Strong Protection by 4-Hydroxyestrone against Erastin-Induced Ferroptotic Cell Death in Estrogen Receptor-Negative Human Breast Cancer Cells: Evidence for Protein Disulfide Isomerase as a Mechanistic Target for Protection.

Ferroptosis is a recently identified form of regulated cell death, characterized by excessive iron-dependent lipid peroxidation. Recent studies have demonstrated that protein disulfide isomerase (PDI) is an important mediator of chemically induced ferroptosis and also a new target for protection against ferroptosis-associated cell death. In the present study, we identified that 4-hydroxyestrone (4-OH-E1), a metabolic derivative of endogenous estrogen, is a potent small-molecule inhibitor of PDI, and can strongly protect against chemically induced ferroptotic cell death in the estrogen receptor-negative MDA-MB-231 human breast cancer cells. Pull-down and CETSA assays demonstrated that 4-OH-E1 can directly bind to PDI both in vitro and in intact cells. Computational modeling analysis revealed that 4-OH-E1 forms two hydrogen bonds with PDI His256, which is essential for its binding interaction and thus inhibition of PDI's catalytic activity. Additionally, PDI knockdown attenuates the protective effect of 4-OH-E1 as well as cystamine (a known PDI inhibitor) against chemically induced ferroptosis in human breast cancer cells. Importantly, inhibition of PDI by 4-OH-E1 and cystamine or PDI knockdown by siRNAs each markedly reduces iNOS activity and NO accumulation, which has recently been demonstrated to play an important role in erastin-induced ferroptosis. In conclusion, this study demonstrates that 4-OH-E1 is a novel inhibitor of PDI and can strongly inhibit ferroptosis in human breast cancer cells in an estrogen receptor-independent manner. The mechanistic understanding gained from the present study may also aid in understanding the estrogen receptor-independent cytoprotective actions of endogenous estrogen metabolites in many noncancer cell types.

Formation of MXene-Derived/NiCoFe-LDH Heterostructures for Supercapacitor Applications.

In this study, MXene-derived/NiCoFe-LDH heterostructures with three-dimensional interconnected porous network microstructures were prepared, leveraging the excellent electrical conductivity and growth platform provided by the MXene material. The remarkable specific capacitance of metal oxides was fully exploited. The composite exhibited high specific capacitance and excellent stability, with a specific capacitance of 1305 F g-1 at 1 A g-1 and a capacitance of 85.7% of the initial performance after 6000 charge/discharge tests at 10 A g-1. A two-electrode assembly was constructed using activated carbon as the negative electrode material corresponding to 49.5 Wh kg-1 at 800 W kg-1, indicating that the electrodes could achieve rapid charge/discharge. The findings of this study indicate that the composite material comprising LDH/MXene has significant potential for supercapacitor applications.

Synthesis and characterization of Ag-decorated litchi-like porous Cu/Cu2O micro/nanoparticles with antibacterial activity.

Efficient and stable inorganic antibacterial material is highly spotted in antibacterial materials. However, the morphology and grain diameter of conventional inorganic compound antibacterial agent carrier are difficult to control and severely deteriorate antibacterial properties. In this research, using diethylene glycol monomer methyl ether as a pore-forming agent, litchi-like porous micro/nano Cu/Cu2O composite antibacterial carriers (Car-MNps) with good dispersion and high crystallinity are prepared by a liquid-phase chemical reduction process. Subsequently, we develop a synergistic system of inorganic composite antibacterial materials decorated with silver (Ag/Car-MNps). The microstructures of the antibacterial materials are characterized by means of various techniques, such as X-ray diffraction, scanning electron microscope, transmission electron microscope, X-ray photoelectron spectroscopy, and nitrogen adsorption. The antibacterial activities are evaluated by methods of bacteriostatic zone and minimum inhibitory concentration (MIC). The results show that the micro- and nano-materials of Car-MNPs exhibit high specific surface area characteristics and show attractive bactericidal properties. The MIC values of Ag/Car-MNps against S. aureus and E. coli decrease from 1000 mg/L and 2000mg/L to 125 and 250 mg/L, respectively, in comparison with those of Car-MNps. Our experiments may show novel insights for the development of inorganic compound antibacterial agents.

Protection against glutathione depletion-associated oxidative neuronal death by neurotransmitters norepinephrine and dopamine: Protein disulfide isomerase as a mechanistic target for neuroprotection.

Oxidative stress is extensively involved in neurodegeneration. Clinical evidence shows that keeping the mind active through mentally-stimulating physical activities can effectively slow down the progression of neurodegeneration. With increased physical activities, more neurotransmitters would be released in the brain. In the present study, we investigated whether some of the released neurotransmitters might have a beneficial effect against oxidative neurodegeneration in vitro. Glutamate-induced, glutathione depletion-associated oxidative cytotoxicity in HT22 mouse hippocampal neuronal cells was used as an experimental model. We showed that norepinephrine (NE, 50 µM) or dopamine (DA, 50 µM) exerted potent protective effect against glutamate-induced cytotoxicity, but this effect was not observed when other neurotransmitters such as histamine, γ-aminobutyric acid, serotonin, glycine and acetylcholine were tested. In glutamate-treated HT22 cells, both NE and DA significantly suppressed glutathione depletion-associated mitochondrial dysfunction including mitochondrial superoxide accumulation, ATP depletion and mitochondrial AIF release. Moreover, both NE and DA inhibited glutathione depletion-associated MAPKs activation, p53 phosphorylation and GADD45α activation. Molecular docking analysis revealed that NE and DA could bind to protein disulfide isomerase (PDI). In biochemical enzymatic assay in vitro, NE and DA dose-dependently inhibited the reductive activity of PDI. We further revealed that the protective effect of NE and DA against glutamate-induced oxidative cytotoxicity was mediated through inhibition of PDI-catalyzed dimerization of the neuronal nitric oxide synthase. Collectively, the results of this study suggest that NE and DA may have a protective effect against oxidative neurodegeneration through inhibition of protein disulfide isomerase and the subsequent activation of the MAPKs‒p53‒GADD45α oxidative cascade.