18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression inCaenorhabditiselegansand Neuronal Cultures

Abstract

Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression. Results: Feeding of wild-type Caenorhabditis elegans with 18a-glycyrrhetinic acid (18a-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1-and proteasome activation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased Ab deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18a-GA treatment. Innovation: This is the first report of the use of 18a-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism. Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet. Antioxid. Redox Signal. 25, 855-869.

Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway

“…Model system Impact on Nrf2 and/or effect on thyroid function/morphology 1,5-Dicaffeoylquinic acid primary culture rat cortical astrocytes [188] mediates glutathione synthesis via Nrf2 A , NP [188] 18α-Glycyrrhetinic Acid HFL-1 human primary fibroblasts [189]; human neuroblastoma SH-SY5Y cells [190]; murine cortical neurons [190]; C. elegans [190] ↑Nrf2, ↑ proteasome subunits [189]; ↑Nrf2, ↑ oxidative stress resistance [190]; ↑ cellular lifespan [190]; ↑ organismal lifespan [190] 3-Caffeoyl, 4-dihydrocaffeoyl quinic acid Hepa1c1c7 cells [191] scavenges ROS, regulates HO-1 via PI3K/Akt-Nrf2 PtW, HP [191] Andalusol Conchitriol Lagascatriol PC12 cells [192] Nrf2 PtW A , NP, AO [192] Antroquinonol B-cell-deficient M [193] Nrf2 PtW A , T cells and NLRP3 I , NephP [193] Carnosic acid PC12 COS7 cells [194] Keap1/Nrf2 Ptw A via cysteine S-alkylation, NP [194] Carnosol PC12 cells [195] ↑Nrf2, ↑HO-1 expression via PI3K/Akt Ptw A , NP [195] Celastrol HaCaT cells [196]; 8505C and SW1736 cells [197] ↑HO-1 expression via ROS/Nrf2/ARE signaling [196]; ↓cell viability, ↑cytotoxic activity, AC [197] Emodin, Aloe emodin mouse primary microglia [198]; thyroid cancer cell line K1 [199] HO-1 and NQO1 induction via AMPK/Nrf2 signaling, AI, NP [198]; promotes apoptosis of K1 cells [199] Kahweol SH-SY5Y cells [199] HO-1 regulation via the PI3K and p38/Nrf2 PtW, NP [199] Kaurenoic acid RAW264.7 and HEK293 cells [200] Nrf2 A , AI [200] Linearol Sidol PC12 cells [201] ↓ROS production via Nrf2 antioxidant system modulation, NP, AO [201] Maslinic Acid…”

Redox regulation of proteasome function

“…Treatment with 18α-glycyrrhetinic acid (18α GA) promotes the proteasome assembly and activity in HFL-1 human primary cells in an Nrf2-dependent manner leading to parallel decreased ROS levels [38]. The positive effects of 18αGA on proteasome status have been shown to be evolutionary conserved; verified at the level of a multi-cellular organism ( C. elegans ) [42]. The flavonoid quercetin, a known Nrf2 activator [88], was shown to enhance proteasome activities, to promote increased oxidative stress resistance and to confer enhanced longevity in HFL-1 cells [86].…”

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

“…This study suggests that pharmacological activation of NRF2 is possible even in late life [86]. Moreover, a later study showed that this compound mediated SKN-1 and proteasome activation in C.elegans with beneficial effects on AD progression in relevant nematode models [134].…”