Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection.

The intrinsic link of ferroptosis to neurodegeneration, such as Parkinson's disease and Alzheimer's disease, has set promises to apply ferroptosis inhibitors for treatment of neurodegenerative disorders. Herein, we report that the natural small molecule hinokitiol (Hino) functions as a potent ferroptosis inhibitor to rescue neuronal damages in vitro and in vivo. The action mechanisms of Hino involve chelating irons and activating cytoprotective transcription factor Nrf2 to upregulate the antioxidant genes including solute carrier family 7 member 11, glutathione peroxidase 4 and Heme oxygenase-1. In vivo studies demonstrate that Hino rescues the deficits of locomotor activity and neurodevelopment in zebrafishes. In addition, Hino shows the efficient blood-brain barrier permeability in mice, supporting the application of Hino for brain disorders. Paclitaxel is one of the most widely used broad-spectrum antineoplastic agents. However, its neurotoxic side effect is a severe concern. We demonstrate that the neurotoxicity of paclitaxel is ferroptosis-related and Hino also alleviates the paclitaxel-induced neurotoxicity without compromising its cytotoxicity to cancer cells. Hino also salvages the neurobehavioral impairment by paclitaxel in zebrafishes. Collectively, the discovery of Hino as a novel ferroptosis inhibitor and disclosure of its action mechanisms establish a foundation for the further development of Hino as a neuroprotective agent.

Isolation, identification, and activity evaluation of diterpenoid alkaloids from Aconitum sinomontanum.

A phytochemical study led to the isolation of 25 diterpenoid alkaloids from Aconitum sinomontanum, of which six were described for the first time. Among them compounds 1-3 are anhydrolycoctonine derivatives, rare rearranged aconitine-type C19-diterpenoid alkaloids. To our best knowledge, less than ten of this type of alkaloids were isolated just from the genus Aconitum. The structures of these unreported compounds were elucidated by extensive analysis of NMR spectroscopic data and X-ray diffraction. The biological activities of compounds 1-3, 5-9, and 12-25 were evaluated. Among the tested compounds, compounds 2 and 17 showed potent inhibitory effect on the capsaicin (selective TRPV1 agonist) mediated activation of transient receptor potential vanilloid 1 (TRPV1) channels expressed in HEK-293 cells with inhibition rate of 31.78% and 30.94% at the concentration of 10 µM. Compounds 1-3, 5-9, 13, and 18-25 exhibited weak cytotoxic activity against human tumor cell lines NCI-H226 and MDA-MB-231 with inhibition rate over 10% at the concentration of 10 µM. Compound 16 showed most inhibitory effect on the expression of Nrf2 (NF-E2-related factor-2)-regulated gene with inhibition rate of 25% at the concentration of 20 µM.

An Azo Coupling Strategy for Protein 3-Nitrotyrosine Derivatization.

Herein, a strategy for the selective derivatization of 3-nitrotyrosine-containing proteins using the classic azo coupling reaction as the key step is described. This novel approach featured multiple advantages and was successfully applied to detect picomole levels of protein tyrosine nitration in biological samples.