8-Methoxypsoralen has Anti-inflammatory and Antioxidant Roles in Osteoarthritis Through SIRT1/NF-κB Pathway

Abstract

Osteoarthritis (OA) is mainly manifested by joint pain, stiffness and mobility disorder, which is the main cause of pain and disability in middle-aged and elderly people. In this study, we aimed to explore the role and mechanism of 8-Methoxypsoralen (8-MOP) in the OA model both in vitro and in vivo. The rat chondrocytes were treated with IL-1β, and the proliferation, apoptosis, inflammatory reactions and oxidative stress responses were determined after treatment with different concentrations of 8-MOP. Real-time quantitative polymerase chain reaction (qRT-PCR) and/or Western blot were implemented to check the AMPK/SIRT1/NF-κB expression in chondrocytes. The NF-κB activity was determined by dual luciferase experiment. The pain threshold of OA rat model dealt with 8-MOP and/or the SIRT1 inhibitor EX527 was measured. Our results revealed that 8-MOP evidently reduced IL-1β-mediated apoptosis and inhibition of proliferation, and mitigated the expression of inflammatory cytokines and oxidative stress factors in chondrocytes. Additionally, 8-MOP promoted phosphorylated level of AMPKα, enhanced SIRT1 expression and inhibited the phosphorylation of NF-κB. After treatment with EX527, 8-MOP-mediated protective effects on chondrocytes were mostly reversed. In vivo, 8-MOP obviously improved the pain threshold in the OA rat model and reduced the injury and apoptosis of chondrocytes in the joints. In addition, 8-MOP relieved inflammatory and oxidative stress responses in the articular cartilage via enhancing SIRT1 and repressing NF-κB activation. After the treatment with EX527, the 8-MOP-mediated protective effects were distinctly weakened. In summary, our study testified that 8-MOP alleviates pain, inflammatory and oxidative stress responses in OA rats through the SIRT1/NF-κB pathway, which is expected to become a new reagent for clinical treatment of OA.

Safranal Treatment Induces Sirt1 Expression and Inhibits Endoplasmic Reticulum Stress in Mouse Chondrocytes and Alleviates Osteoarthritis Progression in a Mouse Model

“…Sirt1 is among the most popular target candidates of anti-ER stress, and there are numerous investigations examining this specific Sirt1 role. , Safranal mediates its effect via interaction with NLRP 3 , PTP1B, MAPK, and PI3K . However, little is known about the relationship between Sirt1 and safranal.…”

Melatonin Prevents Chondrocyte Matrix Degradation in Rats with Experimentally Induced Osteoarthritis by Inhibiting Nuclear Factor-κB via SIRT1

“…Peiqiang Su et al have suggested that MT may reverse IL-1β-induced impaired chondrogenic differentiation in BMSCs by attenuating activation of the NF-κB signaling pathway [ 67 ]. Several studies have found that targeting increased SIRT1 activity can inhibit NF-κB activation, reducing inflammation and oxidative stress in articular cartilage [ 35 , 68 ]. To examine the relationship between MT and the SIRT1/NF-κB pathway, we introduced the SIRT1 inhibitor EX527.…”

“…Chondrocytes containing DMEM-F12 and 10% FBS were in the control group and were induced with 10 ng/mL IL-1β for 24 h as the model group. The MT group was induced with 10 ng/mL IL-1β and different concentrations of MT (100, 200, 400, 800 ng/mL) for 24 h. The inhibitor group was treated with 10 ng/mL IL-1β, MT (800 ng/mL), and SIRT1 inhibitor EX527 (20 uM) for 24 h [ 35 ]. Half an hour after adding the lysate, it was transferred to a centrifuge tube and centrifuged at 12,000 rpm for 15 min at 4 °C, and the supernatants of each group were collected.…”

Xanthotoxin (8‐methoxypsoralen): A review of its chemistry, pharmacology, pharmacokinetics, and toxicity

“…In osteoarthritis model mice, they found that 8‐MOP promotes AMPKɑ phosphorylation and inhibits NF‐κB phosphorylation through SITR1/NF‐κB pathway and enhances sirtuin‐1 (SITR1) expression, thereby alleviating the symptoms of pain and oxidative stress response (Li, Zhang, Qiu, & Huang, 2021). Also, 8‐MOP reduced inflammatory factors in chondrocytes by interfering with IL‐1β‐mediated apoptosis.…”

“…A large number of studies have shown that coumarin components have good antioxidant capacity, and oxidative stress is characterized clinically by impairment in the production and removal of reactive oxygen species(Reilly, Troester, Tyner, Vitale, & Risher, 2010), resulting in diseases such as osteoarthritis and hyperglycemia(Bajerova, Adam, Bajer, & Ventura, 2014;Zhang, Wong, Zhang, Ni, & Li, 2014). The antioxidant pathway of XAT is mainly through scavenging free radicals and prooxidant metal ion chelation, while inhibiting enzyme activity to maintain the level of reactive oxygen species at routine levels.In osteoarthritis model mice, they found that 8-MOP promotes AMPKɑ phosphorylation and inhibits NF-κB phosphorylation through SITR1/NF-κB pathway and enhances sirtuin-1 (SITR1) expression, thereby alleviating the symptoms of pain and oxidative stress response(Li, Zhang, Qiu, & Huang, 2021). Also, 8-MOP reduced inflammatory factors in chondrocytes by interfering with IL-1βmediated apoptosis.…”