Table 1.
Summary of human studies investigating the role of Nrf2 in depression (in vivo, post mortem, in vitro on cell lines).
| Study | Animal | Paradigm/Model | Location | Design | Results Relating to Nrf2 | Conclusions/Observations |
|---|---|---|---|---|---|---|
| Lukic et al., 2014 [37] | Man; 30 patients with MDD (17 ♁; 13 ♂; Ham-D > 14; age 44.77 ± 7.58 yr) vs. 35 HC (19 ♁; 16 ♂; age 39.49 ± 9.64 yr, younger, p = 0.018) | OS | Belgrade, Serbia | PBMC investigated with WB for Nrf2, Keap1, NF-κB, AOEs (MnSOD, CuZnSOD, GPx, GLR) in MDD patients and HC | ↑ Nrf2, Keap1, NF-κB, MnSOD, CuZnSOD, and CAT in MDD vs. HC in PBMC cytoplasm; ≈GPx and GLR between MDD and HC, but ↓GLR/GPx in MDD; MnSOD, CuZnSOD, and CAT levels correlated directly with Nrf2 levels, while MnSOD and CuZnSOD correlated with NF-κB levels | Impaired oxidative detoxification capacity in MDD, ↓ capacity of GPx to defend from OS in PBMC of MDD patients; the up-regulation of Nrf2 and NF-κB and their down-stream targets MnSOD, CuZnSOD, and CAT indicate OS status in PBMCs of MDD patients |
| Mellon et al., 2016 [38] | Man; 20 unmedicated MDD patients (♂, ♁) + 20 HC | MDD human model | San Francisco, CA, USA | I group = 20 unmedicated MDD subjects; II group = 20 age-, sex- and ethnicity-matched HC, before initiation of AD treatment, and in 17/20 of the unmedicated MDD subjects after 8 wk of sertraline treatment→ transcriptome-driven bioinformatic strategy to evaluate the activity of several transcriptional Ctrl pathways | In leukocytes from unmedicated MDD subjects ↑ transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and Nrf2. 8 wk sertraline treatment was associated with ↓ in Ham-D scores and ↓ activity of Nrf2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor, NF-κB and (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment | CREB/ATF and Nrf2 signalling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators |
| Martín-Hernández et al., 2018 [39] | Post-mortem dlPFC samples of 30 Caucasian pts with MDD, ethnic origin-, gender-, and age-matched to 30 HC (sex not specified, although it was said that men were more, age of death not declared) | NI and OS in MDD post mortem | Bilbo, Bizcaia, Euskal Herria, Spain | 2 MDD groups: AD-free (N = 15) and AD-treated (N = 15). WB for levels of TLR-4, Hsp60, Hsp70, p-ERK 1/2, p-JNK, p-p38, p38 α/β, I3K, Keap-1, p11,DUSP-2, Nrf-2, NF-κB p65 subunit in cytosol and nucleus of dlPFC neurones | ↓ Nrf2 pathway in pts with MDD. AD treatments do not reverse the trend | ↑ ERK 1/2 (+22%, t = 2.293, p = 0.03) and JNK (+56%, t = 2.468, p = 0.02) expression in MDD pts, but not p38-MAPK, compared to HC. p-JNK/total JNK and p-p38/total p38 ↑ in MDD > HC. AD-free and AD-treated showed no significant ↑ in Keap-1 expression compared to HC. 21% ↓ of nuclear expression of Nrf2 in MDD pts |
| Kubick et al., 2020 [40] | In vitro cells (macrophage cell line RAW26.7 from 3 ♁ and 4 ♂ human donors, treated with LPS) | Drug repurposing, LPS-induced OS | Hamburg, Germany; Madrid, Spain; Bucharest, Romania; Stockholm, Sweden; Garbatka, Poland | RNA-seq Data Analysis, AI workflow (which drugs activate NRF2?), in vitro cells treated with ZT, Protein Assay (anti-NRF2), Chemiluminescence | RAW264.7 cells treated with ZT (10 μM, 16 h) showed ↑NRF2 levels compared to plac-treated Ctrl cells | Nrf2 pathway is a putative regulator of M1 function in depression; Nrf2 is a potential drug target; ZT activates Nrf2 and its downstream targets |
| Goetzl et al., 2021 [41] | Man; 10 MDD Resp patients (6 ♁; 4 ♂; Ham-D > 14; age 39.0 ± 9.4 yr) 10 MDD NResp patients (6 ♁; 4 ♂; Ham-D > 23; age 41.3 ± 11.6 yr) vs. 10 HC (5 ♁; 5 ♂; age 37.5 ± 10.5 yr) | OS | San Francisco, CA; New Haven, CT, USA | Two groups: MDD Resp → sertraline or escitalopram or fluoxetine × 8 wk at sertraline-equivalent doses; MDD NResp → sertaline or escitalopram, fluoxetine or citalopram at sertraline-equivalent doses; ELISA for Nrf2 and MCh proteins | NDEV levels of NRF2 were statistically ↓ in the NResp at BL and Resp at BL groups than in their Ctrl groups; levels ↑ in the NResp and Resp groups after treatment | NDEV levels of MPs of all functional classes, except complex I-6, NRF2 and PGC-1α, were normalised in MDD participants who responded to SSRI treatment but not in those who failed to respond, as assessed by the psychiatrist; the sample was small |
| X. Li et al., 2022 [42] | Human neuroblastoma SH-SY5Y cells | H2O2 induced SH-SY5Y cell damage | Beijing, China | Human neuroblastoma SH-SY5Y cells used to mimic OS damage in vitro. Four groups: untreated Ctrl, H2O2-induced injury model, kaempferol treatment, and ginsenoside rh2 treatment. WB to detect Nrf2, Trx, and Akt1. TrxR activity was Measur with the Solarbio thioredoxin reductase activity Kit | Kaempferol and ginsenoside rh2 ↑ the expression of Akt1 and Nrf2, which boosted the targets in the Akt1/Nrf2/Trx pathways cascade working conjointly. Kaempferol works better than ginsenoside rh2 in the Akt1/Nrf2/Trx pathways | Kaempferol and Rh2 could enhance the activity of the Trx system by up-regulating Akt1 to activate Nrf2 in vitro |
For abbreviations, see note to Table 2.