Extracellular calmodulin (ExtCaM) regulates stomatal movement by eliciting a cascade of intracellular signaling events including heterotrimeric G protein, hydrogen peroxide (H 2 O 2 ), and Ca 2+ . However, the ExtCaM-mediated guard cell signaling pathway remains poorly understood. In this report, we show that Arabidopsis (Arabidopsis thaliana) NITRIC OXIDE ASSOCIATED1 (AtNOA1)-dependent nitric oxide (NO) accumulation plays a crucial role in ExtCaM-induced stomatal closure. ExtCaM triggered a significant increase in NO levels associated with stomatal closure in the wild type, but both effects were abolished in the Atnoa1 mutant. Furthermore, we found that ExtCaM-mediated NO generation is regulated by GPA1, the Ga-subunit of heterotrimeric G protein. The ExtCaM-dependent NO accumulation was nullified in gpa1 knockout mutants but enhanced by overexpression of a constitutively active form of GPA1 (cGa). In addition, cGa Atnoa1 and gpa1-2 Atnoa1 double mutants exhibited a similar response as did Atnoa1. The defect in gpa1 was rescued by overexpression of AtNOA1. Finally, we demonstrated that G protein activation of NO production depends on H 2 O 2 . Reduced H 2 O 2 levels in guard cells blocked the stomatal response of cGa lines, whereas exogenously applied H 2 O 2 rescued the defect in ExtCaM-mediated stomatal closure in gpa1 mutants. Moreover, the atrbohD/F mutant, which lacks the NADPH oxidase activity in guard cells, had impaired NO generation in response to ExtCaM, and H 2 O 2 -induced stomatal closure and NO accumulation were greatly impaired in Atnoa1. These findings have established a signaling pathway leading to ExtCaM-induced stomatal closure, which involves GPA1-dependent activation of H 2 O 2 production and subsequent AtNOA1-dependent NO accumulation.Plant guard cells control opening and closure of the stomata in response to phytohormones (e.g. abscisic acid [ABA]) and various environmental signals such as light and temperature, thereby regulating gas exchange for photosynthesis and water status via transpiration . Cytosolic calcium ([Ca 2+ ] i ) has been shown to be a key second messenger that changes in response to multiple stimuli in guard cells (McAinsh et al., 1995;Grabov and Blatt, 1998;Wood et al., 2000). A large proportion of Ca 2+ is localized in extracellular space. It has been shown that external Ca 2+ concentration ([Ca 2+ ] o ) promotes stomatal closure and induces oscillation in [Ca 2+ ] i in guard cells (MacRobbie, 1992;McAinsh et al., 1995;Allen et al., 2001 Calmodulin is a well-known Ca 2+ sensor that is activated upon binding of Ca 2+ . It has been shown that calmodulin exists not only intracellularly but also extracellularly in many plant species
The aim of this paper was to build hybrid QSAR models for predicting multiple drug resistance (MDR) modulators modulating activity of 70 compounds based on single multiple linear regression (MLR) models and support vector machine (SVM) models. All models were validated using more strict criteria to make sure that the results are reliable and robust. For the best hybrid model, it gave the best performance, with corresponding correlation coefficients R 2 of 0.85, 0.81, and 0.84 for training, test, and whole data set, respectively. The hybrid method was proved to be a very promising tool in the prediction of MDR-modulating activity. Additionally, the application of strict validation criteria permits the high quality of the hybrid model. Thus, these in silico methods can be applied to predict this property in the early stage of drug development and some of them will be important tools to select new drug candidates.
To obtain more accessible oxidative stress inhibitors, a series of novel spin-labelled derivatives of 3-hydroxybutanolide (2a-d, 3a-d) with the natural active compound (kinsenoside) as the lead compound were designed, synthesised from the nitroxide free radical piperidine (pyrroline) and the main structural unit of kinsenoside: 3-hydroxybutanolide. Antioxidant activity screening of these derivatives was performed using MTT method on rat pheochromocytoma PC12 cells. The antioxidative stress effect was further investigated on the changes of the important antioxidant enzyme activities and intracellular reactive oxygen species production. Among the derivatives, 2b-d, 3a and 3c showed comparable or superior antioxidative stress activity to kinsenoside. Also, most of the tested derivatives displayed obvious antioxidative ability in concentrations. Cytotoxic assay simultaneously indicated that all compounds had very low toxicity to normal cells. Based on the observed results, the structure-activity relationship of these derivatives was discussed.
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