Nifedipine inhibits oxidative stress and ameliorates osteoarthritis by activating the nuclear factor erythroid-2-related factor 2 pathway.

Nifedipine is a voltage-gated calcium channel inhibitor widely used in the treatment of hypertension. Nifedipine has been reported to have antioxidant and anti-apoptotic effects and promotes cell proliferation. However, the effects of nifedipine on oxidative stress and apoptosis in osteoarthritic (OA) chondrocytes are still unclear. In this study, we sought to investigate whether nifedipine alleviates oxidative stress and apoptosis in OA through nuclear factor erythroid-2-related factor 2 (Nrf2) activation. The cytotoxicity of nifedipine against human chondrocytes was detected using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) kit, whereas mRNA and protein expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The oxidative stress level was analyzed by measuring reactive oxygen species (ROS), glutathione peroxidase (GSH-px), catalase (CAT) and superoxide dismutase (SOD) activities. The role of Nrf2 in the effect of nifedipine on OA was analyzed using an Nrf2 inhibitor brusatol (BR). The result showed that nifedipine inhibited the expression of matrix metalloprotein(MMP)-13, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, inducible nitric oxide (NO) synthase (iNOS), and prostaglandin E2 (PGE2), as well as reduced ROS production in human OA chondrocytes, which was partially reversed by BR. Nifedipine prevented cartilage degeneration and contributed to the expression of Nrf-2 in chondrocytes. These results indicate that nifedipine inhibited inflammation and oxidative stress in chondrocytes via activation of Nrf-2/HO-1 signaling.

TREM2 Attenuates Aß1-42-Mediated Neuroinflammation in BV-2 Cells by Downregulating TLR Signaling.

The pathogenesis of late-onset Alzheimer's disease (LOAD) mainly involves abnormal accumulation of extracellular ß-amyloid (Aß) and the consequent neurotoxic effects. The triggering receptor expressed on myeloid cells 2 (TREM2) gene is associated with the pathogenesis of LOAD and plays important roles in mediating the phagocytosis of Aß by microglia and regulating inflammation in central nervous system. However, the exact mechanisms of these processes have not yet been clarified. In this study, we investigated the mechanism by which TREM2 regulates neuroinflammation and promotes Aß1-42 clearance by BV-2 cells and further elucidated the underlying molecular mechanisms. We either silenced or overexpressed TREM2 in BV-2 cells and evaluated the cell viability, Aß1-42 content, and expression of inflammatory markers (IL-1ß, IL-6, and TNF-α). TREM2 overexpression up-regulated cell activity, promoted clearance of Aß1-42 by BV-2 cells, and down-regulated expression of the inflammatory factors. In addition, TREM2 overexpression downregulation the expression of the TLR family (TLR2, TLR4 and TLR6) in BV-2 cells. Moreover, LPS, as an agonist of the TLR family, up-regulated the expression of inflammatory cytokines (IL-1ß, TNF-α, and IL-6) in BV-2 cells overexpressing TREM2. In conclusion, TREM2 promoted clearance of Aß1-42 by BV-2 cells and restored BV-2 cell viability from Aß1-42-mediated neuroinflammation by downregulating TLRs. These findings suggest that TREM2 may be a target for LOAD therapy.

Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND/AIMS: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/ß-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. METHODS: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1ß)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1ß, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/ß-catenin signaling pathway, suggesting that it might serve as a Wnt/ß-catenin antagonist to reduce inflammation and prevent cartilage degradation. CONCLUSION: In conclusion, ART alleviates IL-1ß-mediated inflammatory response and OA progression by regulating the Wnt/ß-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.