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.

a b s t r a c tA series of layered double hydroxides (LDHs) with different metal cations were synthesized to remove phosphate in waste sludge filtrate from a municipal wastewater treatment plant for phosphorus recovery and to help control eutrophication. The highest phosphate adsorption capacity was obtained by using Zn-Al-2-300, that is LDHs with Zn/Al molar ratio of 2 and calcined at 300 • C for 4 h. Circumneutral and mildly alkaline waters appeared suitable for the possible application of Zn-Al LDHs due to the amphoteric nature of aluminum hydroxide. Phosphate adsorption from the sludge filtrate by the LDHs followed pseudo-second-order kinetics, and the adsorption capacity at equilibrium was determined to be ∼50 mg P/g. Adsorption isotherms showed that phosphate uptake in this study was an endothermic process and had a good fit with a Langmuir-type model. The absorbed phosphate can be effectively desorbed (more than 80%) from LDHs particles by a 5 wt% NaOH solution. The regeneration rate of used LDHs was ∼60% after six cycles of adsorption-desorption-regeneration.

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MDM2 is an oncoprotein whose transforming potential is activated by overexpression. The expression level of MDM2 is negatively regulated by orphan receptor TR3 that mainly acts as a transcriptional factor to regulate gene expression. However, the underlying mechanism is largely unclear. Here, we present the first evidence that inhibition of TR3 on MDM2 is mediated by p53. We found that TR3 directly interacts with p53 but not MDM2, and such interaction is critical for TR3 to inhibit MDM2 expression. TR3 downregulates p53 transcriptional activity by blocking its acetylation, leading to a decrease on the transcription level of MDM2. Furthermore, TR3 binding to p53 obstructs its ubiquitination and degradation induced by MDM2, resulting in the MDM2 ubiquitination and degradation. In addition, TR3 could enhance p53-mediated apoptosis induced by UV irradiation. Taken together, our findings demonstrate that p53 mediates the suppression of TR3 on MDM2 at both transcriptional and post-transcriptional level and suggest TR3 as a potential target to develop new anticancer agents that restrict MDM2-induced tumor progression.

The immunosuppressive properties of hepatic stellate cells (HSCs) contribute to the occurrence and development of hepatocellular carcinoma (HCC). The accumulation of cells with immune suppressive activities, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) is a key mechanism for tumor immune evasion. However, the impact of HSCs on immune cell populations in tumor-bearing hosts is unclear. In this study, we established an orthotopic liver tumor mouse model for studying the complex tumor-host interactions in HCC. The activated HSCs promoted HCC growth not only induced tumor angiogenesis and lymphangiogenesis, but also significantly increased the suppressive immune cell population of Tregs and MDSCs in the spleen, bone marrow, and tumor tissues of the tumor-bearing mice. Murine HCC cell line H22-activated HSCs also expanded the expression of Tregs and MDSCs in vitro. In conclusion, our study suggests a novel role for HSCs in the HCC microenvironment. HSCs can promote HCC progression by enhancement of the immunosuppressive cell population. Targeting HSCs, which is a new concept in adjuvant immunotherapy, may be introduced in the near future to improve the outcome of patients with HCC.

Background Adipose tissue-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative medicine. However, long-term in vitro passaging leads to stemness loss and cell senescence of ADSCs, resulting in failure of ADSC-based therapy. Methods In this study, ADSCs were treated with low dose of antioxidants (reduced glutathione and melatonin) with anti-aging and stem cell protection properties in the in vitro passaging, and the cell functions including stem cell senescence, cell migration, cell multidirectional differentiation potential, and ROS content were carefully analyzed. Results We found that GSH and melatonin could maintain ADSC cell functions through reducing cell senescence and promoting cell migration, as well as by preserving stemness and multidirectional differentiation potential, through inhibiting ROS generation during long-term expansion of ADSCs. Conclusions Our results suggested that antioxidant treatment could efficiently prevent the dysfunction and preserve cell functions of ADSCs after long-term passaging, providing a practical strategy to facilitate ADSC-based therapy.