TABLE 1.
A summary of representative protective agents targeting the crosstalk between the Nrf2 and NF-κB pathway in drug-induced toxicity.
| Toxic reaction | Representative drug | Representative promising candidate | Brief summary of regulatory mechanisms based on Nrf2 and NF-κB | References |
|---|---|---|---|---|
| Hepatotoxicity | Acetaminophen | Salvianolic acid B/C | • Regulating drug-metabolizing enzymes, transporter and antioxidant genes through the Nrf2/ARE pathway | Wang et al. (2019a), Lv et al. (2019), Wu et al. (2019), Wang et al. (2019b), Ibrahim et al. (2018), Rada et al. (2018), Yang et al. (2020), Choi et al. (2021), Fan et al. (2014), Jiet al. (2015), Fan et al. (2018), Lv et al. (2018), Lv et al. (2020), Zhang et al. (2020) |
| Corilagin; Isoorientin | • Mitigating mitochondrial oxidative stress, inflammatory response, and caspase-mediated antiapoptotic effect through inhibition of Keap1/Nrf2/HO-1 axis | |||
| Farrerol; Tanshinone IIA | • Exerting antioxidant effects through Nrf2 activation via the AMPK/AKT pathway | |||
| Maltol; Wuzhi tablet | • Upregulating AMPK/GSK3β-Nrf2 signaling pathway | |||
| Rutaecarpine; Quercetin | • Inhibiting oxidative stress and inflammation response via NF-κB and PI3K/Akt pathway | |||
| Tovophyllin A | • Activating the Nrf2 pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1 | |||
| Limonin; Daphnetin | • Regulating Nrf2/Trx-1 axis via decreasing ASK1/JNK and Txnip/NLRP3 inflammasome | |||
| Licochalcone A | ||||
| Isoniazid | Gallic acid; Quercetin | • Increasing the expression of antioxidant enzymes and decreasing CYP expression through the activation of the Nrf2/Keap1 pathway | Wang et al. (2018), Jia et al. (2019), Zhang et al. (2019), He et al. (2020), Sanjay et al. (2021a), Sanjay et al. (2021b) | |
| Pyrrolidine dithiocarbamate | • Increasing BSEP expression, and exhibiting + antioxidant and anti-inflammatory activities | |||
| Sagittaria sagittifolia | • Improving the redox homeostasis by activating Nrf2 and blocking NF-κB/TLR-4 axis | |||
| Triptolide | Arctiin; Quercetin; Licorice | • Acting as an upstream activator to regulate Nrf2 and its downstream target (HO1, NQO1) | Zhou et al. (2020), Feng et al. (2019), Fu et al. (2020), Wei et al. (2017), Yuan et al. (2020), Li et al. (2014b), Hou et al. (2018) | |
| Panax notoginseng saponins | • Inducing phase I/II detoxification enzyme via Nrf2 pathway to increasing metabolic conversion | |||
| Sulforaphane; Catalpol | • Restoring Th17/Treg balance through Tim-3 and TLR4-MyD88-NF-κB pathway | |||
| Polygonum multiflorum | Pioglitazone | • Decreasing serum TNF-α and other inflammatory cytokines, liver tissue PPAR-γ expression, and inhibiting expression of NF-κB p65 | Meng et al. (2017) | |
| Nephrotoxicity | Cisplatin | Cordyceps cicadae Mycelia | • Decreasing phosphorylation of STAT3 and IκKβ STAT3 and IκKβ, inhibiting NF-κB-mediated inflammatory cascade and improving mitochondrial function | Yu et al. (2018), Deng et al. (2020), Qin et al. (2019), Al Fayi et al. (2020), Sun et al. (2020), Taghizadeh et al. (2020), Younis et al. (2020), El-Sayed et al. (2021) |
| Vincamine; Embelin; Polysulfide | • Diminishing oxidative stress and inflammation by activating the signaling pathway of Nrf2/HO-1 and impeding NF-κB | |||
| Celastrol; Gliclazide; Vanillin | ||||
| Thymoquinone and Curcumin | ||||
| Aristolochic Acid | Bardoxolone methyl | • Upregulating Nrf2/Smad7, NQO1, and HO-1 expression and downregulating Keap1 expression | Wu et al. (2014), Song et al. (2019), Bai et al. (2014) | |
| Sedum sarmentosum extract | • Decreasing the activity of the NF-κB signaling pathway, resulting in down-regulated expression of NF-κB-controlled chemokines and pro-inflammatory cytokines | |||
| Contrast | Atorvastatin; Infliximab; stanniocalcin-1 | • Activating the Nrf2/Sirt3/SOD2 or Nrf2/HO-1 pathways | Saritemur et al. (2015), Khaleel et al. (2017), Yue et al. (2017), Khaleel et al. (2019), Zhou Z et al. (2019), Zhao et al. (2020) | |
| Lansoprazole; Sulforaphane | • Suppressing the TLR4/Myd88 pathway and inhibiting the expression of downstream inflammatory cytokines, such as IL-1β, TNF-α, IL-6, and MCP-1 | |||
| Tert-Butylhydroquinone | • Alleviating oxidative DNA damage, mitochondrial damage and apoptosis via the Nrf2 pathway | |||
| Gentamicin | Diallyl sulfide; Diosmin | • Restoring antioxidant enzyme activity, and blocking NF-κB and iNOS activation | Tugcu et al. (2006), Kalayarasan et al. (2009), Lee et al. (2012), Ansari et al. (2016), Arjinajarn et al. (2016), Mahmoud (2017), Ali et al. (2021) | |
| Melatonin; Kiwi fruit | • Upregulating nuclear NF-κB p65 expression, NF-κB-DNA binding activity, and MPO activity | |||
| Pyrolidium dithiocarbamate | • Activating Keap1/Nrf2/ARE, AKT or PKC/Nrf2 antioxidant pathways | |||
| sulfasalazine; Sinapic acid | ||||
| Riceberry bran extract | ||||
| Methotrexate | Berberine; Chicoric acid; Dioscin | • Activating Keap1/Nrf2 signaling and attenuating ROS-induced activation of NF-κB/NLRP3 inflammasome signaling and apoptosis pathways | Hassanein et al. (2018), Mahmoud et al. (2018), Abd El-Twab et al. (2019), Aladaileh et al. (2019), Hassanein et al. (2019), Shalaby et al. (2019), Sherif et al. (2020), Li et al. (2021c) | |
| Commiphora molmol; Vincamine | • Regulating antioxidant pathways and anti-inflammatory pathways via miR145-5p or miR29a | |||
| Formononetin; Umbelliferone | ||||
| Cardiotoxicity | Doxorubicin | Asiatic acid; Apigenin; Geraniol | • Activating the Nrf2/Keap1/ARE pathway | Qi et al. (2020), Yarmohammadi et al. (2021), Sahu et al. (2019), Goda et al. (2021), Younis et al. (2021) |
| Cardamonin; Baicalein; Dioscin | • Inhibiting oxidative stress, MAP kinase activation, NF-κB pathway, PI3K/Akt/mTOR impairment, and cardiac apoptosis | |||
| sulforaphane; tanshinone IIA | ||||
| Trifluoperazine; Wheat phenolics | ||||
| Pulmonary Toxicity | Bleomycin | Artemisitene; Curcumin | • Activating Nrf2 by reducing Nrf2 ubiquitination and improving its stability and inhibit of NF-κB and TGF-β1/Smad2/3/AMPK pathways | Chen et al. (2016), Tang et al. (2016), Beigh et al. (2017), Liu et al. (2017b), Zhou Z et al. (2019), Ahmad et al. (2020), Ma et al. (2020), Shaikh and Prabhakar Bhandary (2020) |
| Hesperidin; Pirfenidone | • Inhibiting the IκBα/NF-κB pathway, which in turn improves the regulation of oxidative inflammatory markers (Nrf2 and HO-1) and proinflammatory markers (TNF-α, IL-1β, IL-6, COX-2, and iNOS) | |||
| Glycyl-L-histidyl-l-lysine | ||||
| Salidroside; Thymoquinone | ||||
| Walnut extract | ||||
| Dermal toxicity | Imiquimod | Dimethylfumarate | • Attenuating psoriasis-related inflammatory, regulating cellular anti-oxidant responses and suppression of keratinocyte hyperproliferation via activation of Nrf2/HO1 and inhibition of NF-κB and STAT3 | Lee et al. (2020), Sangaraju et al. (2021), Ogawa et al. (2020) |
| Tussilagonone (TGN) | • Influencing cytokine production by antigen-presenting cells, inhibiting Th1/Th12 responses, promoting Th2 responses via indirect and/or direct inhibition of NF-κB | |||
| Galangin | ||||
| Neurotoxicity | Cisplatin | Epigallocatechin Gallate | • Inhibiting NF-κB and p53 activation and upregulating Nrf2/HO-1 pathway | Giridharan et al. (2012), Jangra et al. (2016), Arafa and Atteia (2020) |
| Edaravone; Schisandrin B | ||||
| Bortezomib | Dimethyl fumarate | • Activating the Nrf2 pathway | Kawashiri et al. (2018) | |
| Paclitaxel and Qxalipatin | Curcumin; Dimethyl fumarate | • Inhibiting activation of the inflammatory TLR4/NF-κB pathway and promoting the activation of PI3K/Akt-Nrf2 signaling pathway | Kawashiri et al. (2018), Yehia et al. (2019), Lv et al. (2021), Yardım et al. (2021) | |
| Huangqi Guizhi Wuwu Decoction (HGWD) | • Protecting neural stem/progenitor cells and neurons from oxidative damage through the Nrf2-ERK1/2 MAPK pathway | |||
| L-Carnosine |