Notoginsenoside R1 (NGR1), a novel phytoestrogen isolated from Panax notoginseng, has antioxidant and anti-apoptotic properties. Oxidative stress plays a pivotal role in neurodegenerative diseases. To mimic oxidative stress in neurons and explore the neuroprotection of NGR1, H₂O₂-induced neurotoxicity in NGF-induced differentiation of PC12 cells was used. In this study, NGR1 preconditioning provided neuroprotective effects via suppressing H₂O₂-induced the intracellular ROS accumulation, the increase in the product of lipid peroxidation (MDA), protein oxidation (protein carbonyl), and DNA fragmentation (8-OHdG), and mitochondrial membrane depolarization as well as caspase-3 activation. Moreover, NGR1 treatment alone potently increased the nuclear translocation of Nrf2, augmented ARE enhancer activity, and upregulated the expression and activity of phase II antioxidant enzymes including HO-1, NQO-1, and γ-GCSc. NGR1 could also increase the ERE activity and activate Akt and ERK1/2 pathways. NGR1-mediated activation of Nrf2/ARE signaling and neuroprotection were abolished by genetic silencing of Nrf2 using siRNA or the pharmacological blockade of estrogen receptors using ICI-182780, and partially inhibited by Akt siRNA or ERK siRNA transfection. In addition, the phosphorylation of ERK1/2 mediated by NGR1 was markedly inhibited in PC12 cells transfected with Akt siRNA. On the contrary, ERK1/2 siRNA transfection hardly had any effect on the phosphorylation of Akt mediated by NGR1. NGR1-mediated activation of Akt and ERK1/2 pathways was blocked by ICI-182780. In conclusion, NGR1 provided neuroprotection via inducing an estrogen receptor-dependent crosstalk between Akt and ERK1/2 pathways, subsequently activating Nrf2/ARE signaling and thereby up-regulating phase II antioxidant enzymes.
Background: Advanced GC pts have limited treatment options and poor prognosis. Immune checkpoint inhibitors (ICIs) showed promising activities in pretreated pts, especially for those with high PD-L1 expression. Blockade of TGF-b pathway may enhance the tumor response to ICIs.Methods: This phase I study composed of a dose escalation and expansion (ESC & EXP) period in solid tumors and multiple clinical expansion cohorts. Based on findings of the ESC & EXP period, 30 mg/kg Q3W was determined as RP2D. In the GC clinical expansion cohort, pts who had progressed on or were intolerant to 2L standard therapies were given SHR-1701 at the RP2D. Prior ICIs were not allowed. Primary endpoint was ORR per RECIST v1.1.Results: 35 pts were enrolled: stage IV, 91.4%; 2L prior systemic therapies, 54.3%. By Apr 6, 2021, median SHR-1701 exposure was 12.0 wk (range 3.0-64.9). Of the 31 pts with post-baseline scan(s), 16 (51.6%) pts showed tumor shrinkage. 1 CR and 7 PR were achieved, and ORR was 25.8% (95% CI 11.9-44.6). 2 PR were not confirmed yet as there was no consequent scan after first PR as of data cutoff. Confirmed ORR was 19.4% (95% CI 7.5-37.5; 1 CR + 5 PR; ongoing responses: 66.7% [4/6]). DCR was 41.9% (95% CI 24.5-60.9). CBR (CR + PR + SD23 wk) was 25.8% (95% CI 11.9-44.6). Median PFS was 1.4 mo (95% CI 1.3-9.6), and 6-mo PFS rate was 38.7% (95% CI 22.0-55.1). Median OS was not reached yet. Exploratory analyses showed a trend towards favourable responses for pts with a PD-L1 CPS 5 (Table ). Most common TRAEs (incidence >10% in 35 pts) were rash, increased AST/ALT, decreased FT3 and pruritus. Incidence of irAEs was 45.7%. Grade 3 or 4 TRAEs occurred in 17.1% of pts, and no pts died due to TRAEs. Incidence of grade 3 irAEs was 11.4%. Table: 1375P Efficacy outcomes* in all patients and subgroups by PD-L1 expression All patients (N[31) CPS <5 (N[10) CPS ‡5 (N[9) ORR, n (%; 95% CI) 6 (19.4%; 7.
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