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Evidences reported that high mobility group box 1 (HMGB1) played a pivotal role in the modulation of chronic inflammatory pain. Celastrol, a bioactive component extracted from Tripterygium wilfordii Hook, possesses anti-inflammatory activity, but the underlying mechanism remains to be fully clarified. We aim to investigate whether HMGB1 in dorsal root ganglion (DRG) participates in the effect of celastrol on inflammatory pain. Complete Freund's adjuvant (CFA)-induced inflammatory pain rat model was used. Paw withdrawal latency (PWL) was detected to evaluate the effects of celastrol on CFA-evoked inflammatory pain. After application of celastrol (1mg/kg, i.p.) on day 1, 3, 7 and 14 post-CFA injection, the expression levels of HMGB1, NF-κB, some proinflammatory markers, GFAP and CD11b in DRG were determined by qRT-PCR and western blot analysis. These results showed that celastrol significantly suppressed HMGB1, NF-κB and IL-1β mRNA and protein expression in DRG and alleviated CFA-evoked thermal hyperalgesia. Furthermore, celastrol obviously inhibited COX-2 protein expression and down-regulated IL-6, IL-17, TNF-α, MCP-1, GFAP and CD11b mRNA levels in DRG of CFA rats. Collectively, the present study firstly provide evidences of the anti-inflammatory effect of celastrol via suppressing CFA-induced the activation of HMGB1/NF-κB signaling pathway in DRG, which maybe a potential therapeutic target for celastrol alleviating inflammatory pain., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Triggering receptor expressed on myeloid cells-2 (TREM2) was a newly identified receptor expressed on microglia. Several observations support the hypothesis that TREM2 variation may confer susceptibility to Parkinson's disease (PD). Therefore, in this paper, we explored the role of TREM2 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results revealed that overexpression of TREM2 remarkably reduced MPTP-induced neuropathology including the dopaminergic neurodegeneration and neuroinflammation in vivo. Further mechanistic study revealed that TREM2 inhibited neuroinflammation by negatively regulating the TRAF6/TLR4-mediated activation of the MAPK and NF-κB signaling pathways. Taken together, our data suggest that TREM2 may have important neuroprotective effects against PD by critically modulating neuroinflammatory responses. These findings provide insights into the role of TREM2 in PD pathogenesis, and highlight TREM2 as a potential therapeutic target for this kind of disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Increasing evidences suggest that innate immunity is involved in cerebral ischemia-reperfusion (I/R) injury, but the liable innate immune receptors have not been completely elucidated. Here, we explored the role of the nucleotide-binding oligomerization domain (NOD)2, a member of the cytosolic NOD-like receptor family, in acute focal cerebral I/R injury., Methods: An in vivo middle cerebral artery occlusion (MCAO) model that in wild type (WT) and NOD2 deficient (NOD2(-/-)) mice and in vitro model of oxygen glucose deprivation and reoxygenation (OGD/R) in cultured primary microglia and astrocytes were used to investigate the expression of NOD2 and explore the roles of NOD2 in ischemic stroke., Results: Our results showed that NOD2 expression was significantly increased in microglia and astrocytes in response to the I/R insult. Pretreatment with muramyl dipeptide, an extrinsic ligand of NOD2, significantly increased the infarct volume and neurological dysfunction in mice subjected to MCAO. Genetic ablation of the NOD2 gene significantly improved stroke outcomes and reduced inflammation, as evidenced by a lower expression of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα in conjunction with attenuated activation of nuclear factor κB (NF-κB), p38 mitogen activated protein kinases (MAPK) and JNK. Moreover, NOD2 deficiency prevented the upregulation of the NADPH oxidase (NOX) 2 and ROS generation induced by I/R. Mechanistically, NOD2-induced production of IL-6 in primary cultured microglia was mediated through activation of NOX2., Conclusions: This study showed the contribution of NOD2 to inflammatory response and provided direct evidence that NOX2-mediated oxidative stress as an important target molecule linked NOD2 to inflammatory damage in ischemic stroke. Pharmacological targeting of NOD2-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.

Neuroinflammation is involved in various central nervous system (CNS) disorders, including brain infections, ischemia, trauma, stroke, and degenerative CNS diseases. In the CNS inflammation, secretory phospholipase A₂-IIA (sPLA₂-IIA) acts as a mediator, resulting in the generation of the precursors of pro-inflammatory lipid mediators, such as prostaglandins (PGs) and leukotrienes (LTs). However, the role of sPLA₂-IIA in neuroinflammation is more complicated and remains unclear yet. In the present study, we investigated the effect of sPLA₂-IIA inhibition by specific inhibitor SC-215 on the inflammation in LPS-induced mice cerebral cortex and primary astrocytes. Our results showed that the inhibition of sPLA₂-IIA alleviated the release of PGE₂ by suppressing the activation of ERK1/2, cPLA₂α, COX-2 and mPGES-1. These findings demonstrated that sPLA₂-IIA showed the potential to regulate the neuroinflammation in vivo and in vitro, indicating that sPLA₂-IIA might be a novel target for the treatment of acute neuroinflammation.

Hydroxysafflor Yellow A has been demonstrated to attenuate pressure overloaded hypertrophy in rats and inhibit platelet aggregation. Herein we found that Hydroxysafflor Yellow A prevented cerebral ischemia-reperfusion injury by inhibition of thrombin generation. In addition, treatment with Hydroxysafflor Yellow A significantly inhibited NF-kappaB p65 nuclear translation and p65 binding activity, both mRNA and protein levels of ICAM-1 and the infiltration of neutrophils. Mean while, Hydroxysafflor Yellow A had the capacity to improve neurological deficit scores, increase the number of the surviving hippocampal CA1 pyramidal cells and decrease the plasma angiotensin II level. These results illustrated that anti-cerebral ischemic mechanism of Hydroxysafflor Yellow A may be due to its suppression of thrombin generation and inhibition of thrombin-induced inflammatory responses by reducing angiotensin II content., (2010. Published by Elsevier Ltd.)

We previously reported that nucleotide‐binding oligomerization domain‐containing protein (NOD) 2 was involved in the inflammatory responses to cerebral ischaemia/reperfusion (I/R) insult. However, the mechanism by which NOD2 participates in brain ischaemic injury and the regulation of NOD2 in the process are still obscure. Increased β‐arrestin 2 (ARRB2) expression was observed in microglia following cerebral I/R in wild‐type mice besides the up‐regulation of NOD2 and TRAF6. Stimulation of NOD2 by muramyl dipeptide (MDP) in BV2 cells induced the activation of NF‐κB by the phosphorylation of p65 subunit and the degradation of IκBα. Meanwhile, the protein level of Cyclooxygenase‐2 (COX‐2), the protein expression and activity of MMP‐9 were significantly increased in BV2 cells after administration of MDP. Furthermore, overexpression of ARRB2 significantly suppressed the inflammation induced by MDP, silence of ARRB2 significantly enhanced the inflammation induced by MDP in BV2 cells. In addition, we observed endogenous interaction of TRAF6 and ARRB2 after stimulation of MDP or cerebral I/R insult, indicating ARRB2 negatively regulates NOD2‐triggered inflammatory signalling pathway by associating with TRAF6 in microglia after cerebral I/R injury. Finally, the in vivo study clearly confirmed that ARRB2 negatively regulated NOD2‐induced inflammatory response, as ARRB2 deficiency exacerbated stroke outcomes and aggravated the NF‐κB signalling pathway induced by NOD2 stimulation after cerebral I/R injury. These findings revealed ARRB2 negatively regulated NOD2 signalling pathway through the association with TRAF6 in cerebral I/R injury. [ABSTRACT FROM AUTHOR]

The present study compared vertebral deformities of hatchery-reared and wild-caught juvenile Japanese flounder, Paralichthys olivaceus. A total of 362 hatchery-reared flounder (total length 122.5-155.8 mm) were collected from three commercial hatcheries located in Yantai, East China, and 89 wild fish (total length 124.7-161.3 mm) were caught off Yangma Island near Yantai City (37°27′N, 121°36′E). All the fish were dissected, photographed, and images of the axial skeleton were examined for vertebral deformities. Compared with wild-caught flounder in which no deformed vertebrae were detected, 48 (13.3%) hatcheryreared fish had deformed vertebrae. The deformities were classified as compression, compression-ankylosis, and dislocation-ankylosis. The vertebral deformities were mainly localized between post-cranial vertebra 1 and 3, with vertebrae number 1 as the most commonly deformed. The causative factors leading to vertebral deformities in reared Japanese flounder may be related to unfavorable temperature conditions, inflammation, damage, or rupture to the intervertebral ligaments under rearing conditions. Furthermore, no significant difference in the total number of vertebral bodies was observed between wild-caught (38.8±0.4) and hatchery-reared flounder (38.1±0.9) ( P>0.05). However, the number of vertebral bodies of hatchery-reared and wild-caught flounder ranged from 35 to 39 and from 38 to 39, respectively. [ABSTRACT FROM AUTHOR]

Background/Aims: Although the pathogenesis of myocardial infarction (MI) is multifactorial, activation of innate immune system to induce inflammation has emerged as a key pathophysiological process in MI. NOD2, one member of the NOD-like receptor (NLR) family, plays an important role in the innate immune response. This study was to examine the role of NOD2 during MI. Methods: MI was induced by permanent ligation of the left coronary artery in wild type and NOD2-/- mice and cardiac fibroblasts were isolated. Results: NOD2 expression was significantly increased in myocardium in post-MI mice. NOD2 deficiency improved cardiac dysfunction and remodeling after MI as evidenced by echocardiographic analysis, reduced the levels of cytokines, inflammatory cell infiltration and matrix metalloproteinase-9 (MMP-9) activity. In vitro, we further found that NOD2 activation induced the activation of MAPK signaling pathways, production of proinflammatory mediators and MMP-9 activity in cardiac fibroblasts. Conclusions: Our studies demonstrate that NOD2 is a critical component of a signal transduction pathway that links cardiac injury by exacerbation of inflammation and MMP-9 activity. Pharmacological targeting of NOD2-mediated signaling pathways may provide a novel approach to treatment of cardiovascular diseases. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Neuroinflammation is involved in various central nervous system (CNS) disorders, including brain infections, ischemia, trauma, stroke, and degenerative CNS diseases. In the CNS inflammation, secretory phospholipase A2-IIA (sPLA2-IIA) acts as a mediator, resulting in the generation of the precursors of pro-inflammatory lipid mediators, such as prostaglandins (PGs) and leukotrienes (LTs). However, the role of sPLA2-IIA in neuroinflammation is more complicated and remains unclear yet. In the present study, we investigated the effect of sPLA2-IIA inhibition by specific inhibitor SC-215 on the inflammation in LPS-induced mice cerebral cortex and primary astrocytes. Our results showed that the inhibition of sPLA2-IIA alleviated the release of PGE2 by suppressing the activation of ERK1/2, cPLA2α, COX-2 and mPGES-1. These findings demonstrated that sPLA2-IIA showed the potential to regulate the neuroinflammation in vivo and in vitro, indicating that sPLA2-IIA might be a novel target for the treatment of acute neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract: Considerable evidence has been accumulated demonstrating an important role for inflammation in ischemic brain injury and its contribution to greater cerebral damage after ischemia. Blocking the inflammatory reaction promotes neuroprotection and shows therapeutic potential for clinical treatment of ischemic brain injury. Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, demonstrates antiedematous and anti-inflammatory effects. Here we assessed neuroprotective effects of escin with a transient global cerebral ischemia model. Global cerebral ischemia was induced by occluding both common carotid arteries and withdrawing 0.3ml of blood from the tail vein in mice. Treatment with escin was initiated 0.5h after ischemia induction and given once a day for three consecutive days. Then animals were assessed using the Morris water–maze test and step-down passive avoidance test. Acetylcholinesterase (AChE) activity, histological pathology, and expression of inflammatory genes in the hippocampus were determined. The results showed escin significantly improved learning and memory recovery and reduced hippocampal damage in the cerebral ischemic mice. However, donepezil merely improved learning and memory recovery but did not ameliorate hippocampal damage in the cerebral ischemic mice. Furthermore, we found escin significantly downregulated certain inflammatory gene expression and upregulated expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was recently reported as a neuroprotective protein in the brain. Our results indicate that inhibition of inflammation and protection of hippocampal neurons by escin may be a potentially useful therapy for ischemic brain injury. [Copyright &y& Elsevier]

Abstract: Norcantharidin (NCTD), the demethylated analogue of cantharidin, inhibits the proliferation of a variety of human tumor cell lines, and appears to cause the least nephrotoxic and inflammatory side effects. Although NCTD has been used to treat human cancers in China for years, there is no report regarding its metabolism up to now. This is the first report to separate and identify the main metabolites of NCTD in vivo by GC–MS using TMS derivatives. Two hydrolyzed products and five phase I or phase II metabolites were found in rat by the chromatogram comparisons of the blank with incurred biological samples. Multiple stages of fragmentation patterns were used to confirm the metabolites characterizations. The established GC–MS method can also be applied to identifying unknown metabolites of the drugs containing hydroxyl or carbonyl groups in molecular structure. [Copyright &y& Elsevier]

Abstract: Aims: An inflammatory reaction is commonly found in the pathogenesis of diabetic nephropathy (DN). Cilostazol, a type 3 phosphodiesterase (PDE) inhibitor, has been previously reported to be anti-inflammatory, independent of an anti-platelet property. In the present study, we evaluated the hypothesis that cilostazol has protective effects on diabetic nephropathy by modulating the inflammatory process. Main methods: Cilostazol was administered (27 or 9 mg kg−1 d−1) to streptozotocin (STZ)-induced diabetic rats for eight weeks. We studied the kidney expression of vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 by immunofluorescence, western blotting and real-time PCR. The renal monocyte chemoattractant protein (MCP)-1 and vascular endothelial growth factor (VEGF) levels were examined by ELISA. The nuclear factor (NF)-κB-DNA binding activity was assessed by electrophoresis mobility shift assay (EMSA). Key findings: Our results showed cilostazol inhibited diabetes-induced hypertrophy of the glomeruli and infiltration of inflammatory cells, as well as the increase in the VCAM-1 and ICAM-1 mRNA and protein expression, and MCP-1 and VEGF contents in the kidneys. Consistent with these findings, cilostazol attenuated the enhanced activation of NF-κB in diabetic rats. Significance: These results demonstrate that the renoprotective effects of cilostazol may be mediated by its anti-inflammatory actions, including inhibition of NF-κB activation and the subsequent decrease in proinflammatory factors, such as VCAM-1, ICAM-1, MCP-1 and VEGF expression in kidneys of diabetic rats. [Copyright &y& Elsevier]