Cyclopropanyldehydrocostunolide LJ attenuates high glucose-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.

The aim of this research was to investigate the effects of cyclopropanyldehydrocostunolide (also named LJ), a derivative of sesquiterpene lactones (SLs), on high glucose (HG)-induced podocyte injury and the associated molecular mechanisms. Differentiated mouse podocytes were incubated in different treatments. The migration and albumin filtration of podocytes were examined by Transwell filters. The protein and mRNA levels of MCP-1 were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (q-PCR). Protein expression and phosphorylation were detected by western blot, and the nuclear translocation of NF-κB was performed with a confocal microscope. The gene expression of the receptor activator for NF-κB (RANK) was silenced by small interfering RNA (siRNA). Our results showed that HG enhanced migration, albumin filtration and MCP-1 expression in podocytes. At the molecular level, HG promoted the phosphorylation of NF-κB/p65, IKKβ, IκBα, mitogen-activated protein kinase (MAPK) and the nuclear translocation of p65. LJ reversed the effects of HG in a dose-dependent manner. Furthermore, our data provided the first demonstration that the receptor activator for NF-κB ligand (RANKL) and its cognate receptor RANK were overexpressed in HG-induced podocytes and were downregulated by LJ. RANK siRNA also attenuated HG-induced podocyte injury and markedly inhibited the activation of NF-κB and MAPK signaling pathways. LJ attenuates HG-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.

Chen XW ，Liu WT ，Wang YX ，Chen WJ ，Li HY ，Chen YH ，Du XY ，Peng FF ，Zhou WD ，Xu ZZ ，Long HB ... -  《-》

Sesquiterpene lactones inhibit advanced oxidation protein product-induced MCP-1 expression in podocytes via an IKK/NF-κB-dependent mechanism.

Zhao Y ，Chen SJ ，Wang JC ，Niu HX ，Jia QQ ，Chen XW ，Du XY ，Lu L ，Huang B ，Zhang Q ，Chen Y ，Long HB ... -  《-》

Receptor activator of NF-kappaB and podocytes: towards a function of a novel receptor-ligand pair in the survival response of podocyte injury.

Liu S ，Shi W ，Xiao H ，Liang X ，Deng C ，Ye Z ，Mei P ，Wang S ，Liu X ，Shan Z ，Liang Y ，Zhang B ，Wang W ，Liu Y ，Xu L ，Xia Y ，Ma J ，Li Z ... -  《PLoS One》

Effects of ROS-relative NF-κB signaling on high glucose-induced TLR4 and MCP-1 expression in podocyte injury.

High glucose (HG) induced inflammation is central to progression in diabetic nephropathy (DN). Recent studies have suggested that nuclear factor-kappa B (NF-κB) signaling activation is associated with DN, and podocyte damage may be involved in orchestrating these effects. Therefore, the aim of this study was to investigate the effects of NF-κB signaling on podocytes under HG conditions. The effects of HG and NF-κB signaling on podocytes were assessed by CCK-8 assay, cellular NF-κB translocation assay, measurement of reactive oxygen species (ROS) and Western blot analysis. We found that HG reduced cell viability, activated NF-κB signaling and up-regulated toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP-1). In these cells, NF-κB inhibition with ammonium pyrrolidinethiocarbamate (PDTC) resulted in effectively constraining TLR4 and MCP-1 up-regulation, indicating that protective effects associated with the inhibition of NF-κB were linked to TLR4 and MCP-1 down-regulation in podocytes. Furthermore, HG significantly increased the production of intracellular ROS. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited intracellular ROS generation and increased cell viability, accompanied by a significant NF-κB inhibition and suppression of TLR4 and inflammatory cytokine MCP-1 expression. Collectively, our novel data suggest that HG induces the over-experssion of TLR-4 and MCP-1 through a NF-κB-dependent signaling. NF-κB-mediated increased inflammation is possibly via ROS and contributes to the cell injury. These results may provide potential therapeutic target for diabetic nephropathy in the future.

Wei M ，Li Z ，Xiao L ，Yang Z ... -  《-》

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways.

Activation of NF-κB and MAPK/activator protein 1 (AP-1) signaling pathways by receptor activator NF-κB ligand (RANKL) is essential for osteoclast activity. Targeting NF-κB and MAPK/AP-1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases. In this study we examined the effects of maslinic acid (MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL-induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, MA inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis-related marker gene expression, including TRACP, MMP9, c-Src, CTR, and cathepsin K. Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage. In ovariectomized mice, administration of MA prevented ovariectomy-induced bone loss by inhibiting osteoclast activity. At molecular levels, MA abrogated the phosphorylation of MAPKs and AP-1 activity, inhibited the IκBα phosphorylation and degradation, blocked NF-κB/p65 phosphorylation, nuclear translocation, and DNA-binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6. Together our data demonstrate that MA suppresses RANKL-induced osteoclastogenesis through NF-κB and MAPK/AP-1 signaling pathways and that MA is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.

Li C ，Yang Z ，Li Z ，Ma Y ，Zhang L ，Zheng C ，Qiu W ，Wu X ，Wang X ，Li H ，Tang J ，Qian M ，Li D ，Wang P ，Luo J ，Liu M ... -  《-》