Visfatin significantly induced apoptosis and superoxide anion production, increased miR-34a, miR-181a, superoxide dismutase (SOD)-2, catalase (CAT), NRF2 and decreased BCL2 gene and protein expression in OA chondrocytes.
In order to test the hypothesis that SA is protective against the development of osteoarthritis (OA), primary mouse chondrocytes were treated <i>in vitro</i> with SA and the promoter transactivation activity of heme oxygenase 1 (HO-1), nuclear translocation of Nrf2, and protein expression of HO-1 were assayed.
The finding in mice that deletion of SOD2 or the anti-oxidant gene transcriptional regulator nuclear factor-erythroid 2- related factor (Nrf2) result in more severe OA, while overexpression or treatment with mitochondrial targeted anti-oxidants reduces OA, further support a role for excessive ROS in the pathogenesis of OA.
DC32 remarkably inhibited the activation of ERK and NF-κB pathway, increased the expression of Nrf2 and HO-1 in cultured OA-FLSs detected by western blot.
In conclusion, this study has demonstrated that SIN inhibits the IL-1β-induced inflammatory response and cartilage destruction by activating the Nrf2/HO-1 signaling pathway and inhibiting the NF-κB signaling pathway in mouse chondrocytes, suggesting a new use for SIN in the treatment of OA.
Meanwhile, specific inhibition of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) level by short-interfering RNA (siRNA) strongly reversed the anti-inflammatory and chondroprotective effects of PD in human OA chondrocytes.
Altogether, we concluded that the protective effect of BRD4 inhibition against oxidative stress-mediated apoptosis and cartilage matrix degeneration occurred through Nrf2-heme oxygenase-1 signaling, implying that BRD4 inhibition may be a more effective therapeutic strategy against osteoarthritis.
Importantly, Nrf2 over-expression activated ERK1/2 and its downstream targets-ELK1, P70S6K and P90RSK and suppressed the IL-1β-induced apoptosis whereas inhibition of ERK1/2 activation abrogated the protective effects of Nrf2 in OA chondrocytes.
Inducible nitric oxide synthase, nuclear factor (NF)‑κB, phosphorylated‑(p)‑AMP‑activated protein kinase and sirtuin 1 protein expression were significantly suppressed and heme oxygenase 1 (HO‑1) and nuclear factor erythroid 2‑related factor 2 (Nrf‑2) protein expression was stimulated in rats with OA treated with resveratrol.
Compared to the control, OA-treatment led to a result as follows: (1) increased the intracellular levels of TG and NO; (2) up-regulated the protein expression of SREBP-1C, PNPLA3, pJNK, CYP 2E1 and CYP 4A; (3) decreased the uptake of 2-NBDG; (4) down-regulated the protein expression of CFLAR, PPARα, PI3K, pAKT and NRF2.
This study indicates that AP exerts protection effects on oxidative stress via activation of the Keap1-Nrf2-Are pathway in chondrocytes injured by H<sub>2</sub> O<sub>2</sub> , which may be promising for the therapy of OA.
Reducing ROS production in the mitochondria, stimulating antioxidant gene expression through Nrf2 activation, or inhibiting specific redox-sensitive signaling proteins represent additional approaches to disease modification in osteoarthritis that require further investigation.
<i>Ex vivo</i> experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM <i>versus</i> non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) release was increased in samples with low HO-1 expression.
Genetic ablation of Nrf2 using specific siRNA, significantly abrogated the anti-inflammatory and chondroprotective potential of Wogonin in IL-1β-stimulated OA chondrocytes.
Piceatannol inhibits the IL-1β-induced inflammatory response in human osteoarthritic chondrocytes and ameliorates osteoarthritis in mice by activating Nrf2.