Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.

A doubly interpenetrating porous metal-organic framework (SNU-77) has been synthesized from the solvothermal reaction of the extended carboxylic acid tris(4'-carboxybiphenyl)amine (H(3)TCBPA) and Zn(NO(3))(2)⋅6H(2)O in N,N-dimethylacetamide (DMA). SNU-77 undergoes single-crystal-to-single-crystal transformations during various activation processes, such as room-temperature evacuation, supercritical CO(2) drying, and high temperature evacuation, to afford SNU-77R, SNU-77S, and SNU-77H, respectively. These guest-free MOFs exhibited different fine structures with different window shapes and different effective window sizes at room temperature. Variable-temperature synchrotron single-crystal X-ray analyses reveal that the guest-free structure is also affected by changes in temperature. Despite the different fine structures, SNU-77R, SNU-77S, and SNU-77H show similar gas sorption properties due to the nonbreathing nature of the framework and an additional structural change upon cooling to cryogenic gas sorption temperature. SNU-77H exhibits a large surface area (BET, 3670 m(2)  g(-1)), a large pore volume (1.52 cm(3)  g(-1)), and exceptionally high uptake capacities for N(2), H(2), O(2), CO(2), and CH(4) gases.

BackgroundGlutamate (an endogenous excitatory neurotransmitter) at high concentrations contributes to the development of neurodegenerative diseases. Aronia melanocarpa (A. melanocarpa) berries contain anthocyanins and have high antioxidant activities. In this study, we evaluated whether A. melanocarpa berries could protect neuronal cells against glutamate-induced oxidative stress.Method A. melanocarpa berries exerted a protective effect against cytotoxicity in HT22 mouse hippocampal cells by MTT assay. We evaluated oxidative stress parameters including ROS level, intracellular Ca2+ level, glutathione level and antioxidant enzyme activity in HT22 cells to elucidate the mechanism of its neuroprotective effect.Results A. melanocarpa berries decreased glutamate-induced death of HT22 cells. In addition, A. melanocarpa berries reduced ROS and intracellular Ca2+ levels. Glutathione level, antioxidant enzymes, glutathione reductase and glutathione peroxide activities and mitochondrial membrane potential were also increased in HT22 cells.ConclusionThese results suggested that A. melanocarpa berries protected HT22 cells by exerting an antioxidant effect.

Magnoliae Flos (MF) is a traditional medicinal herb used for managing rhinitis, sinusitis and headache. The purpose of the present study was to determine the neuroprotective effect of MF against glutamate-induced oxidative stress and to assess the underlying mechanism. Glutamate is a major endogenous excitatory neurotransmitter in the brain and contributes to the development of neurodegenerative diseases by excessive activation. MF extract was subjected to a neuroprotective effect assay in HT22 mouse hippocampal cells. The mechanism underlying the neuroprotective effect of MF extract was evaluated by assaying reactive oxygen species (ROS) levels, intracellular Ca2+ levels, mitochondrial membrane potential, glutathione level and antioxidant enzyme activity in HT22 cells. MF extract significantly decreased glutamate-induced death of HT22 cells (80.83 ± 7.34% relative neuroprotection). MF extract reduced the intracellular ROS and Ca2+ levels and increased the glutathione level and glutathione reductase and glutathione peroxide activities. Moreover, MF extract attenuated the mitochondrial membrane potential in HT22 cells. These results suggested that MF extract exerts a neuroprotective effect against oxidative stress HT22 cells, which was mediated by its antioxidant activity.