Anagliptin prevents lipopolysaccharide (LPS)- induced inflammation and activation of macrophages.

Sepsis is a multiple organ dysfunction syndrome (MODS) induced by infection, which significantly threatens public health. The overactivation of inflammatory reactions and oxidative stress participate in the pathogenesis of sepsis. Anagliptin, a novel anti-diabetic agent widely applied for the treatment of type II diabetes, has been recently claimed to possess anti-inflammatory properties. Here, the protective effects of anagliptin on lipopolysaccharide (LPS)- stimulated macrophages will be checked to explore the possible pharmacological property of anagliptin on sepsis. The state of oxidative stress was dramatically activated by LPS, accompanied by the upregulation of toll-like receptor 4 (TLR4) and high mobility group box-1 (HMGB-1), as well as the elevated expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). After treatment with anagliptin, the state of oxidative stress in macrophages was alleviated, with the downregulation of TLR4, HMGB-1, iNOS, and the declined release of NO. The excessive secretion of inflammatory factors, activation of the NF-κB pathway, and promoted expression level of receptor-interacting protein 1 (RIP1) were observed in LPS- stimulated macrophages, all of which were greatly reversed by the introduction of anagliptin. Lastly, the protective properties of anagliptin on LPS- treated macrophages, including the inhibitory effects on inflammation and the NF-κB pathway, were dramatically abolished by the overexpression of RIP1 in macrophages. Collectively, anagliptin prevented LPS-induced inflammation and activation of P338D1 macrophages by repressing the expression level of RIP1.

Yu F ，Tian W ，Dong J 《-》

Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation.

Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages.

Ikedo T ，Minami M ，Kataoka H ，Hayashi K ，Nagata M ，Fujikawa R ，Higuchi S ，Yasui M ，Aoki T ，Fukuda M ，Yokode M ，Miyamoto S ... -  《Journal of the American Heart Association》

Nodakenin suppresses lipopolysaccharide-induced inflammatory responses in macrophage cells by inhibiting tumor necrosis factor receptor-associated factor 6 and nuclear factor-κB pathways and protects mice from lethal endotoxin shock.

Rim HK ，Cho W ，Sung SH ，Lee KT ... -  《-》

Melatonin modulates TLR4-mediated inflammatory genes through MyD88- and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells.

Increasing evidence demonstrates that melatonin has an anti-inflammatory effect. Nevertheless, the molecular mechanisms remain obscure. In this study, we investigated the effect of melatonin on toll-like receptor 4 (TLR4)-mediated molecule myeloid differentiation factor 88 (MyD88)-dependent and TRIF-dependent signaling pathways in lipopolysaccharide (LPS)-stimulated macrophages. RAW264.7 cells were incubated with LPS (2.0 μg/mL) in the absence or presence of melatonin (10, 100, 1000 μm). As expected, melatonin inhibited TLR4-mediated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-8, and IL-10 in LPS-stimulated macrophages. In addition, melatonin significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in macrophages. Further analysis showed that melatonin inhibited the expression of MyD88 in LPS-stimulated macrophages. Although it had no effect on TLR4-mediated phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular regulated protein kinase (ERK), melatonin significantly attenuated the activation of nuclear factor kappa B (NF-κB) in LPS-stimulated macrophages. In addition, melatonin inhibited TLR4-mediated Akt phosphorylation in LPS-stimulated macrophages. Moreover, melatonin significantly attenuated the elevation of interferon (IFN)-regulated factor-3 (IRF3), which was involved in TLR4-mediated TRIF-dependent signaling pathway, in LPS-stimulated macrophages. Correspondingly, melatonin significantly alleviated LPS-induced IFN-β in macrophages. In conclusion, melatonin modulates TLR4-mediated inflammatory genes through MyD88-dependent and TRIF-dependent signaling pathways.

Xia MZ ，Liang YL ，Wang H ，Chen X ，Huang YY ，Zhang ZH ，Chen YH ，Zhang C ，Zhao M ，Xu DX ，Song LH ... -  《-》

Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages.

Although xanthotoxin has been reported to possess skin-protective and anti-oxidative properties, its anti-inflammatory capacity has not been studied to date. Therefore, we investigated this role as well as the molecular mechanisms of xanthotoxin in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Xanthotoxin inhibited production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) by the LPS-induced macrophages in a concentration-dependent manner. It also suppressed the LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at the protein levels and iNOS, COX-2, TNF-α, and IL-6 at the mRNA levels. At a molecular level, the effects were related to xanthotoxin-mediated attenuation of the LPS-induced transcriptional and DNA-binding activity of activator protein-1 (AP-1). This attenuation was associated with decreased phosphorylation of c-Fos, but not c-Jun. Xanthotoxin also displayed a suppressive effect on the transcriptional and DNA-binding activity of nuclear transcription factor kappa-B (NF-κB) by inhibiting p65 nuclear translocation. In addition, xanthotoxin significantly reduced the phosphorylation at signal transducers and activators of transcription 1 (STAT1, Ser 727 and Tyr 701) and STAT3 (Tyr 705), as well as Janus kinase (JAK) 1 and 2 in LPS-induced RAW 264.7 macrophages. Finally, xanthotoxin suppressed the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK). Taken together, these results indicate that xanthotoxin decreases NO, PGE2, TNF-α, and IL-6 production by downregulation of the NF-κB, AP-1, and JAK/STAT signaling pathways in LPS-induced RAW 264.7 macrophages.

Lee SB ，Lee WS ，Shin JS ，Jang DS ，Lee KT ... -  《-》