Wenjin Su

Cytosporone B is an agonist for nuclear orphan receptor Nur77

Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.

A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro.

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.

Role of tumor metastasis suppressor gene KAI1 in digestive tract carcinomas and cancer cells

The KAI1 gene is identified as a tumor metastasis suppressor gene in many types of cancer. We examined KAI1 gene and its protein KAI1/CD82 expression by in situ hybridization and immunohistochemical analysis, and found that KAI1 mRNA and protein expression were inversely correlated with lymph node and distant metastasis in digestive tract carcinomas, but not with age and gender of the patient, or with tumor differentiation. Moreover, KAI1/CD82 protein expression positively reflected the survival outcome of patients. Western blot analysis showed that VP-16 increased KAI1/CD82 protein expression obviously in various cancer cell lines, especially in those that were highly metastatic. This increased KAI1/CD82 expression was associated with its translocation from the cytomembrane to the nucleus, in which it interacted with nuclear p53 protein, forming a strong complex, observed by confocal microscopy and co-immunoprecipitation, respectively. In nude mice, after feeding with VP-16, the number of tumors metastasized from spleen to liver was obviously reduced, and KAI1/CD82 protein expression became stronger in those metastatic tumors. Accordingly, this demonstrated that KAI1 might be used as an indicator for predicting the clinical outcome, and VP-16 may be clinically considered as a promising candidate for anti-metastasis with regard to its potential to upregulate KAI1 expression.

X-ray crystal structure of cytochalasin D produced by Tubercularia sp., a novel endophytic fungus of Taxus mairei

The crystal structure of cytochalasin D, which was isolated from Tubercularia sp., a novel endophytic fungus of Taxus mairei, and cocrystallized with dimethyl sulfoxide, is reported. The title compound crystallizes in the monoclinic space group P21, with a = 7.583(6) Å, b = 11.053(10) Å, c = 18.632(10) Å, β = 95.79(6)°, V = 1553.6(3) Å3, Z = 2. The structure was solved by direct methods and refined by least-squares methods to a final R factor of 0.103 for 2937 independent reflections.

1-(2,4-Di­hydroxy-3,5-di­methylphenyl)-ethano­ne (Clavatol)

To study the mechanism of formation and inhibition of Ce conversion films on Al 2024-T3 alloy, scanning microreference electrode technique (SMRE) is used to probe the potential map on Al 2024-T3 in CeCl3 solution, the localized corrosion of Al alloy decreases with immersion time and disappears finally, which results from the competition of Cl- aggression and Ce3+ inhibition on alloy surface. The results of X-ray photoelectron spectroscopy (XPS) indicate that the Ce conversion films consist of Al2O3, CeO2 and Ce2O3(Ce(OH)3), and CeO2/Ce2O3 ratio decreases with the immersion time. When a critical pH for Ce(OH)3 formation was reached, Ce(OH)3 will precipitate on the micro cathodic area on alloy surface. Consequently, H2O2, the product of the catholic reaction will oxidize a part of Ce(OH)3 to CeO2, which appears a better corrosion resistance for Al alloys.