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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.

SUBMITTER: Li J

PROVIDER: S-EPMC8450503 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In Indonesia, there are many types of citrus where parts of the fruit, leaves, and peel can be utilized as food, drinks, spices, and medicine. This research aims to determine the phytochemical characteristics, antioxidant activities, and anti-inflammatory activity through inhibition of NF-κB and sEH, and the main phytoconstituents of three types of citrus fruits that are commonly used as herbs in Indonesia. The flesh and peel of Citrus amblycarpa/CAm, C. aurantiifolia/CAu, and C. hystrix/CH were extracted by Ultrasound-Assisted Extraction (UAE) with 70 % ethanol and then concentrated. All extracts were tested for total flavonoid content (TFC), total polyphenolic content (TPC), chemical constituents using LCMS, and DPPH radical scavenging activity. Molecular docking tests of 33 compounds containing CAm, CAu, and CH fruit peels from the literature study against NF-κB (Nuclear Factor Kappa Beta) and sEH (Soluble Epoxide Hydrolase) were also conducted. The TFC in fruit peels was 13.47-17.34 mg QE/g extract, and in flesh was 1.35-2.51 mg QE/g extract. The TPC in fruit peels was 4.28-6.3 mg GAE/g extract, and in flesh was 0.85-2.09 mg GAE/g extract. The IC50 values of antioxidant activity on fruit peel were 74.01-168.54 µg/mL; and flesh 185.62-2669 µg/mL. CAu peels provided the highest antioxidant activity and polyphenol content. The LC-MS/MS test on citrus peels shows the main chemical compounds: naringin (C27H32O14), naringenin (C15H12O5), hesperidin (C28H34O15), and hesperitin (C16H14O6). Molecular docking shows that naringin and neohesperidin predicted inhibit NF-κB, and hesperidin, neohesperidin, narirutin, naringin, apigenin, kaempferol, quercetin, rutin, eriocitrin, sinensetin, and vitamin A predicted can inhibit sEH enzyme. All citrus peel has stronger antioxidant activity and more flavonoids and phenolics than the flesh. Naringin and neohesperidin can inhibit NF-κB and sEH enzymes. The main flavonoid contents of the citrus peels and presumed to have activity are hesperidin and naringin. These flavonoids and their glycosides can be used as marker phytoconstituents in the quality assurance of pharmaceutical products.

Project description:BackgroundIt has been demonstrated that vitamin D deficiency is associated with an increased risk of patients developing lumbar disc herniation. However, intervertebral disc degeneration caused by active vitamin D deficiency has not been reported. Thus, the purpose of this study was to e investigate the role and mechanism of 1,25-dihydroxyvitamin D (1,25(OH)2D) insufficiency in promoting intervertebral disc degeneration.MethodsThe phenotypes of intervertebral discs were compared in wild-type mice and mice with heterozygous deletion of 1α-hydroxylase [1α(OH)ase+/-] at 8 mouths of age using iconography, histology and molecular biology. A mouse model that overexpressed Sirt1 in mesenchymal stem cells on a 1α(OH)ase+/- background (Sirt1Tg/1α(OH)ase+/-) was generated by crossing Prx1-Sirt1 transgenic mice with 1α(OH)ase+/- mice and comparing their intervertebral disc phenotypes with those of Sirt1Tg, 1α(OH)ase+/- and wild-type littermates at 8 months of age. A vitamin D receptor (VDR)-deficient cellular model was generated by knock-down of endogenous VDR using Ad-siVDR transfection into nucleus pulposus cells; VDR-deficient nucleus pulposus cells were then treated with or without resveratrol. The interactions between Sirt1 and acetylated p65, and p65 nuclear localization, were examined using co-immunoprecipitation, Western blots and immunofluorescence staining. VDR-deficient nucleus pulposus cells were also treated with 1,25(OH)2D3, or resveratrol or 1,25(OH)2D3 plus Ex527 (an inhibitor of Sirt1). Effects on Sirt1 expression, cell proliferation, cell senescence, extracellular matrix protein synthesis and degradation, nuclear factor-κB (NF-κB), and expression of inflammatory molecules, were examined, using immunofluorescence staining, Western blots and real-time RT-PCR.Results1,25(OH)2D insufficiency accelerated intervertebral disc degeneration by reducing extracellular matrix protein synthesis and enhancing extracellular matrix protein degradation with reduced Sirt1 expression in nucleus pulposus tissues. Overexpression of Sirt1 in MSCs protected against 1,25(OH)2D deficiency-induced intervertebral disc degeneration by decreasing acetylation and phosphorylation of p65 and inhibiting the NF-κB inflammatory pathway. VDR or resveratrol activated Sirt1 to deacetylate p65 and inhibit its nuclear translocation into nucleus pulposus cells. Knockdown of VDR decreased VDR expression and significantly reduced the proliferation and extracellular matrix protein synthesis of nucleus pulposus cells, significantly increased the senescence of nucleus pulposus cells and significantly downregulated Sirt1 expression, and upregulated matrix metallopeptidase 13 (MMP13), tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) expression; the ratios of acetylated and phosphorylated p65/p65 in nucleus pulposus cells were also increased. Treatment of nucleus pulposus cells with VDR reduction using 1,25(OH)2D3 or resveratrol partially rescued the degeneration phenotypes, by up-regulating Sirt1 expression and inhibiting NF-κB inflammatory pathway; these effects in nucleus pulposus cells were blocked by inhibition of Sirt1.ConclusionResults from this study indicate that the 1,25(OH)2D/VDR pathway can prevent the degeneration of nucleus pulposus cells by inhibiting the NF-κB inflammatory pathway mediated by Sirt1.The Translational Potential of This Article: This study provides new insights into the use of 1,25(OH)2D3 to prevent and treat intervertebral disc degeneration caused by vitamin D deficiency.

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

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