[Show abstract][Hide abstract] ABSTRACT: Mercury (Hg) is a widespread persistent pollutant in aquatic ecosystems. We investigated the protein profiles of medaka (Oryzias melastigma) liver chronically exposed to different mercuric chloride (HgCl(2)) concentrations (1 or 10μg/L) for 60 d using two-dimensional difference gel electrophoresis (2D-DIGE), as well as cell ultrastructure and Hg content analysis of the hepatic tissue. The results showed that Hg exposure significantly increased metal accumulation in the liver, and subsequently damaged liver ultrastructure. Comparison of the 2D-DIGE protein profiles of the exposed and control groups revealed that the abundance of 45 protein spots was remarkably altered in response to Hg treatment. The altered spots were subjected to matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry analysis, with the resultant identification of 33 spots. These proteins were mainly involved in cytoskeleton assembly, oxidative stress, and energy production. Among them, several proteins related to mitochondrial function (e.g. respiratory metabolism) were significantly altered in the treated hepatocytes, implying that this organelle might be the primary target for Hg attack in the cells. This study provided new insights into the molecular mechanisms and/or toxic pathways by which chronic Hg hepatotoxicity affects aquatic organisms, and also provided basic information for screening potential biomarkers for aquatic Hg monitoring.
[Show abstract][Hide abstract] ABSTRACT: Okadaic acid (OA) is a principal diarrhetic shellfish poisoning toxin produced by marine dinoflagellates. This study compared protein profiles of mice small intestines at four time points (0, 3, 6 and 24 h) after a single oral administration of 750 μg/kg OA, and identified the differentially expressed proteins using 2-D DIGE and MALDI-TOF-TOF mass spectrometry. The results showed that the toxin content of the intestines reached its peak 3h after oral administration and then decreased rapidly. OA remarkably inhibited the intestinal PP activity but it recovered to the normal levels within 6 to 24 h. Electron microscope revealed the collapse of the villous architecture and the intestinal microvilli fell off at 3 h, but were repaired within 24h. Notable damage to the intestinal ultrastructure was observed after oral administration. Comparison of the small intestine protein profiles at four time points revealed that 58 proteins were remarkably altered in abundance, and these proteins were involved in macromolecular metabolism, cytoskeleton reorganization, signal transduction, molecular chaperoning and oxidative stress, suggesting that OA toxicity in mouse intestines was complex and diverse, and that multiple proteins other than PP were involved in the diarrhetic process. Villin 1 and hnRNP F might be the key triggers inducing diarrhea in the mouse small intestines.
Journal of proteomics 01/2012; 75(7):2038-52. DOI:10.1016/j.jprot.2012.01.010 · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mercury is a widespread and persistent pollutant occurring in a variety of forms in freshwater and marine ecosystems. Using the proteomic approach, this study examined the protein profiles of the medaka (Oryzias melastigma) liver and brain exposed to an acute mercuric chloride (HgCl(2)) concentration (1000μg/L) for 8h. The results showed that acute exposure of medaka to inorganic mercury enhanced metal accumulation in both the liver and brain, and a higher content of mercury was detected in the latter. Comparison of the two-dimensional electrophoresis protein profiles of HgCl(2)-exposed and non-exposed group revealed that altered protein expression was quantitatively detected in 20 spots in the brain and 27 in the liver. The altered protein spots were subjected to matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry analysis, with the resultant identification of 46 proteins. The proteins identified were involved in oxidative stress, cytoskeletonal assembly, signal transduction, protein modification, metabolism and other related functions (e.g. immune response, ionoregulation and transporting), highlighting the fact that inorganic mercury toxicity in fish seems to be complex and diverse. This study provided basic information to aid our understanding of the possible molecular mechanisms of acute inorganic mercury toxicity in aquatic organisms, as well as potential protein biomarker candidates for aquatic environmental monitoring.
[Show abstract][Hide abstract] ABSTRACT: Nur77 is a steroid orphan receptor that plays a critical role in regulating proliferation, differentiation, and apoptosis, including acting as a switch for Bcl-2 function. We previously reported that the octaketide cytosporone B (Csn-B) is a natural agonist for Nur77. In this study, we synthesized a series of Csn-B analogues and performed a structure-activity analysis that suggested criteria for the development of a unique pharmacophore to activate Nur77. The components of the pharmacophore necessary for binding Nur77 included the benzene ring, the phenolic hydroxyl group, and the acyl chain of the Csn-B scaffold, whereas the key feature for activating the biological function of Nur77 was the ester group. Csn-B analogues that bound Nur77 tightly not only stimulated its transactivation activity but also initiated mitochondrial apoptosis by means of novel cross-talk between Nur77 and BRE, an antiapoptotic protein regulated at the transcriptional level. Notably, the derivative n-amyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate exhibited greater antitumor activity in vivo than its parent compounds, highlighting particular interest in this compound. Our findings describe a pathway for rational design of Csn-B-derived Nur77 agonists as a new class of potent and effective antitumor agents.
Cancer Research 04/2010; 70(9):3628-37. DOI:10.1158/0008-5472.CAN-09-3160 · 9.33 Impact Factor