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The intense and prolonged inflammatory response after ischemic stroke significantly contributes to the secondary neural injury. PI3Kγ, which is involved in the regulation of vascular permeability, chemotactic leukocyte migration and microglia activation, is a key target for intervention in the inflammatory response. In this study, we identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). The results showed that administration of AS605240 could improve the neurological function score, reduce the infarct size and decrease astrocyte activation in the tMCAO mice after injury. The inhibitory effect of AS605240 on microglia activation is relatively clear. Therefore, in this study, the effects of AS605240 on astrocytes were studied in cell cultures. IL-6 and its soluble receptor were used to construct the astrocyte activation model. AS605240 treatment significantly reduced the astrocyte activation markers and the morphological changes of cells. We also identified 13 inflammatory factors whose expression was significantly upregulated by IL-6/sIL-6R and significantly inhibited by AS605240 at the protein level, and seven of those factors were verified at the mRNA level. These results indicated that specific inhibition of PI3Kγ could reduce astrocyte activation induced by inflammation, which might aid the repair and remodeling of neurons in the later stage after ischemic stroke., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Reperfusion after tourniquet use can induce inflammation and cause remote organ injury. We evaluated the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) on inflammatory mediators and lung function in patients receiving lower limb tourniquets. Forty patients undergoing unilateral lower extremity surgery with tourniquet were randomly assigned to two groups: the TEAS group and ischemia-reperfusion (I/R) group. The C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8 (CXCL8), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor- α (TNF- α ), and arterial blood gas analysis were measured preoperatively and 6 h after tourniquet removal. The levels of CXCL8, IL-1, IL-6, TNF- α , and CCL2 were significantly increased compared to baseline values in both groups, but the increase was significantly smaller in the TEAS group. In the TEAS group, the partial pressure of oxygen and arterial-alveolar oxygen tension ratio were significantly decreased, and the alveolar-arterial oxygen tension difference and respiratory index were significantly increased, compared to those in the I/R group at 6 h after reperfusion. In conclusion, TEAS diminished the upregulation of proinflammatory factors in response to lower limb ischemia-reperfusion and improved pulmonary gas exchange.

Background: Inflammation is relevant to the pathophysiology of severe neuropsychiatric disorders, schizophrenia (SCZ) and bipolar disorders (BD). Multiple pathophysiological biomarkers are valuable for the study of inflammatory processes. This study investigated albumin-related biomarkers in SCZ and BD to explore their roles in disease.Methods: A total of 5,577 SCZ, 3442 BD-manic (BD-M) and 1405 BD-depression (BD-D) in acute stage and 5000 health controls (HCs) were enrolled. The differences in these biomarker levels among different groups were compared, and the contributing factors for the occurrence of SCZ, BD, and subgroups of BD were analyzed.Results: Both SCZ and BD exhibit lower prognostic nutritional index (PNI), but higher neutrophil percentage-to-albumin ratio (NPAR) and creatinine–albumin ratio (CRA) compared with HC. Compared with BD-D, BD-M had higher NPAR and platelet-to-albumin ratio (PAR) and lower CRA. In logistic regression, lower prognostic nutritional index (PNI) and higher CRA were associated with both SCZ and BD, while higher NPAR was associated with BD. In the subgroup of BD, higher NPAR, CRA and lower PNI were associated with BD-M; lower PAR, PNI and higher CRA were associated with BD-D.Conclusion: Our study reaffirmed the role of inflammation in the pathophysiology of SCZ and BD. Diagnostic value has been demonstrated in NPAR, PAR, PNI and CRA for BD and SCZ. [ABSTRACT FROM AUTHOR]

Simple Summary: In the current study, the roles of dietary cinnamaldehyde, carvacrol, and thymol blend in the tibia characteristics in post-peak laying hens were evaluated. We firstly analyzed the tibia bone properties and demonstrated that a diet supplemented with a 100 mg/kg combination of cinnamaldehyde with carvacrol or thymol could increase the strength of tibia in layers. We also found that the role of dietary essential oils enhanced intestinal barrier, decreased systemic inflammation, and reduced bone resorption marker in serum. These data indicated that a diet with a blend of cinnamaldehyde and carvacrol or thymol could improve the mechanical properties of tibiae for laying hens, in which enhancing intestinal barrier and decreasing systemic inflammation might be a key mediator. Roles of plant-derived cinnamaldehyde, carvacrol, and thymol in the gut and bone health of laying hens was evaluated in the present study. After acclimation for 2 weeks, a total 384 of 52-week-old laying hens were allocated into three groups for 6 weeks: (1) basal diet group (Ctrl), (2) combination of cinnamaldehyde with carvacrol group (CAR+CIN), and (3) blend of cinnamaldehyde with thymol (THY+CIN). The dietary essential oil level was 100 mg/kg. Each treatment group had eight replicate pens (16 birds/pen). The stiffness and ultimate load of the tibiae from both the CAR+CIN and THY+CIN groups were higher than that of the Ctrl group (p < 0.05), along with comparable tibia ash, calcium, and phosphorus content among groups. At the same time, the manipulation of essential oils upregulated the transcription abundances of intestinal barrier proteins to varying degrees, whereas the experimental treatment failed to affect the composition in phyla of cecal microbiota. When compared to the Ctrl group, birds fed the CAR+CIN and THY+CIN diet displayed decreased bone resorption markers, reduced interleukin-1 concentrations, and increased transforming growth factor beta levels in serum. These findings suggest that cinnamaldehyde with carvacrol or thymol in feed of hens could enhance intestinal barrier and improve the mechanical properties of tibiae through structural modelling but not increase the mineral density, which might be involved in suppressing inflammation-mediated bone resorption. [ABSTRACT FROM AUTHOR]

It has been reported that matrix metalloproteinases (MMPs) are induced by many cytokines, and they are involved in various inflammatory processes, including periodontitis. However, the effects of interleukin-1β (IL-1β) on MMP-9 expression in cementoblasts, the cells responsible for cementum production, remain largely unknown. In this study, we used qPCR and gelatin zymogram analysis to show that IL-1β upregulated MMP-9 expression in cementoblast-derived cell line. Several signaling pathways, such as ERK1/2, JNK, p38, and AP-1 (c-Fos and ATF-2), were activated in response to IL-1β stimulation. Furthermore, enhancement of AP-1 activity by IL-1β was further confirmed by the AP-1 reporter assay and the electrophoretic mobility shift assay (EMSA). Pretreatment with specific inhibitors of ERK1/2 (U0126), JNK (SP600125), and AP-1 (tanshinone IIA) attenuated IL-1β-induced MMP-9 expression. In addition, inhibitors of ERK1/2 (U0126) and JNK (SP600125) attenuated IL-1β-enhanced AP-1 activity. This suggested that IL-1β stimulated AP-1 activation, at least partially, through ERK1/2 and JNK signaling pathways. Moreover, we found that IL-1β also upregulated the expression of MMP-13 and enhanced MMP-mediated degradation of type I collagen. Collectively, these results suggested that IL-1β induced MMP-9 expression by activation of AP-1 through the ERK1/2 and JNK signaling pathways in cementoblast-derived cell line and enhanced MMP-mediated collagen degradation possibly by MMP-13 and MMP-9. [ABSTRACT FROM AUTHOR]

Abstract Runx3, a member of the Runt-related transcription factor family, has attracted extensive attention due to its important role in the development of immune systems, especially in the differentiation of T cells. Accumulated evidence indicated that altered expression of Runx3 regulates a variety of target genes in different tissues/cells. Studies in animal models suggested that Runx3 may regulate the development of T cell lineage including those of innate lymphoid cells, Treg cells and dendritic cells, which may contribute to the development of hypersensitivity and asthma. Specifically, Runx3 modulates Th1/Th2 balance and hence, the production of interleukins, which induce inflammatory responses. Understanding the roles and mechanisms of Runx3 in the regulation of immune function provides a basis for the design of novel preventive and treatment models for bronchial asthma. This article reviews published data from cell lines, animal models, and patients, concerning the relationship between Runx3 expression alteration and asthma. Epigenetic regulation of Runx3 by DNA hypermethylation and microRNA, and the implication of these pathways in asthma are also discussed. Highlights • Runx3 may play a significant role for the pathogenesis of bronchial asthma. • Alteration of Runx3 expression may affects the Th1/Th2 balance. • Runx3 regulates the development of innate lymphoid cells, Treg cells and dendritic cells. • Runx3 gene is a potential target for asthma prevention and treatment. [ABSTRACT FROM AUTHOR]

Currently, most anti-cancer therapies are still haunted by serious and deleterious adverse effects. Here, we report a highly biocompatible tumor cell-targeting delivery systems utilizing exosome-like vesicles (ELVs) that delivers a low-toxicity anti-cancer agent imperialine against non-small cell lung cancer (NSCLC). First, we introduced a novel micelle-aided method to efficiently load imperialine into intact ELVs. Then, integrin α3β1-binding octapeptide cNGQGEQc was modified onto ELV platform for tumor targeting as integrin α3β1 is overexpressed on NSCLC cells. This system not only significantly improved imperialine tumor accumulation and retention, but also had extremely low systemic toxicity both in vitro and in vivo. Our discoveries offer new ways to utilize ELV more efficiently for both drug loading and targeting. The solid pharmacokinetics improvement and extraordinary safety of this system also highlight possibilities of alternative long course cancer therapies using similar strategies. Unlabelled Image [ABSTRACT FROM AUTHOR]