No abstract

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.

Background and aims As drought threatens the yield and quality of maize (Zea mays L.), it is important to dissect the molecular basis of maize drought tolerance. Flavonoids, participate in the scavenging of oxygen free radicals and alleviate stress-induced oxidative damages. This study aims to dissect the function of flavonoids in the improvement of maize drought tolerance. Methods Using far-infrared imaging screening, we previously isolated a drought overly insensitivity (doi) mutant from an ethyl methanesulfonate (EMS)-mutagenized maize library and designated it as doi57. In this study, we performed a physiological characterization and transcriptome profiling of doi57 in comparison to corresponding wild-type B73 under drought stress. Results Under drought stress, doi57 seedlings displayed lower leaf-surface temperature (LST), faster water loss, and better performance in growth than B73. Transcriptome analysis reveals that key genes involved in flavonoid biosynthesis are enriched among differentially expressed genes in doi57. In line with these results, more flavonols and less hydrogen peroxide (H2O2) were accumulated in guard cells of doi57 than in those of B73 with the decrease of soil water content (SWC). Moreover, the capacity determined from doi57 seedling extracts to scavenge oxygen free radicals was more effective than that of B73 under the drought treatment. Additionally, doi57 seedlings had higher photosynthetic rates, stomatal conductance, transpiration rates, and water use efficiency than B73 exposed to drought stress, resulting in high biomass and greater root/shoot ratios in doi57 mutant plants. Conclusion Flavonoids may facilitate maize seedling drought tolerance by lowering drought-induced oxidative damage as well regulating stomatal movement.

Although the administration of progesterone has been shown to be neuroprotective in experimental models of traumatic brain injury (TBI), the mechanisms for this beneficial effect are still poorly understood. The present study examined the effects of progesterone on mRNA and protein levels of the Bcl-2 apoptosis regulatory genes, bax, bad, bcl-2, and bcl-x(L), in cerebral cortex after TBI. Male Sprague-Dawley rats were subjected to either sham surgery or lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm). Within 1 h post-surgery, progesterone (4 mg/kg) or vehicle (corn oil) administration was initiated for 1-7 days postoperatively. Our results indicate that bax and bad mRNA levels and Bax and Bad protein expression in the ipsilateral, injured cerebral cortex were significantly elevated post-TBI, while mRNA levels of bcl-2 and bcl-x(L) or Bcl-2 and Bcl-x(L) protein expression were not changed. Under the sham-treated condition, progesterone significantly increased mRNA levels of the anti-apoptotic gene, bcl-2, but down-regulated pro-apoptotic gene expression (bax and bad) in cerebral cortex. After TBI, progesterone treatment reduced bax and bad mRNA levels in the ipsilateral cerebral cortex of TBI rats, and decreased Bax and Bad protein levels. In addition, bcl-2 and bcl-x(L) mRNA levels, as well as Bcl-2 and Bcl-x(L) protein expression, were increased by progesterone in TBI injured cortex. These data indicate that one of the neuroprotective mechanisms of progesterone may be related to its differential regulation of apoptotic signals.