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.
Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.
Developing superior deep-ultraviolet (deep-UV) nonlinear optical (NLO) materials is a great challenge because of the contradiction between deep-UV transparency and enhanced second harmonic generation (SHG), especially for deep-UV NLO phosphates in which the constituent P−O groups have relatively small microscopic SHG coefficients. Here we report a new noncentrosymmetric phosphate Cs 2 LiPO 4 (I), whose crystal structure consists of [LiPO 4 ] ∞ layered structural units with a novel honeycomb-like topology. As compared with the benchmark deep-UV NLO material KBe 2 BO 3 F 2 , I is beryllium-free, and it is relatively easy to grow its large single crystals because of its congruent melting. Furthermore, it not only is deep-UV transparent but also exhibits an unexpectedly enhanced SHG response of 1.8 × KH 2 PO 4 that hits a new high in deep-UV NLO phosphates. These results demonstrate that I satisfies the key requirements of being a promising deep-UV NLO candidate. Theory calculations and structural analysis reveal that the enhanced SHG response can be attributed to the honeycomb-like topological structure, which endows the constituent [PO 4 ] 3− monomers of I with an aligned arrangement and as a result a favorable superposition of their microscopic SHG coefficients. These findings may provide useful insights into the development of both deep-UV NLO materials and honeycomb-like topological structures.
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