Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor prognosis in patients with advanced cancers. We evaluated the relationships between clinical status, laboratory factors and progression free survival (PFS), and overall survival (OS) in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy.</p> <p>Methods</p> <p>We reviewed 402 patients with advanced gastric adenocarcinoma who received first-line palliative chemotherapy from June 2004 and December 2009. Various chemotherapy regimens were used. Eastern Cooperative Oncology Group performance status (ECOG PS), C-reactive protein (CRP), albumin, Glasgow prognostic score (GPS), and clinical factors were recorded immediately prior to first-line chemotherapy. Patients with both an elevated CRP (>1.0 mg/dL) and hypoalbuminemia (<3.5 mg/dL) were assigned a GPS of 2. Patients in whom only one of these biochemical abnormalities was present were assigned a GPS of 1, and patients with a normal CRP and albumin were assigned a score of 0. To evaluate the factors that affected PFS and OS, univariate and multivariate analyses were performed.</p> <p>Results</p> <p>According to multivariate analysis, the factors independently associated with PFS were ECOG PS (HR 1.37, 95% CI 1.02-1.84, <it>P </it>= 0.035), bone metastasis (HR 1.74, 95% CI 1.14-2.65, <it>P </it>= 0.009), and CRP elevation (HR 1.64, 95% CI 1.28-2.09, <it>P </it>= 0.001). The factors independently associated with OS were ECOG PS (HR 1.33, 95% CI 1.01-1.76, <it>P </it>= 0.037), bone metastasis (HR 1.61, 95% CI 1.08-2.39, <it>P </it>= 0.017), and GPS ≥ 1 (HR 1.76, 95% CI 1.41-2.19, <it>P </it>= 0.001).</p> <p>Conclusions</p> <p>The results of this study showed that the presence of a systemic inflammatory response as evidenced by the CRP, GPS was significantly associated with shorter PFS and OS in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy. Bone metastasis and GPS were very useful indicator for survival in patients with recurrent or metastatic gastric cancer receiving palliative chemotherapy.</p

Translocator Protein 18 kDa Negatively Regulates Inflammation in Microglia

Translocator protein 18 kDa (TSPO) is a mitochondrial outer membrane protein. Although TSPO expression is up-regulated during neuroinflammation, the role of TSPO and its signaling mechanisms in regulation of neuroinflammation remains to be elucidated at the molecular level. Here we demonstrate that TSPO is a negative regulator of neuroinflammation in microglia. Over-expression of TSPO decreased production of pro-inflammatory cytokines upon lipopolysaccharide treatment while TSPO knock-down had the opposite effect. Anti-inflammatory activity of TSPO is also supported by increased expression of alternatively activated M2 stage-related genes. These data suggest that up-regulation of TSPO level during neuroinflammation may be an adaptive response mechanism. We also provide the evidence that the repressive activity of TSPO is at least partially mediated by the attenuation of NF-κB activation. Neurodegenerative diseases are characterized by loss of specific subsets of neurons at the particular anatomical regions of the central nervous system. Cause of neuronal death is still largely unknown, but it is becoming clear that neuroinflammation plays a significant role in the pathophysiology of neurodegenerative diseases. Understanding the mechanisms underlying the inhibitory effects of TSPO on neuroinflammation can contribute to the therapeutic design for neurodegenerative diseases. © 2014 Springer Science+Business Media.

Extracts from Dendropanax morbifera Leaves Have Modulatory Effects on Neuroinflammation in Microglia

Dendropanax morbifera (D. morbifera), a species endemic to Korea, is largely distributed throughout the southern part of the country. Its leaves, stems, roots, and seeds have been used as a form of alternative medicine for various diseases and neurological disorders including paralysis, stroke, and migraine. However, the molecular mechanisms that underlie the remedial effects of D. morbifera remain largely unknown. In this paper, extracts from D. morbifera leaves were prepared using ethyl acetate as a solvent (abbreviated as DMLE). The modulatory effects of DMLE on neuroinflammation were studied in a lipopolysaccharide (LPS)-stimulated BV2 murine microglial cell line. Production of pro-inflammatory cytokines, activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB), and different M1/M2 activation states of microglia were examined. DMLE treatment suppressed the production of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) in LPS-stimulated BV2 cells. DMLE treatment also attenuated the activation of MAPKs and NF-κB. In a novel discovery, we found that DMLE up-regulated the marker genes representing an alternative, anti-inflammatory M2 polarization, while suppressing the expression of the classical, pro-inflammatory M1 activation state genes. Here, we uncovered the cellular mechanisms underlying the beneficial effects of D. morbifera against neuroinflammation using BV2 microglia cells. These results strongly suggest that DMLE was able to counter the effects of LPS on BV2 cells via control of microglia polarization states. Additionally, study results indicated that DMLE may have therapeutic potential as a neuroinflammation-suppressing treatment for neurodegenerative diseases. © 2016 World Scientific Publishing Company.

A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation

Ro5-4864 and PK11195, prototypical synthetic ligands of translocator protein 18 kDa (TSPO), have shown anti-inflammatory effects in several models of inflammatory diseases; however, their biochemical mechanisms remain poorly understood. Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation as a part of the innate immune system, has been implicated in a variety of inflammatory diseases. Here, we demonstrate for the first time that TSPO ligands, especially Ro5-4864, potently suppressed ATP-induced NLRP3 inflammasome activation in THP-1 and BMDM cells. Detailed action mechanism was further investigated in THP-1 cells. Ro5-4864 efficiently attenuated NLRP3 translocation to mitochondria, inflammasome assembly/oligomerization, activation of caspase-1, and subsequent secretion of the mature forms of interleukin-1β and -18. Ro5-4864 also reduced the production of mitochondrial superoxide and preserved the mitochondrial membrane potential in ATP-treated cells, suggesting that Ro5-4864 may act on mitochondria or more upstream targets in NLRP3 inflammasome signaling. We also observed the distinct effects of the TSPO ligands between THP-1 monocytes and macrophages, which suggested different NLRP3 inflammasome signaling depending on cell type. Collectively, our novel findings demonstrate that Ro5-4864 effectively inhibited ATP-induced NLRP3 inflammasome activation through the prevention of mitochondrial perturbation. Our results indicate Ro5-4864 as a promising candidate for the treatment of NLRP3 inflammasome-related diseases. © 2016 Elsevier Inc. All rights reserved.