Neuroprotective Indole Alkaloids from the Soil-Derived Fungus Trichocladium sp. XZ8

Journal of Natural Products, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

A chemical investigation of the soil-derived fungus Trichocladium sp. XZ8 led to isolation five new indole alkaloids, trichindoles A–E (1–5), with diverse architectures, along seven known analogues (6–12). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations determined single-crystal X-ray diffraction modified Mosher's method. Compound 1 is a polyketide-alkaloid hybrid incorporating rare succinimide motif, compound 2 represents first example dimeric isopentenyl indole-containing alkaloid bridged propane-1,2-diol moiety. Compounds 1, 4, 8, 11, 12 showed significant neuroprotective effects against RSL3-induced ferroptosis in PC12 cells at 10 μM. Moreover, 4 might ameliorate through regulation SLC7A11 pathway ferritinophagy, suggesting potential as promising lead compounds for treatment neurodegenerative diseases.

Language: Английский

Targeting eEF2K induces oxidative stress and sensitizes cancer cells to ferroptosis induction

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177746 - 177746

Published: May 1, 2025

Eukaryotic elongation factor 2 kinase (eEF2K), a calcium/calmodulin-dependent protein kinase, exhibits paradoxical activation and overexpression in numerous tumors, suggesting potential advantageous role for cancer cells. eEF2K phosphorylates inactivates its downstream target, eukaryotic (eEF2), thereby negatively regulating synthesis. Despite being translation inhibitor, inhibition alone has demonstrated limited anti-cancer efficacy. This study investigates novel approach to targeting therapy, exploring beyond established synthesis regulation. We found that pharmacological of using A484954 resulted minimal cytotoxicity but effectively reduced eEF2 phosphorylation. Surprisingly, impaired de novo induced mild oxidative stress across multiple cell lines. Furthermore, compromised cellular antioxidant defenses, leading enhanced ROS accumulation when challenged with stressors. Notably, potentiated ferroptosis induction lipid peroxidation combined inducers or glutathione depletion. These findings were corroborated by silencing, which similarly increased basal levels, sensitivity stress, promoted ferroptosis. Our results reveal previously unrecognized maintaining redox homeostasis suggest may be promising strategy sensitize cells ferroptosis-inducing therapies.

Language: Английский

Targeting NFE2L2/GPX4 signaling pathway: Therapeutic potential of arsenic sulfide-induced ferroptosis in combating rhabdomyosarcoma

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 143, P. 113614 - 113614

Published: Nov. 15, 2024

Language: Английский