No abstract

Activation of the prefrontal cortex occurs during acute and chronic pain and models of experimental hyperalgesia. The present study was carried out to determine possible miRNA changes in the prefrontal cortex, after inflammatory pain induced by facial carrageenan injection in mice. miRNA microarray analyses showed significantly increased levels of miR-155 and miR-223 in the prefrontal cortex of carrageenan-injected mice. The changes were verified by real-time RT-PCR, and shown to occur bilaterally. The potential targets of the two miRNAs were predicted, and changes in two of the miRNA targets, c/ebp Beta and granulocyte colony-stimulating factor (GCSF) verified by real-time RT-PCR. Significantly downregulated c/ebp Beta but upregulated GCSF, accompanied by increased immunolabeling with an antibody to myeloperoxidase were found in the prefrontal cortex of facial carrageenan treated mice. It is postulated that this could lead to increased inflammation and activation of the prefrontal cortex. Further studies are necessary to determine if specific miRNAs could be useful as therapeutic molecules for pain.

Functional neuroimaging studies have implicated the prefrontal cortex (PFCTX) in descending modulation of pain and the placebo effect. This study was performed to elucidate comprehensive PFCTX gene expression in an animal model of persistent trigeminal pain. Adult male C57BL/6J mice received facial carrageenan injection and showed sustained increase in nociceptive responses. Microarray analyses of differentially expressed genes in the PFCTX at 3 d after injection showed "immune system process" as the dominant ontology term and increased mRNA expression of S100a8, S100a9, Lcn2, Il2rg, Fcgr1, Fcgr2b, C1qb, Ptprc, Ccl12, and Cd52 were verified by RT-PCR. Upregulation of S100A8, S100A9, and lipocalin 2 (LCN2) were confirmed by Western blots, and cells in the PFCTX were double immunolabeled with MPO, indicating they were neutrophils. Analyses of blood of facial carrageenan-injected mice also showed increased mRNA expression of these markers, suggesting transmigration of activated neutrophils into the brain. Other immune-related genes, Il2rg, Fcgr2b, C1qb, Ptprc, and Ccl12 were upregulated in the PFCTX but not blood. Approximately 70% of S100A9-positive cells in the PFCTX of carrageenan-injected mice were located in capillaries adherent to endothelial cells, whereas 30% were within the brain parenchyma. Carrageenan-injected mice showed significantly reduced nociceptive responses after injection of C terminus of murine S100A9 protein in the lateral ventricles and PFCTX but not somatosensory barrel cortex. Together, these findings demonstrate activation of immunerelated genes in the PFCTX during inflammatory pain and highlight an exciting role of neutrophils in linking peripheral inflammation with immune activation of the PFCTX and antinociception.

Blood miRNAs could be useful as biomarkers for exposure to nanoparticles. miR-298 regulates β-amyloid (Aβ) precursor protein-converting enzyme-1 (BACE1) in Alzheimer's disease.

The present study was carried out to examine global gene expression in the brainstem, in a mouse facial carrageenan injection model of orofacial pain. Mice that received facial carrageenan injection showed increased mechanical allodynia, demonstrated by increased responses to von Frey hair stimulation of the face. The brainstem was harvested at 3 days post-injection, corresponding to the time of peak responses, and analyzed by Affymetrix Mouse Genome 430 2.0 microarrays. We sought to identify common genes that are changed in the respective sides of the brainstem after either right- or left-sided facial carrageenan injection. The result is a relatively small list of genes (22 genes), which were then classified using DAVID software. Many of them fell into the categories of "response to stress", "defence response", "response to biotic stimulus", "cell adhesion" and "leukocyte adhesion". Of these, increased expression of P-selectin, ICAM-1 and CCL12 after carrageenan injection could be verified by real-time RT-PCR on both the right and left sides, and increased in P-selectin and ICAM-1 further verified by Western blot analysis. P-selectin and ICAM-1 were immunolocalized to endothelial cells, and were double labelled with von Willebrand factor. Intraperitoneal injection of the P-selectin inhibitor KF38789 significantly reduced mechanical allodynia in the facial carrageenan-injected mice. P-selectin mediates the capturing of leukocytes from the bloodstream and rolling of leukocytes along the endothelial surface. We hypothesize that increased nociceptive input to the brainstem could attract circulating macrophages into the brain, resulting in neuroinflammation and pain.

Results: We included 6136 REGARDS participants at mean age 67.6 years, 308 of whom had low LDL-C (<70 mg/dl) at baseline. Over about 7-year average follow-up, 1,376 (22.4%) participants died, 508 (8.3%) -from a coronary death, and 352 (5.7%) -from a stroke. We found evidence of a non-linear relationship between LDL-C and all-cause mortality, which remained significant after adjustment for all covariates (Figure 1) (p<0.0001; test for nonlinearity p=0.0021). LDL measurements between approximately 70 mg/dl and 200 mg/dl appeared to be protective against all-cause mortality with levels below 70 mg/dl not being associated with decreased mortality risk. Analyzing incident CHD risk fully-adjusted spline plots indicated an approximate doubling of incident CHD risk between baseline LDL-C concentrations of 150 mg/dl and 250 mg/dl (Figure 2). Nonlinearity was not observed in either unadjusted or adjusted data and we noticed marginally significant (p=0.0565 for the unadjusted, and p=0.0691 for the adjusted) association between LDL-C and incident CHD. We did not find any significant associations between LDL-C and incident stroke. Conclusions:We found evidence for a non-linear relationship between LDL and all-cause mortality, which remained significant after adjustment for all covariates. We showed marginally significant association between LDL-C and incident CHD and lack of such association for incident stroke. LDL-C levels lower than 70 mg/dl did not show further benefits in reduction of cardiovascular and mortality risk. As these data are at odds with the results from RCTs further investigation is necessary to explain these discrepancies. Background: Interventions that raise HDL cholesterol do not reduce risk of atherosclerotic cardiovascular disease (ASCVD). Therefore, studies of HDL functionalities rather than HDL cholesterol levels are encouraged. HDL cholesterol efflux capacity, the ability of HDL to accept cholesterol from macrophages, may be a more important factor. We previously reported that cholesterol efflux capacity was independently and inversely associated with the presence of ASCVD in Japanese patients with familial hypercholesterolemia. However, it remains unclear whether cholesterol efflux capacity is related to incident ASCVD events in non-Western general populations. Purpose: The aim of this study was to investigate the epidemiology of cholesterol efflux capacity and its association with incident ASCVD outcomes in a Japanese general population cohort. Methods: We measured cholesterol efflux capacity at baseline in 1815 adults free from cardiovascular disease and assessed its relation with cardiovascular risk factors and incident ASCVD. Cholesterol efflux capacity was quantified by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apolipoprotein B-depleted serum from study participants. The primary end point was ASCVD, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascu...