TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies

Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression

DataSheet1_Mesoporous nanoplatform integrating photothermal effect and enhanced drug delivery to treat breast cancer bone metastasis.docx

Bone metastatic breast cancer has severely threatened the survival and life quality of patients. Due to the suboptimal efficacy of anti-metastatic chemotherapeutic drugs and the complicated bone marrow microenvironments, effective treatment of metastatic breast cancer remains challenging for traditional clinical approaches. In this work, we developed a mesoporous nanoplatform (m-CuS-PEG) with the co-loading of CuS nanodots and a chemotherapeutic drug cisplatin for the combined photothermal-chemotherapy of bone-metastasized breast cancer. The CuS nanodots were decorated onto mesoporous silica (m-SiO2) surface with dendritic mesoporous channels, into which the cisplatin was accommodated. The carboxyl-terminated poly (ethylene glycol) (PEG) was further functionalized onto the surface to obtain the functional nanoplatform m-CuS-PEG. The drug release of the loaded cisplatin exhibited pH- and thermal-dual responsive manner. The attached CuS nanodots rendered the mesoporous nanoplatform with high photothermal conversion ability. Upon irradiation with a near-infrared laser in the second near-infrared (NIR-II) window, m-CuS-PEG dispersions exhibited rapid temperature elevation and high photostability. The results revealed that m-CuS-PEG had excellent biocompatibility. The cisplatin-loaded m-CuS-PEG not only showed superior cancer cell-killing effects, but also significantly inhibit the growth of metastatic tumors. The tumor-induced bone destruction was also dramatically attenuated by the mesoporous nanoplatform-mediated combined therapy. Overall, the developed functional nanoplatform integrates photothermal therapy and efficient chemotherapeutic drug delivery to offer an alternative approach for combating breast cancer bone metastasis.</p