Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane
Abstract
:1. Overview of Chemistry and Biological Relevance
2. Anti-Inflammatory Effects In Vivo
3. Anti-inflammatory Studies In Vitro
3.1. Anti-inflammatory Effect of Sulforaphane through the Suppression of Pro-Inflammatory Cytokines and Chemokine Production
3.2. Anti-Inflammatory Effect of Sulforaphane through the Inhibition of the Expression of Adhesion Molecules
3.3. Anti-inflammatory Effect of Sulforaphane through the Suppression of COX-2 Expression
3.4. Anti-inflammatory Effect of Sulforaphane through the Inhibition of iNOS Expression
3.5. Anti-Inflammatory Effect of Sulforaphane through the Inhibition of Inflammation-Associated Oxidative Stress
4. Mechanistic Overview of the Anti-Inflammatory Effect of Sulforaphane
4.1. Induction of Nrf2
4.2. Inhibition of NF-κB
4.3. Nrf2-NF-κB Crosstalk
4.4. Signalling Paradox
4.5. Anti-Inflammatory Effect of Sulforaphane by Targeting Sirtuin 1 (SIRT1) Signalling
4.6. Anti-inflammatory Effect of Sulforaphane by Targeting STATs
4.7. The Emerging Role of Activator Protein-1 (AP-1) as an Anti-Inflammatory Target for Sulforaphane
4.8. MicroRNAs as Potential Therapeutic Targets for Sulforaphane
5. General Summary and Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cellular Model and Treatment | Concentration | Key Findings | Reference |
---|---|---|---|
Neutrophils and PBMCs from healthy volunteers | 140 or 280 µM (note the high dose used) | Treatment reduces ROS production, the release of myeloperoxidase from azurophilic granules, and inflammatory cytokines (TNF-α and IL-6) and suppresses phagocytosis. | Wakasugi-Onogi et al. [64] |
Alveolar macrophages from patients with COPD | 10 µM | Activation of Nrf2 restored bacteria recognition and phagocytosis of clinical isolates of nontypeable Haemophilus influenza and Pseudomonas aeruginosa; Nrf2-dependent effect confirmed by siRNA. | Harvey et al. [65,66] |
Alveolar macrophages from patients with COPD | 5 μM | Glutathione-dependent effect activates Nrf2 to HDAC2 and restores dexamethasone sensitivity. | Malhotra et al. [67] |
Alveolar macrophages from alcohol-fed rats | 5 μM | Treatment reverses the decrease in cellular RAGE expression and phagocytosis power—effect similar with a glutathione supplement. | Staitieh et al. [68] |
Alveolar macrophages from HIV-1 transgenic rats; rat macrophage cell line (NR8383 cells) treated with the HIV-related proteins gp120 or Tat; human monocyte (from peripheral blood)-derived macrophages infected with HIV-1 | 5 μM | Treatment reverses the decrease in protein expression of Nrf2, NQO1, and GCLC and improves their phagocytic function (confirmed by siRNA to Nrf2). | Staitieh et al. [69] |
Porcine pulmonary alveolar macrophages stimulated by LPS | 5 µM | Treatment suppresses TRAM, TRIF, RIPK1, TRAF3, TNF-α, IL-1β and IFN-β, and DNMT3a expression. Effect mediated via the suppression of CD14 activation. | Yang et al. [70] |
LPS-stimulated peritoneal macrophage from Nrf2 (+/+) and Nrf2 (−/−) mice | 5, 10, or 20 µM | Treatment suppresses induced mRNA expression, protein expression, and production of TNF-α, IL-1β, COX-2, and iNOS and HO-1 expression in Nrf2 (+/+) but not in Nrf2 (−/−) macrophages. | Lin et al. [71] |
LPS-simulated murine bone marrow-derived macrophages | 5 or 10 µM | Treatment diminishes M1 marker expression (IL-1β, IL-6, TNF-α, iNOS, NO, and ROS). | Bahiraii et al. [72] |
LPS plus IFN-γ-stimulated bone marrow-derived macrophage from mice | 10 μM | Treatment decreases the levels of IL-1β, TNF-α, and IL-6, induces M1-to-M2 phenotype polarisation (cell marker analysis), and promotes STAT3 activation and the production of IL-10. | Sun et al. [73] |
Bone marrow-derived dendritic cells co-cultured with CD4+ T-cells isolated from the spleen and lymph nodes of mice activated by anti-CD3ε and anti-CD28 Abs stimulated by LPS | 0.1 μM | Treatment inhibits TLR4-induced IL-12 and IL-23 production, suppresses Th1 and Th17 development of T-cells, increases HO-1 expression, and inhibits NF-κB p65 activity. | Geisel et al. [74] |
LPS-stimulated PBMC and adipose tissue macrophages | 40 µM | Treatment reduces TNF-α, IL-1β, and inflammasome gene expression. | Williams et al. [75] |
Human monocyte-derived dendritic cells | 10 µM | Treatment reduces the expression of cell-surface markers (CD80, CD83, CD86, HLA-DR, and PD-L1) and Th2 proliferative response, with a decrease in the IL-9 and IL-13 levels, and increases IL-10 levels. | Fernandez-Prades et al. [76] |
LPS-stimulated human PBMC- or THP-1-derived macrophages | 25 μM | Treatment reduces the expression levels of M1 marker genes, upregulates the M2 marker gene MRC1, decreases the intracellular S. aureus load while increasing the intracellular survival of E. coli in THP-1 but not in PBMC, and suppresses IL-1β, IL-6, and TNF-α gene expression. | Ali et al. [77] |
Human peripheral blood mononuclear cells stimulated by acrolein | 1, 5, or 10 µM | Treatment suppresses ROS generation by upregulating Nrf-2 expression and suppresses COX-2 and PGE2 levels. | Qin et al. [78] |
Human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody | 1, 5, or 10 μM | Treatment inhibits the production of IL-6, TNF-α, and IL-17. | Moon et al. [79] |
PBMC stimulated by LPS and viral (imiquimod) TLRs | 10 or 50 µM | Treatment reduces the pro-inflammatory cytokines (IL-6, IL-1β, and MCP-1) irrespective of TLR stimulations and reduces the proportion of NK cells and monocytes while increasing the proportion of DCs, T-cells, and B-cells. | Mazarakis et al. [80] |
Monocytes and CD4+ T-cells infection by HIV (monocyte (THP89GFP and U1) as well as T-cell lines (J89GFP and ACH-2)) | 10 μM | Treatment suppresses the reactivation of HIV-1 and antagonises the reactivating agents (TNF-α and PMA)—an effect dependent on Nrf2 activation and the downregulation of NF-κB. | Jamal et al. [81] |
PBMCs and monocytes from the blood of children with autism spectrum disorder | 5 μM | Treatment reverses the deficiency in Nrf2 release, reduces SOD1, GPx1, and GR, and suppresses NF-κB signalling, pro-inflammatory (IL-1β, iNOS, and IL-6) proteins, and mRNA expression stimulated by LPS. | Nadeem et al. [82] |
Monocyte-derived macrophages from patients with COPD—LPS- or Pam3CysSerLys4 (Pam3CSK4)-induced inflammation | 20 μM | These cells have high levels of TLR2, TLR4, and downstream MyD88 expression, as well as IL-6 and TNF-α levels, compared to normal cells. Their activation further increases these levels, which was supressed by sulforaphane. | Zeng et al. [83,84] |
THP-1 or PBMC differentiated by PMA and treated with LPS and IFNγ | 10 μM | Treatment shifts macrophage polarisation to a direction specific to the M2 phenotype (CD36 high and CD197 extremely low); this effect was associated with the inhibition of COX-2 expression via the stimulation of MEK-1/2 and JNK1/2 (partial inhibition) to reduce COX-2 expression, but not in p38. | Pal et al. [85] |
Human monocytic THP-1 treated with mycoplasma-derived membrane lipoprotein or its analogue, MALP-2 | 0.5, 1, or 5 μM | Treatment upregulates Nrf2 and HO-1 expression and inhibits TNF-α, IL-1β, and IL-8 secretion and NF-κB activation; a selective inhibitor (SnPP) of HO-1 reversed the inhibitory actions, while a carbon monoxide-releasing molecule (CORM-2) caused a significant decrease in MALP-2-induced cytokine secretion. | Luo et al. [86] |
LPS-stimulated J774.1 or RAW264.7 macrophage | 5 μM | Treatment activates Nrf2, leading ferroportin 1 (iron exporter) expression and iron release, which reverses the effect of LPS on iron sequestration via the downregulation of ferroportin 1 expression. | Harada et al. [87] |
RAW264.7 cells exposed to hypoxia (<1% O2) or cobalt chloride (CoCl2) | 10 or 20 µM | Treatment suppresses the induced upregulation of the TLR4 mRNA and protein by inhibiting PI3K/Akt activation and the subsequent nuclear accumulation and transcriptional activation of HIF-1α (confirmed by selective inhibitor and siRNA knockdown studies). | Kim et al. [88] |
LPS-stimulated RAW 264.7 cells | 2.5 or 5 µM | Treatment suppresses iNOS and COX-2 expression and inhibits TNF-α, IL-1β, and IL-6 production. | Ranaweera et al. [89] |
LPS/IFN-γ-stimulated RAW264.7 cells | 10 or 20 µM | Treatment suppresses iNOS gene expression and the production of NO, IL-6, TNF-α, and IL-1β via activating the gene expression (mRNA expression) of Nrf2 and HO-1. | Ruhee et al. [90] |
LPS/IFN-γ-stimulated RAW264.7 cells | 10 or 20 µM | Treatment inhibits the induction of iNOS, TNF-α, and IL-6 and attenuates miR-146a and miR-155 levels. | Saleh et al. [91] |
LPS-stimulated RAW264.7 cells | 5, 10, or 20 µM | Treatment suppresses TNF-α, IL-6, and iNOS (mRNA and protein) levels, suppresses miR-146a and miR-155 levels, and attenuates the further increase in these inflammation markers by doxorubicin. | Sato et al. [92] |
LPS-stimulated RAW264.7 cells | 5, 10, or 20 µM | Treatment suppresses NO, iNOS, COX-2, and IL-1β production, inhibits ROS level while enhancing CAT, GPx, Nrf2, NQO1, and HO-1, and, in combination with acetaminophen, increases activity. | Vuong et al. [93] |
LPS-activated RAW264.7 cells | 15 µM | Treatment suppresses COX-2 protein and mRNA expression, inhibits NF-κB activation but not IκB degradation, inhibits C/EBP- and CREB-binding activity, and inhibits JNK phosphorylation. | Woo et al. [94] |
LPS-stimulated RAW 264.7 cells and human monocytes isolated from blood | 2-20 µM | Treatment suppresses the expression and release of pro-inflammatory mediators (IL-1β, IL-6, TNF-α, and MMP-9), inhibits antibody-independent phagocytic and chemotactic migratory abilities, suppresses NF-κB and MAPK (p38 and JNK) signalling, and interacts with the cysteines in IKKβ—IκBα. | Reddy et al. [95] |
LPS-activated RAW264.7 cells | 0.3 or 0.6 μM | Treatment decreases iNOS and COX-2 protein expression levels, induces HO-1 protein expression, and suppresses 0IL-1 and TNF-α mRNA levels, a synergistic effect with nobiletin. | Guo et al. [96] |
LPS-stimulated RAW264.7 macrophages | 1 μM | Treatment inhibits NO production, reduces the expression levels of pro-inflammatory proteins involving the NF-κB pathway, as well as STAT3 activation, suppresses inflammatory proteins such as iNOS, COX-2, IL-6, and IL-1β, reduces the ROS level in cells, and increases the expression of Nrf2 and HO-1, a synergistic effect with luteolin. | Rakariyatham et al. [97] |
RAW264.7 and mouse bone marrow-derived macrophages activated with anthrax lethal toxin | 50 μM | Treatment inhibits pyroptosis, IL-1β maturation for the NLRP1b, NLRP3, NAIP5/NLRC4, and AIM2 inflammasomes, without affecting caspase-1 enzymatic activity—an effect not altered by ROS scavengers (NAC)—and the NLRP3 inflammasome in an Nrf2-independent manner (Nrf2 (−/−) studies). | Greaney et al. [98] |
Human THP-1-derived macrophages and primary human PBMC-derived macrophage with a Staphylococcus aureus infection | 10 µM | Treatment suppresses S. aureus-induced transcriptional expression of genes coding for the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as for the M1 markers C-CR7, IL-23, and iNOS, and inhibits p38 and JNK phosphorylation. | Deramaudt et al. [99] |
THP-1 macrophages treated with Aβ1-42 | 5 μM | Treatment inhibits the induced intracellular Ca2+ level, rescues the decrease in MerTK expression by blocking NF-κB nuclear translocation, and decreases IL-1β and TNF-α production upon Aβ1-42 stimulation. This effect is abolished by the siRNA-mediated knockdown of MerTK. | Jhang et al. [100] |
Primary human T-cells from healthy donors or patients with rheumatoid arthritis | 5 or 10 μM | Treatment inhibits the activation of untransformed human T-cells and downregulates the expression of the transcription factor RORγt and TH17-related cytokines (IL-17A, IL-17F, and IL-22); this effect is reversed by exogenously supplied GSH and by treatment with NAC. | Liang et al. [101] |
PMA- and a23187 (PMACI)-stimulated human mast cells (HMC-1 cells) | 0.1, 1, or 10 μM | Treatment inhibits the levels of inflammatory mediators including TSLP, TNF-α, IL-1β, IL-6, and IL-8, suppresses the translocation of NF-κBp65 into the nucleus and the phosphorylation of IκBα in the cytosol, and downregulates the phosphorylation of MAPK. | Jeon et al. [102] |
Cellular Model and Treatment | Concentration | Key Findings | Reference |
---|---|---|---|
LPS-stimulated mouse microglial BV2 cells | 5 µM | Treatment improves mitochondrial impairment and neuroinflammation (levels of IL-1β, TNF-α, and NF-κB activity)—an effect dependent on HO-1 induction (confirmed by the inhibitor and the sRNA of Nrf2 studies). | Brasil et al. [103] |
EOC-20 microglial cells treated with Aβ oligomers | 5 µM | Treatment reverses the decrease in phagocytic (fluorescent latex beads) activity. | Chilakala et al. [104] |
LPS-activated N9 murine microglial cells | 5 µM | Treatment induces the translocation of Nrf2 to the nucleus and activates the ERK1/2 pathway. The siRNA-mediated knockdown of Nrf2 partly abolishes the reduction in ROS, NO, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), induces the Mox phenotype, inhibits microglia-mediated neurotoxicity (SH-SY5Y cells), suppresses the induced expression of miRNA and miR-155 expression, and inhibits the NF-κB, c-Fos, and c-Jun subunits of AP-1 activities. | Eren et al. [105] |
Primary astroglial cultures of rat or mouse cerebral cortices | 10 μM | Treatment suppresses ROS and NO production after glutathione depletion and increases HO-1 gene expression. | Iizumi et al. [106] |
Primary cultures of cortical astrocytes from the newborn pig brain treated with TNF-α and an excitotoxic glutamate | 1 µM | Treatment inhibits Nox4 activity, reduces ROS production, and suppresses apoptosis. | Liu et al. [107] |
Senescent astrocytes isolated from Wistar newborn rats | 1 μM | Treatment decreases IL-1α secretion while increasing IL-10. | Maciel-Barón et al. [108] |
LPS-stimulated primary glial cell cultures | ITH12674—melatonin-sulforaphane hybrid—10 μM | Treatment reduces inflammatory markers, NO release, and iNOS expression, suppresses IL-1β and TNFα release, and increases the Nrf2-dependent enzymes (GCLM and HO-1). The effect is Nrf2-dependent, as evidenced by Nrf2 knockout (NRF2−/−), but not totally abolished. It also prevents NF-κB translocation and reduces the overexpression of P-p38 and the binding of LPS to the TLR4/MD2 dimer. | Michalska et al. [109] |
BV2 microglial cells treated with MGO-derived AGEs | 5 or 10 µM | Treatment inhibits the formation of MGO-AGEs, suppresses the production of ROS, iNOS, and COX-2 and NLRP3 protein expression, lowers the expression levels of the AGE receptor (RAGE), inhibits GSK3β activation and p38 phosphorylation (but not ERK and JNK phosphorylation), and inhibits NF-κB activation/translocation and cytokine (TNF-α and IL-6) production. | Subedi et al. [110] |
LPS-activated primary co-cultures of rat microglial and astroglial cells | 1–15 µM | Treatment suppresses the release of TNF-α, IL-1β, IL-6, and NO, increases the mRNA level and the activity of NQO-1, and increases the cellular glutathione content. | Wierinck et al. [111] |
LPS-stimulated primary cultured microglia | 30 µM | Treatment reduces the mRNA levels of TNF-α and IL-1β while increasing IL-10—an effect abolished by Akt inhibition and also conformed in vivo. | Wu et al. [112] |
BV-2 microglia stimulated by LPS | 5–15 µM | Treatment suppresses TNF-α, IL-1β, IL-6, and iNOS and blocks MAPKs (p38, JNK) and NF-κB p65. | Qin et al. [113] |
Müller cells (glial cells found in the human retina) exposed to 25 mM glucose | 2.5 µM | Treatment reduces the generation of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), enhances the activity of antioxidant enzymes (GSH, SOD, and CAT) and the nuclear accumulation of Nrf2, and increases the expression of HO-1 and NQO1. | Li et al. [51] |
Primary rat microglia and the murine microglia cell line BV2 stimulated by LPS | 1 µM | Treatment decreases NO production and inhibits the induced ERK1/2 and JNK phosphorylation and NF-κB and AP-1 activation. | Brandenburg, et al. [114] |
LPS-activated BV2 microglia cells | 5 or 10 µM | Treatment inhibits NO production and iNOS and COX-2 expression, the phosphorylation of JNK, ERK, and p38, NF-κB and AP-1, and the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and PGE2 and increases Nrf2 and HO-1. | Subedi et al. [115] |
C6 astrocyte cell line stimulated with LPS | 5 µM | Treatment increases the mRNA levels of HO1, suppresses NADPH oxidase activity while enhancing SOD activity and the glutathione metabolism, suppresses the mRNA expression of TNF-α, IL-1β, p65 NF-κB, COX-2, and iNOS, increases the IL-10 level, suppresses TLR (mRNA) expression and NOX activity, reduces the ROS levels while increasing the activities of SOD, CAT, and GPx, GCL activity, GCL mRNA expression, and the GSH levels—an effect dependent on HO-1 (inhibitor studies). | Bobermin et al. [116] |
Cellular Model and Treatment | Concentration | Key Findings | Reference |
---|---|---|---|
HUVECs treated with serum from patients with severe COVID-19 | 1 µM | Treatment abolishes increased ROS generation via enhancing Nrf2 activity and partially restores the reduced NO level. | Rodrigues et al. [117] |
Angiotensin II-mediated HUVEC injury | 2 μM | Treatment inhibits oxidative stress and mitochondria-related apoptosis—effects mediated via Nrf2. | Zhang et al. [118] |
AGE-stimulated HUVECs and -i rat aorta | 1.6 μM | Treatment suppresses induced MCP-1, ICAM-1, and VCAM-1 gene expression and inhibits THP-1 cell adhesion to activated HUVECs, oxidative stress generation, and NADPH oxidase activation. | Matsui et al. [119] |
LPS-stimulated HUVECs | 1, 10, or 20 µM | Treatment prevents induced ICAM-1 and VCAM-1 expression, inhibits the induced phosphorylation of STAT3—an effect similar can be obtained with the STAT3 inhibitor (Stattic) or the STAT3 small interfering RNA— and suppresses THP-1 monocyte adhesion to activated HUVECs. | Cho et al. [120] |
TNF-α-stimulated HUVECs | 0.5–8 μM | Treatment suppresses MCP-1, IL-8, soluble VCAM-1, and soluble E-selectin production and inhibits NF-κB transcriptional activity, IκBα degradation, NF-κB p65 nuclear translocation, and monocyte adhesion to activated HUVECs. | Nallasamy et al. [121,122] |
PMA-, TNF-α-, IL-1β-, and caecal ligation-stimulated HUVECs | 5–30 μM | Treatment inhibits the induced endothelial cell protein C receptor (EPCR) shedding and the expression and activity of PMA-induced TACE and reduces the induced phosphorylation of p38, ERK 1/2, and JNK. | Ku et al. [123] |
ECV304 endothelial cells stimulated with TNF-α | 2.5–10 µM | Treatment inhibits the expression of ICAM-1, the production of IL-1β, IL-6, and IL-8, the phosphorylation of IκB kinase (IKK) and IκBα, Rho A, ROCK, ERK1/2, and the plasminogen activator inhibitor-1 levels. | Ku and Bae [124] |
HUVEC treated with TNF-α | 10–50 μM | Treatment inhibits the production of thrombin and FXa, thrombin-catalysed fibrin polymerisation, and platelet aggregation and suppresses the activity of thrombin and FXa. | Ku and Bae [124] |
LPS-stimulated ECV304 | 10 μM | Treatment inhibits the translocation of NF-κB into the nucleus, decreases the phosphorylation of ERK, JNK, and p38 MAPK—a main effect via p38 MAPK and JNK (confirmed by gene blockade studies)—and downregulates the LPS receptor (TLR-4). | Shan et al. [125] |
TNF-α-stimulated HUVECs and human aortic endothelial cells | 10 μM | Treatment inhibits the induced expression of endothelial lipase expression (mRNA and protein), the induced phosphorylation of IκB kinase (IKK) 1/2 and IκB-α, and the binding of NF-κB to binding sites in the LIPG gene. | Kivelä et al. [126] |
Human saphenous vein endothelial cell hypoxia-reoxygenation model | 5 μM | Treatment increases Nrf2 protein expression, SOD activity, and the mRNA levels of SOD1/2 and NQO-1 and suppresses p65 and p-p65 expression and the level of TNF-α, IL-1β, IL-6, and MCP-1 mRNA; this effect is dependent on Nrf2 (knockout studies). | Fukunaga et al. [127] |
Human brain endothelial cell line (HBMEC-3) | 10 µM | Treatment suppresses E-selectin and VCAM-1 expression, activates Nrf2 and its nuclear translocation, and suppresses ROS production. | Holloway et al. [128] |
Human aortic endothelial cells | 1–4 μM | Treatment suppresses TNF-α-induced MCP-1 and VCAM-1 mRNA and protein levels but not ICAM-1 expression, and it inhibits the induced activation of p38 MAPK, but not JNK; this effect is not mediated via Nrf2 expression. | Chen et al. [129] |
Cellular Model and Treatment | Concentration | Key Findings | Reference |
---|---|---|---|
LPS-stimulated primary goat mammary epithelial cells | 1.25–5 µM | Treatment suppresses TNF-α, IL-1β, and IL-6 mRNA levels and the protein levels of COX-2 and iNOS, downregulates the phosphorylation levels of the IκBα and NF-κB p65 proteins, suppresses the ROS level while increasing the levels of the expression of phase II detoxifying enzymes including HO-1, NQO1, GCLC, and GCLM, induces autophagy, and promotes autophagosome formation. | Shao et al. [130] |
Bronchial epithelial IB3-1 cells exposed to the SARS-CoV-2 spike protein (S-protein) | 5 or 10 µM | Treatment inhibits mRNA and protein-level expression of IL-6 and IL-8; other cytokines and chemokines inhibited in terms of their protein level are PDGF, IL-9, G-CSF, GM-CSF, IFN-γ, MCP-1, and MIP-1β. | Gasparello et al. [131] |
Human bronchial epithelial cells exposed to particulate matter PM2.5 | 1–5 µM | Treatment suppresses ROS production and MDA level, improves cell viability, suppresses inflammatory mediator (IL-6 and IL-8) production, and increases the nuclear levels of Nrf2 and the cytoplasmic levels of HO-1. | Qin et al. [132] |
Human retinal pigment epithelial (ARPE-19) cells exposed to PM2.5 | 1 μM | Treatment improves cell viability, and reduces the ROS level, enhances SOD and CAT activities, and increases cell survival factor serum- and glucocorticoid-inducible kinase 1 (SGK1). | Sim et al. [133] |
Human retinal pigment epithelial (ARPE-19) cells exposed to blue light | 5 μM | Treatment improves cell viability; reduces oxidative stress, activates Nrf-2, HO-1, and thioredoxin-1, enhances the GSH levels—an effect abolished by the Nrf2 inhibitor (ML385)—inhibits ICAM-1 expression also induced by TNF-α,blocks NF-κB p65 nuclear translocation, and increases the protein expression of SIRT1 and PGC-1α gene expression. | Yang et al. [134] |
LPS-treated Caco-2 cells | 0.5, 1 or 5 μM | Treatment increases cell viability and abolishes apoptosis, reduces the ROS level, increases antioxidants (SOD, GPx, CAT, and total antioxidant capacity), suppresses the level of inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α), and upregulates phosphorylated AMPK, SIRT1, and PGC-1α. | Zhang and Wu [135] |
Human lung epithelial cells (BEAS-2B) exposed to cigarette smoke extract and particulate matter | 10 μM | Treatment suppresses ROS and cytokines and chemokines production such as IL-6, IL-8, IL-1β, MCP-1, TNF-α, and CXCL-1; it also enhances the nuclear transcriptional activity of Nrf2 as well as the mRNA levels of downstream genes (NQO1, HO-1, TXN, and TXNRD and suppresses the phosphorylation levels of ERK and JNK. | Son et al. [136] |
Human bronchial epithelial (BEAS-2B) cells exposed to diesel exhaust particles | 10 µM | Treatment activates (mRNA and genes) the Nrf2, NQO1, and HO-1 and increases autophagy marker p62 and LC3B through an Nrf2-mediated response (siRNA studies). | Frias et al. [137] |
Human sinonasal epithelial cell derived from patients stimulated by house dust mite | 10 μM | Treatment reverses epithelial cell junction protein ZO-1 and a decrease in transepithelial electrical resistance. | London et al. [138] |
Primary mouse and tracheal and human bronchial epithelial cells sensitised by allergens (house dust mite (HDM) or Alternaria alternata (ALT)) | 10–30 μM | Treatment suppresses IL-33, IL-17E, and IL-1α levels (also in vivo) and inhibits the activation of DUOX1, ROS formation, and EGFR activation. | Danyal et al. [139] |
Human mammary epithelial (MCF-10A) cells stimulated by TPA | 2.5, 12.5, or 25 μM | Treatment inhibits the expression of COX-2 (protein and mRNA), which was NF-κB-dependent, inhibits NF-κB (by modulating the phosphorylation and the subsequent degradation of IκBα) and IκB kinase (IKK) activation—effects confirmed by transfection and specific siRNA studies. The TPA effect is mediated by ERK1/2 signalling, which is inhibited. | Kim et al. [140] |
Retinal pigment epithelial (RPE) 19 cell exposed to H2O2 | 10 μM | Treatment enhances cell viability and gene (microarray mRNA) expression of NQO1, sulphiredoxin 1 homolog (SRXN1), GCLM, the thioredoxin-interacting protein (TXNIP), CCL2, bradykinin receptor B1, TXN 1, and transcription factor Nrf2, upregulates antioxidant enzymes (NQO1; SRXN1, GCLM, Trx1, and SRXN1), and enhances the nuclear translocation of Nrf2. | Ye et al. [141] |
Human nasal epithelial (HEK293T) cell exposed to influenza A virus | 1 μM | Treatment decreases viral entry and replication and increases antiviral mediators/responses—RIG-I, IFN-β, and MxA—at the baseline, in the absence of infection. There is an inverse relationship between Nrf2 expression and viral entry/replication. | Kesic et al. [142] |
BEAS-2B cells exposed to cigarette smoke extract | 5 μM | Treatment enhances the translocation of Nrf2, increases the Nrf2-dependent gene expression of NQO1, GCLM, and HO-1, and inhibits IL-8 and MCP-1 production. | Starrett et al., 2011 [143] |
Human airway epithelial (NCI-H292) cells | 10–30 µM | Treatment downregulates MUC5AC synthesis by inhibiting ROS generation and augmenting leukocyte proteinase inhibitor production—an Nrf2-dependent effect (confirmed via an siRNA study). | Qi et al. [144] |
Airway epithelial (BEAS-2B) cells stimulated by diesel particles | 0.3–6.25 µM | Treatment increases phase II enzyme genes GSTM1 and NQO1, increases GST activity, and suppresses IL-1β, IL-8, and GM-CSF. | Ritz et al. [145] |
LPS-stimulated HepG2 cells | 2 μM | Treatment suppressed IL-6 and hepcidin production. | Al-Bakheit et al. [146] |
Cellular Model and Treatment | Concentration | Key Findings | Reference |
---|---|---|---|
Mouse C2C12 embryonic myoblasts treated by LPS | 1–10 μM | Treatment reduces IL-1β secretion, ROS production, and the levels of TLR4, NLRP3, apoptosis-associated speck-like protein, and Caspase-1. | Wang et al. [147] |
C2C12 myotubes in palmitic acid-induced oxidative stress and inflammation | 5–10 μM | Treatment suppresses IL-6 and TNF-α, enhances Nrf2)/haem oxygenase-1(HO-1) pathway protein, and suppresses CX3CL1 and CX3CR1 expression. | Faridvand et al. [148] |
VSMCs stimulated by TNF-α | 5 μM | Treatment inhibits IκBα degradation and NF-κB p65, ICAM-1 mRNA, andVCAM-1, p65 (and translocation), and GATA6 expression, and reduces the binding of GATA6 to the VCAM-1 promoter. | Kwon et al. [149] |
Cultured mouse vascular smooth muscle cell lines stimulated by TNF-α | 8.5–42.6 μM | Treatment inhibits ROS production and the activation of p38, ERK, and JNK, inhibits NK-κB, AP-1, ΙκΒ kinase activation, the degradation of ΙκΒα, and the nuclear translocation of p65 NF-κB, decreases the c-Jun and c-Fos protein levels, and inhibits VCAM-1 expression. | Kim et al. [150] |
Oxyhaemoglobin-induced inflammation in rat VSMCs | 5 μM | Treatment enhances the activity of the Nrf2-ARE pathway and suppresses cytokine (IL-1β, IL-6, and TNF-α) release. | Zhao et al. [151] |
Chondrocytes from patients with knee osteoarthritis stimulated with IL-1β or TNF-α | 5 μM | Treatment inhibits mPGES, COX-2, and iNOS at the mRNA and protein levels and proteoglycan and type II collagen degradation products’ release in explant cultures and inhibits the production of PGE2 and NO. | Kim et al. [152] |
Primary human articular chondrocytes, in fibroblast-like synovial cells and the SW-1353 cell line stimulated with IL-1 | 10 μM | Treatment attenuates NF-κB signalling at least through the inhibition of DNA binding—cytokine-induced destruction of bovine nasal cartilage at both the proteoglycan and collagen breakdown levels. Nrf2 knockdown reduces HMOX1 expression but not MMP1 expression, induces the phosphorylation of JNK and p38 MAPK, and inhibits the transcription of NF-κB. | Davidson et al. [153] |
LPS-treated retinal pigment epithelial (ARPE-19) cells | 5–30 μM | Treatment downregulates PWRN2 and inhibits NF-κB activation. | Song et al. [154] |
Synoviocytes treated with TNF-α | 2.5 μM | Treatment inhibits NF-κB activity and IL-1β and IL-6 secretion, activates Nrf2, and induces apoptosis in TNF-α-activated synoviocytes. | Fragoulis et al. [155] |
Human embryonic kidney 293T (HEK293T) cells transfected with NOD2 | 5 or 10 μM | Treatment suppresses ligand-induced NF-κB activity. Note: NOD2 functions as an intracellular PRR for muramyl dipeptide. | Folkard et al. [156] |
IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts | 20 µM and higher | Treatment inhibits cell proliferation and the induced expression of MMP-1, MMP-3, and COX-2 mRNA and proteins and suppresses PGE2 production, the phosphorylation of ERK-1/2, p-38, and JNK, and the activation of NF-κB. | Choi et al. [157] |
Mouse pancreatic acinar cells | 10 μM | Treatment increases Nrf2 expression and Nrf2-regulated redox genes (NQO1, HO-1, SOD1, and GPx1), suppresses the cerulein-induced activation of the NLRP3 inflammasome and suppresses NF-κB activation and modulated NF-κB-responsive cytokine (TNF-α, IL-1β, and IL-6) expression (mRNA). | Dong et al. [158] |
Ex vivo human full-thickness skin combined with in vitro HaCaT keratinocytes—UV exposure | 5 or 10 μM | Treatment increases Nrf2 activity and Nrf2-dependent gene expression (GCLM, HO-1, NQO1) and reverses the reduced level of CAT, cell death, and structural damage. | Ernst et al. [159] |
HaCaT, human keratinocyte cells activated by IFN-γ and TNF-α | 10 or 20 μM | Treatment inhibits induced NF-κB and STAT1 activation and suppresses induced TARC/CCL17 and MDC/CCL22 production through the induction of HO-1 (effect completely abolished by HO-1 siRNA). | Jeong et al. [160] |
Hydrogen peroxide-stimulated human neuroblastoma SH-SY5Y cells | 5 μM | Treatment reduces the secretion of IL-1β and TNF-α, as well as the levels of COX-2, and decreases the activity of NF-κB and the p65 NF-κB subunit in the cell nucleus—an effect abolished by the HO-1 inhibitor and the silencing (siRNA) Nrf2. | de Oliveira et al. [161] |
N2a/APPswe cells—cellular model of AD | 1.25 or 2.5 μM | Treatment decreases the levels of Aβ1-40 and Aβ1-42, reduces the level of ROS, IL-1β, and IL-6, increases SOD, reduces phosphorylated NF-κBp65 COX-2 (and the iNOS protein), upregulates the expression of Nrf2 and its nuclear translocation, and decreases the DNA demethylation levels of the Nrf2 promoter. | Zhao et al. [162] |
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Habtemariam, S. Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane. Biomedicines 2024, 12, 1169. https://doi.org/10.3390/biomedicines12061169
Habtemariam S. Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane. Biomedicines. 2024; 12(6):1169. https://doi.org/10.3390/biomedicines12061169
Chicago/Turabian StyleHabtemariam, Solomon. 2024. "Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane" Biomedicines 12, no. 6: 1169. https://doi.org/10.3390/biomedicines12061169
APA StyleHabtemariam, S. (2024). Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane. Biomedicines, 12(6), 1169. https://doi.org/10.3390/biomedicines12061169