Abstract
Oxidative stress has been implicated in the etiology of Parkinson’s disease (PD). Molecules non-covalently binding to the Keap1–Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine (1), and asperpendoline (2) with a scarce skeleton of pyrimido[1,6-a]indole were discovered from the co-cultivated fungi of Aspergillus ochraceus MCCC 3A00521 and Penicillium sp. HUBU 0120. Compound 2 exhibited potential neuroprotective activity on SH-SY5Y cells against oxidative stress. Molecular mechanism research demonstrated that 2 inhibited Keap1 expression, resulting in the translocation of Nrf2 from the cytoplasm to the nucleus, activating the downstream genes expression of HO-1 and NQO1, leading to the reduction in reactive oxygen species (ROS) and the augment of glutathione. Molecular docking and dynamic simulation analyses manifested that 2 interacted with Keap1 (PDB ID: 1X2R) via forming typical hydrogen and hydrophobic bonds with residues and presented less fluctuation of RMSD and RMSF during a natural physiological condition.
Highlights
As one of the most commonplace neurodegenerative movement disorders, Parkinson’s disease (PD) affects more than 10 million individuals worldwide [1]
The results showed that the 2-treated group distinctly increased translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) for the green fluorescence in the nucleus of cells (Figure 7A)
The level of cytosolic and nuclear Nrf2 protein exhibited the reverse trend in control and H2O2-insult groups, while consistent uptrend presented after H2O2-induced cells were administrated 2 with the concentrations ranging from 10–50 μM (Figure 7B), which may be attributable to disturbance of Kelch-like ECH-associated protein 1 (Keap1)–Nrf2 protein–protein interaction (PPI) by 2, releasing Nrf2 from ubiquitylation system
Summary
As one of the most commonplace neurodegenerative movement disorders, Parkinson’s disease (PD) affects more than 10 million individuals worldwide [1]. It is commonly identified that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression level of intracellular ROS and glutathione (GSH), which is a positive transcriptional regulation factor for modulating the expression of genes carrying with antioxidant response elements (ARE) [5]. Nrf binds with Kelch-like ECH-associated protein 1 (Keap1), which sequesters the former in the cytoplasm to promote its degradation via the ubiquitylation system, leads to blocking the nuclear translocation of Nrf. Disruption of the Keap1–Nrf protein–protein interaction (PPI) was beneficial to release Nrf, which stimulated Nrf translocating from cytoplasm to nucleus, binding to ARE, and activating the antioxidative defense system to generate antioxidative enzymes such as. 2 of 16 2 of 15 enzymes such as heme oxygenase 1 (HO-1) and NADPH quinone oxidoreductase 1 (hNemQOe o1)xy[4g]e.nAalsteho1u(HghOa-c1c)uamndulNatAinDgPrHeseqauricnhondeevoexliodpoerdedNurcft2asaect1iv(NatQorOs 1in) v[4o]l.vAinlgthcoouvgahlaecnctulmy ubloantidnigngresweiatrhchKdeeavpe1l,otpheedsNmraf2lla-mctiovlaetcourlseinnvoonl-vcionvgacleonvtalylentatlrygbetoinndginogf twhiethKKeeaapp11–, Nthref2smcoamll-pmleoxlemcualye onfofenr-cboevttaelrensatlfyettyarogwetiinnggtoofitmheprKoevaepd1e–fNfircfa2cycoamndplseexlemctaivyiotyff[e6r,7b]e.tter safetySmowalilnmgotoleicmulpersomveedtaebfofilcizaecyd afrnodmsefulencgtiivpitoys[s6e,s7s].versatile skeletons, whose fascinating bSiomaactllivmitoielescoufletrsemateintagbohluizmedanfrmomalafudniegsi aproeswseessllvdeorcsuatmileenskteedleatonnds,hwavheosbeeefanscainnaotriinggibnioalacdtrivivitiniegs foofrtcreeaftoirngcohnutimnuanoumslaylaedxipelsoarrinegwleelalddodcruumgsen[8t–e1d0a].nPdrhenavyelabteedeninadnoolerigaliknaa-l ldoriidvsinwgefroerocebtfaoirnecodnmtianiunolyusflryomexdpilvoerirnseg slepaedciedsruogf sA[s8p–e1rg0i]l.luPsraenndylPateendiciilnliduomlefualnkgailo[1id0–s w12e]r, eproebsteanintiendg nmeauirnolpyrfortoemctidveiveefrfseectsspoenciSeHs -oSfYA5Yspceregllislluosr BanVd-2Pceenllisciallniudmprfiumnagriy[1m0i–c1r2o]-, pglrieaslecnetlilnsg[1n3e–u1r5o]p. H01U20BUwe0r1e2c0o-wineorecucloa-tiendoocunltahteedpootnattohedepxottraotsoe dagexartr(oPsDe Aag) afor r(P7DdAay)sfoa◦nr d7 tdhaeynscaunltdivtahteedn in Erlenmeyer flasks (150 × 500 mL) containing sterilized rice at 25 C for one month (cFuilgtiuvraeteSd1)i.nTEherleenthmyleyaceertfaltaes(kEstO(1A50c)×e5x0tr0acmt Lw)acsocnhtraoinminatgogstrearpilhizededexrihcaeuastti2v5el°yCtofoarffoonrde mnoovnetlhp(rFeignuyrlaetSed1).inTdhoeleethalyklaalcoeidtastetr(iEvtiOalAlyc)teerxmtreadct awspasercphernomazaintoeg(r1a)pahnedd eaxshpaeurpsteinvdeloytlionaef(f2o)r.d novel prenylated indole alkaloids trivially termed asperpenazine (1) and asperpendoline (2)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
