1-1-diphenyl-2-picrylhydrazyl and Neuroblastoma

Spinocerebellar ataxias (SCAs), caused by expanded CAG repeats encoding a long polyglutamine (polyQ) tract in the respective proteins, are characterized by the accumulation of intranuclear and cytoplasmic misfolded polyQ aggregation that leads to cell death. Suppression of aggregate formation can inhibit a wide range of downstream pathogenic events and is expected to be a therapeutic strategy for SCAs. Here we show the anti-aggregation potential of Gardenia jasminoides (G. jasminoides) and its components/metabolite geniposide, crocin, and genipin, in ATXN3/Q75-GFP 293 cells, a putative SCA3 cell model. We found the aggregation can be significantly prohibited by G. jasminoides, genipin, geniposide and crocin. Meanwhile, G. jasminoides, genipin, geniposide, and crocin up-regulated anti-oxidative markers NFE2L2, NQO1, GCLC and GSTP1, and reduced the production of reactive oxidative species (ROS) in the same cell models. All of them further inhibited the aggregation in neurally differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate that G. jasminoides, genipin, geniposide and crocin work on polyQ-aggregation reduction by suppressing ROS. These findings indicate the therapeutic applications of G. jasminoides in treating SCAs. Furthermore, oxidative stress inhibition could be a good target for drug development of anti-polyQ aggregation.

Topics: Antioxidants; Ataxin-3; Biphenyl Compounds; Caspase 3; Cell Line, Tumor; Dose-Response Relationship, Drug; Gene Expression Regulation; Green Fluorescent Proteins; HEK293 Cells; Humans; Inhibitory Concentration 50; Monoterpenes; Nerve Tissue Proteins; Neuroblastoma; NF-E2-Related Factor 2; Nuclear Proteins; Oxidative Stress; Peptides; Picrates; Plant Extracts; Reactive Oxygen Species; Repressor Proteins; Time Factors; Transfection

A new series of tacrine-flavonoid hybrids (13a-u) had been designed, synthesized, and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of the molecules exhibited a significant ability to inhibit ChE and self-induced amyloid-β (Aβ₁₋₄₂) aggregation. Kinetic and molecular modeling studies also indicated compounds were mixed-type inhibitors, binding simultaneously to active, peripheral and mid-gorge sites of AChE. Particularly, compound 13k was found to be highly potent and showed a balanced inhibitory profile against ChE and self-induced Aβ₁₋₄₂ aggregation. Moreover, it also showed excellent metal chelating property and low cell toxicity. These results suggested that 13k might be an excellent multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Chelating Agents; Cholinesterase Inhibitors; Cholinesterases; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; Free Radical Scavengers; Humans; Mice; Neuroblastoma; Organometallic Compounds; Oxidation-Reduction; Peptide Fragments; Picrates; Structure-Activity Relationship; Tacrine