry, low-elevation portions of these ranges are characterized by relatively low above-ground biomass, thin soils, minimal soil organic matter, steep slopes, and high drainage densities; conversely, cooler, wetter, higher elevations have systematically higher biomass, thicker organic-rich soils, gentler slopes, and lower drainage densities. To test if eco-pedo-geomorphic feedbacks drive this pattern, we developed a landscape evolution model that couples pedogenesis and topographic development over geologic time scales, with rates explicitly dependent on vegetation density. The model self-organizes into states similar to those observed in SCM and PM. Our results highlight the potential importance of eco-pedo-geomorphic feedbacks, mediated by soil thickness, in water-limited systems