No abstract

The β2 adrenergic receptor (ADRB2) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder (COPD). Although a number of ADRB2 agonists have been developed for use in asthma therapy, indacaterol is the only ultra-long-acting inhaled β2-agonist (LABA) approved by the FDA for relieving the symptoms in COPD patients.The precise molecular mechanism underlying the pharmacological effect of indacaterol, however, remains unclear. Here, we show that β-arrestin-2 mediates the internalization of ADRB2 following indacaterol treatment. Moreover, we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α (TNF-α)-induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα, thereby decreasing NF-κB nuclear translocation and the expression of MMP-9, an NF-κB target gene. Subsequently, we show that indacaterol significantly inhibits TNF-α/NF-κB-induced cell invasiveness and migration in a human cancer cell line. In conclusion, we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner, preventing further lung damage and improving lung function in COPD patients.

Brazilin, is a bioactive compound extracted from Caesalpinia sappan Linn, has been reported the protective effect of the immune system. Particular attention is now devoted to better understanding of the molecular basis of bazilin anti-inflammatory activity. In the present study, we studied the effect of brazilin on the Raw264.7 macrophage cell lines by a nutrigenomics approaches. Raw264.7 cells were treated with braziln, then treated with LPS to cause inflammation. The nuclear transcription κB (NF-κB) promoter activity were analyzed with dual luciferase assay kit. The gene expression and production levels of pro-inflammatory cytokine interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 were evaluated with semi-quantitative RT-PCR and with ELISA, respectively. We also examined inflammatory signaling, including mitogen-activated protein kinase (MAPK) pathway, iNOS, COX2, and IRAK4. Our findings demonstrated that brazilin down-regulated the expression of IRAK4 protein lead to suppress of c-Jun NH 2 terminal kinase (JNK) signaling, and subsequently inactivation of nuclear transcription κB (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) thus promoting the expression of the downstream target pro-inflammatory cytokines such as IL-1β, TNFα and IL-6 in LPS stimulated Raw264.7 macrophage cell. Thus, brazilin showed anti-inflammatory activity in Raw264.7 macrophage cell targeting IRAK4 mediated signaling pathway.

Ardisia tinctoria (AT) is a plant of the Myrsinaceae family. No studies on its anti-inflammatory effects have yet been reported. This study investigated the anti-inflammatory activity of AT. A non-cytotoxic methanol extract of AT inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), leading to significantly reduced levels of nitric oxide (NO) and prostaglandin E2 (PGE2) and of two proteins regulated by these, interleukin-1β (IL-1β) and IL-6, in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The thickness of paw edema induced in vivo in mice by carrageenan administration was effectively reduced by the AT extract. Translocation of the nuclear factor-κB (NF-κB) subunit 65 (p65) into the nucleus and phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-related kinase (ERK) were inhibited by the AT extract. Our results indicated that a methanol extract of AT downregulates the inflammatory response by blocking phosphorylation of MEK and ERK and activation of NF-κB. To the best of our knowledge, this is the first study of anti-inflammatory effects of an AT extract, and demonstrates its potential in the treatment of inflammatory diseases.

Melicope ptelefolia has been traditionally used to treat rheumatism and fever. The present study aimed to investigate the therapeutic effect of 3,5-di-C-β-d-glucopyranosyl phloroacetophenone (βGP), a main component of M. ptelefolia, on rheumatoid arthritis (RA). A model of collagen-induced arthritis (CIA) was established in mice using the RAW 264.7 murine macrophage cell line and mouse embryonic fibroblasts (MEFs). The clinical scores of arthritis, swelling, histopathological findings, and micro-computed tomography in CIA mouse paws were assessed. The levels of anti-type II collagen antibody and cytokines were determined in the plasma and cell culture supernatant, respectively. Protein and gene expression levels were analyzed by western blot and reverse transcription-quantitative polymerase chain reaction analyses. βGP significantly decreased the gross arthritic scores of CIA mice and joint swelling, and decreased articular inflammation, cartilage degradation and bone erosion. However, βGP did not exert any effect on anti-type II collagen immunoglobulin G plasma levels or inflammatory cytokine expression in macrophages. βGP significantly suppressed the expression of interleukin-6 and leukemia inhibitory factor and decreased the phosphorylation of signal transducer and activator of transcription 3, and expression of receptor activator of nuclear factor-κB ligand in tumor necrosis factor-α-stimulated MEFs and in CIA mouse paws. Osteoclast-related gene expression was significantly reduced in CIA mouse paws. Taken together, βGP suppressed the development of RA by regulating the activation of synovial fibroblasts.