Cyclo(His‐Pro) promotes cytoprotection by activating Nrf2‐mediated up‐regulation of antioxidant defence

Abstract

Hystidyl-proline [cyclo(His-Pro)] is an endogenous cyclic dipeptide produced by the cleavage of thyrotropin releasing hormone. Previous studies have shown that cyclo(His-Pro) protects against oxidative stress, although the underlying mechanism has remained elusive. Here, we addressed this issue and found that cyclo(His-Pro) triggered nuclear accumulation of NF-E2-related factor-2 (Nrf2), a transcription factor that up-regulates antioxidant-/electrophile-responsive element (ARE-EpRE)-related genes, in PC12 cells. Cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion caused by glutamate, rotenone, paraquat and β-amyloid treatment. Moreover, real-time PCR analyses revealed that cyclo(His-Pro) induced the expression of a number of ARE-related genes and protected cells against hydrogen peroxide-mediated apoptotic death. Furthermore, these effects were abolished by RNA interference-mediated Nrf2 knockdown. Finally, pharmacological inhibition of p-38 MAPK partially prevented both cyclo(His-Pro)-mediated Nrf2 activation and cellular protection. These results suggest that the signalling mechanism responsible for the cytoprotective actions of cyclo(His-Pro) would involve p-38 MAPK activation leading to Nrf2-mediated up-regulation of antioxidant cellular defence.

Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity

“…One of the major cellular antioxidant responses is mediated by the transcription factor Nrf2 that binds to the EpRE/ARE sequences, thus activating the transcription of antioxidant and phase II detoxifying genes [10,11,[17][18][19].…”

“…ROS signaling induces thiol modifications in Keap1 leading to Nrf2 release and nuclear translocation. Nrf2 regulates the expression of several antioxidant enzymes, such as NAD(P)H:quinone oxidoreductase, heme oxygenase-1 (HO-1), thioredoxin reductase 1, L-cystine and L-glutamic acid exchange transporter (XCt), glutamate-cysteine ligase modifier subunit (GCLM) and glutamatecysteine ligase catalytic subunit (GCLC) [10,11].…”

20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway

“…NQO1 is a cytoplasmic two electron reductase that catalyzes the reduction of a wide range of substrates, including quinones, quinone-imines, and nitro-compounds [31] . Thus, the up-regulation of HO-1 and NQO1 in response to oxidative stresses provides an effective endogenous antioxidant defense mechanism in rotenone-induced PC12 cells [32,33] . To determine whether the Nrf2/ARE/HO-1 signaling pathway is involved in the neuroprotective effect of 20C, we investigated the changes in the Nrf2/ARE/HO-1 signaling pathway in the 20C-treated cells.…”

Prevention and Treatment of Obesity and Diabetes and their Related Complications

“…In general its side effects are irritation of stomach other than megadose of more than 1 g of zinc element which could induce serious pathological condition and fatal if taken more than 10 g at a time. CHP side effects are not well established without any report of side effects but some studies of anti-toxicity of CHP have been published [100,117,118]. The long term side effect in humans will be established in our long term clinical trial and in the toxicological studies in dogs with high dose of Cyclo-Z for one year.…”