BackgroundLysophosphatidic acid (LPA) is an active compound of oxidized low-density lipoprotein that serves as an endogenous TLR4 ligand. Ligand activation of TLR4 activates nuclear factor-kappaB (NF-κB) and the transcription of NF-κB-regulated inflammatory cytokines, which are involved in the development of atherosclerosis. MMP9 is a member of the MMP family and can affect plaque stability. However, the mechanism responsible for the effect of LPA on the expression and activation of MMP9 has not been fully elucidated. In the present study we examined the effect of LPA on MMP9 expression and activity in THP-1 cells and the involvement of Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway in this effect.Material/MethodsHuman THP-1 cells were treated with 0–10 μM LPA for 4 h, or treated with 1 μM LPA for 0–8 h, and were then transfected with TLR4-specific siRNA or treated with 20 μg/ml cafestol acid phenethyl ester (CAPE, an NF-κB inhibitor). MMP9 mRNA and protein levels were measured by quantitative RT-PCR and Western blot analysis, respectively, and MMP9 activity was measured by zymography.ResultsLPA upregulated MMP9 mRNA and protein levels and MMP9 activity in THP-1 cells in both concentration- and time-dependent manners. Transfection of cells with TLR4-siRNA-2 or treatment with CAPE significantly inhibited the upregulated MMP9 expression and activation. This inhibition was further enhanced by combining the TLR4-siRNA-2 transfection and CAPE pretreatment.ConclusionsLPA can promote MMP9 expression and enhance MMP9 activity in THP-1 cells, in part via the TLR4/NF-κB signaling pathway.
Toll-like receptors (TLRs) are major receptors that mediate the innate immune and inflammatory responses, of which TLR4 has been found most closely related to human atherosclerosis. After ligands are polymerized and activated by TLR, the mitogen-activated protein kinase and nuclear factor-κB (NF-κB) pathways are activated, leading to promotion of NF-κB-regulated transcription of inflammatory factors, thus playing a role in the physiological and pathological processes in atherosclerosis. Oxidized lipoproteins or their components, oxidized lipids, have been confirmed as endogenous TLR receptors. Lysophosphatidic acid (LPA) is an active component of low-density lipoprotein that induces vascular endothelial lesions. However, the mechanism of the TLR4/NF-κB signaling system involved in LPA-induced atherosclerosis has not been fully elucidated. In this study, we investigated the effects of LPA on TLR4 expression, nuclear translocation of NF-κB p65 subunit, and changes in the cytokine tumor necrosis factor α (TNF-α) in human THP-1 cells. LPA upregulated expression of the TLR4 mRNA and protein in THP-1 cells in a dose- and time-dependent manner, induced NF-κB p65 activation synchronously in THP-1 cells, and increased TNF-α secretion. After TLR4 was blocked using TLR4 monoclonal antibody, NF-κB p65 expression and TNF-α secretion were inhibited significantly. These data suggest that LPA can significantly upregulate TLR4 expression and promote NF-κB activation and proinflammatory cytokine secretion in THP-1 cells; it is possible that the TLR4/NF-κB signaling pathway mediates the atherogenic effect of LPA.
Objective. In recent years, public health experts have concluded that the impact of osteoarthritis is equal in magnitude to that of cardiovascular disease. Osteoarthritis of the knee is prevalent in the elderly population; however, there are currently no effective treatments for this condition. In this study, we investigated the efficacy of “meridian-sinew release,” a newly developed technique which entails using a meridian-sinew scope and a meridian-sinew knife to treat osteoarthritis of the knee. Methods. Patients (N = 90) with knee osteoarthritis were prospectively randomized to meridian-sinew release therapy, acupuncture therapy, or drug therapy groups, respectively. Outcome evaluation included pain, stiffness, physiological function, total symptom score, and overall changes in the condition. Results. After 12 weeks, patients' general assessment (GA) and doctors' general assessment (GA) of the condition were not significantly different among the three groups. However, significant differences in primary endpoint pain, joint stiffness, and total symptom score were found between the meridian-sinew group and the acupuncture group and between the meridian-sinew group and the control group (P < 0.05). No adverse events occurred during the trial. Conclusion. Our study suggests that meridian-sinew release therapy can improve knee osteoarthritis, alleviate joint pain, and improve functional movement disorder. It is a safe and effective treatment for knee osteoarthritis.
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