System biology approaches to identify hub genes linked with ECM organization and inflammatory signaling pathways in schizophrenia pathogenesis.

Schizophrenia (SZ) is a chronic and devastating mental illness that affects around 20 million individuals worldwide. Cognitive deficits and structural and functional changes of the brain, abnormalities of brain ECM components, chronic neuroinflammation, and devastating clinical manifestation during SZ are likely etiological factors shown by affected individuals. However, the pathophysiological events associated with multiple regulatory pathways involved in the brain of this complex disorder are still unclear. This study aimed to develop a pipeline based on bioinformatics and systems biology approaches for identifying potential therapeutic targets involving possible biological mechanisms from SZ patients and healthy volunteers. About 420 overlapping differentially expressed genes (DEGs) from three RNA-seq datasets were identified. Gene ontology (GO), and pathways analysis showed several biological mechanisms enriched by the commonly shared DEGs, including extracellular matrix organization (ECM) organization, collagen fibril organization, integrin signaling pathway, inflammation mediated by chemokines and cytokines signaling pathway, and GABA-B receptor II and IL4 mediated signaling. Besides, 15 hub genes (FN1, COL1A1, COL3A1, COL1A2, COL5A1, COL2A1, COL6A2, COL6A3, MMP2, THBS1, DCN, LUM, HLA-A, HLA-C, and FBN1) were discovered by comprehensive analysis, which was mainly involved in the ECM organization and inflammatory signaling pathway. Furthermore, the miRNA target of the hub genes was analyzed with the random-forest-based approach software miRTarBase. In addition, the transcriptional factors and protein kinases regulating overlapping DEGs in SZ, namely, SUZ12, EZH2, TRIM28, TP53, EGR1, CSNK2A1, GSK3B, CDK1, and MAPK14, were also identified. The results point to a new understanding that the hub genes (fibronectin 1, collagen, matrix metalloproteinase-2, and lumican) in the ECM organization and inflammatory signaling pathways may be involved in the SZ occurrence and pathogenesis.

Effect of remimazolam vs. propofol on hemodynamics during general anesthesia induction in elderly patients: Single-center, randomized controlled trial.

The current study aimed to compare the effects between remimazolam and propofol on hemodynamic stability during the induction of general anesthesia in elderly patients. We used propofol at a rate of 60 mg/(kg·h) in the propofol group (group P) or remimazolam at a rate of 6 mg/(kg·h) in the remimazolam group (group R) for the induction. A processed electroencephalogram was used to determine whether the induction was successful and when to stop the infusion of the study drug. We measured when patients entered the operating room (T 0), when the induction was successful (T 1), and when before (T 2) and 5 min after successful endotracheal intubation (T 3). We found that mean arterial pressure (MAP) was lower at T 1-3, compared with T 0 in both groups, but higher at T 2 in the group R, while ΔMAP T0-T2 and ΔMAP max were smaller in the group R (ΔMAP T0-T2: the difference between MAP at time point T 0 and T 2, ΔMAP max: the difference between MAP at time point T 0 and the lowest value from T 0 to T 3). Cardiac index and stroke volume index did not differ between groups, whereas systemic vascular resistance index was higher at T 1-3 in the group R. These findings show that remimazolam, compared with propofol, better maintains hemodynamic stability during the induction, which may be attributed to its ability to better maintain systemic vascular resistance levels.

Peripheral surgery triggers mast cells activation: Focusing on neuroinflammation.

Peripheral surgery can lead to a systemic aseptic inflammatory response comprising several mediators aiming at restoring tissue homeostasis. It induces inflammatory mechanisms through neuroimmune interaction between the periphery and to brain which also plays a critical role in causing cognitive impairments. Accumulating scientific evidence revealed that acute neuroinflammation of the brain triggered by peripheral surgery that causes peripheral inflammation leads to transmitting signals into the brain through immune cells. Mast cells (MCs) play an important role in the acute neuroinflammation induced by peripheral surgical trauma. After peripheral surgery, brain-resident MCs can be rapidly activated followed by releasing histamine, tryptase, and other inflammatory mediators. These mediators then interact with other immune cells in the peripheral and amplify the signal into the brain by disrupting BBB and activating principle innate immune cells of brain including microglia, astrocytes, and vascular endothelial cells, which release abundant inflammatory mediators and in turn accelerate the activation of brain MCs, amplify the cascade effect of neuroinflammatory response. Surgical stress may induce HPA axis activation by releasing corticotropin-releasing hormone (CRH) subsequently influence the activation of brain MCs, thus resulting in impaired synaptic plasticity. Herein, we discuss the better understating of MCs mediated neuroinflammation mechanisms after peripheral surgery and potential therapeutic targets for controlling inflammatory cascades.

Prognostic factors for trigeminocardiac reflex during cerebrovascular intervention operation.

Introduction: Trigeminocardiac reflex (TCR) is a brainstem reflexive response of hemodynamic instability during surgery. Identification of risk factors relevant to TCR during cerebrovascular intervention procedures is helpful to efficiently prevent and treat its occurrence. The purpose of this study was to demonstrate the risk factors for Onyx embolization during cerebrovascular intervention operation so as to optimize perioperative management strategies on TCR. Methods: We performed a retrospective study on the patients with Onyx embolization under general anaesthesia over 6-years period from 2013 to 2018. 354 patients were finally eligible for inclusion, and then divided into TCR group (group T) and control group (group N). Patient characteristics, clinical diagnosis, comorbidities, lesion sites, hemodynamics changes, and complications were compared between two groups. Several multivariable regression models were applied to analyze the risk factors associated with TCR. Results: TCR occurred in 59 patients (16.7%) among 354 patients. There was no significant difference in patient characteristics between two groups (P > 0.05). During DMSO/Onyx injection, HR and MAP were much lower in group T than group N (P < 0.01). Notably, univariable analysis revealed that the patients with dural arteriovenous fistula (DAVF) and middle meningeal artery being affected were associated with a higher incidence of TCR (P < 0.01). Furthermore, multivariable analysis showed that there was a close link of TCR with DAVF [OR = 4.12; 95% CI (1.83-10.65)] and middle meningeal artery embolization [OR = 3.90; 95% CI (1.58-9.63)]. Further stratified analysis of patients with TCR found that patients with middle meningeal artery embolization were more likely to experience hypotension during TCR episode (P < 0.05). Finally, more incidence of postoperative adverse events was observed when TCR episode (P < 0.05). Conclusion: We found that DAVF and middle meningeal artery embolization were independent risk factors for TCR episodes during Onyx endovascular embolization, highly likely leading to intraoperative hemodynamics fluctuations and postoperative adverse events.

Network Biology Approaches to Uncover Therapeutic Targets Associated with Molecular Signaling Pathways from circRNA in Postoperative Cognitive Dysfunction Pathogenesis.

Postoperative cognitive dysfunction (POCD) is a cognitive deterioration and dementia that arise after a surgical procedure, affecting up to 40% of surgery patients over the age of 60. The precise etiology and molecular mechanisms underlying POCD remain uncovered. These reasons led us to employ integrative bioinformatics and machine learning methodologies to identify several biological signaling pathways involved and molecular signatures to better understand the pathophysiology of POCD. A total of 223 differentially expressed genes (DEGs) comprising 156 upregulated and 67 downregulated genes were identified from the circRNA microarray dataset by comparing POCD and non-POCD samples. Gene ontology (GO) analyses of DEGs were significantly involved in neurogenesis, autophagy regulation, translation in the postsynapse, modulating synaptic transmission, regulation of the cellular catabolic process, macromolecule modification, and chromatin remodeling. Pathway enrichment analysis indicated some key molecular pathways, including mTOR signaling pathway, AKT phosphorylation of cytosolic targets, MAPK and NF-κB signaling pathway, PI3K/AKT signaling pathway, nitric oxide signaling pathway, chaperones that modulate interferon signaling pathway, apoptosis signaling pathway, VEGF signaling pathway, cellular senescence, RANKL/RARK signaling pathway, and AGE/RAGE pathway. Furthermore, seven hub genes were identified from the PPI network and also determined transcription factors and protein kinases. Finally, we identified a new predictive drug for the treatment of SCZ using the LINCS L1000, GCP, and P100 databases. Together, our results bring a new era of the pathogenesis of a deeper understanding of POCD, identified novel therapeutic targets, and predicted drug inhibitors in POCD.

Electroacupuncture Ameliorates Tibial Fracture-Induced Cognitive Dysfunction by Elevating α7nAChR Expression and Suppressing Mast Cell Degranulation in the Hippocampus of Rats.

Intracerebral neuroinflammation, closely related to brain mast cell (MC) activation, performs an integral function in the pathogenic process of postoperative cognitive dysfunction (POCD). In addition to regulating cognitive activities, the alpha-7-nicotinic acetylcholine receptor (α7nAChR) engages in the progression of cognitive deficiency. In this research, we aimed to investigate how electroacupuncture (EA) affects the cognitive function in rats after tibial fracture surgery to determine whether the underlying mechanism involves the inhibition of hippocampal MC degranulation via α7nAChR. A rat model of tibial fracture surgery for inducing POCD was developed and subjected to treatment with EA or the α7nAChR antagonist α-bungarotoxin (α-BGT) and the α7nAChR agonist PHA-543613. The spatial memory tasks in the Morris Water Maze (MWM) test showed that both EA and PHA-543613-treated rats performed significantly better than untreated rats, with reduced escape latency and increased frequency of passage through the platform. However, EA and PHA-543613 intervention decreased the protein and mRNA levels of High-mobility group box-1(HMGB-1) and proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) in the serum and hippocampus, respectively, by upregulating α7nAChR in the hippocampus. Furthermore, EA and PHA-543613 pretreatment reduced the number of activated MCs and suppressed neuronal apoptosis after tibial fracture surgery in the hippocampal CA1 regions, which was reversed by α-BGT. The findings indicated that EA pretreatment ameliorated POCD after tibial fracture surgery in rats by inhibiting brain MC activation and neuroinflammation mediated by the α7nAChR-dependent cholinergic anti-inflammatory system.

Analysis of Risk Factors for Intraoperative Hypotension in Cesarean Section and Poor Prognosis of Neonates.

Objective: To analyze the risk factors of intraoperative hypotension in cesarean section women and poor prognosis of neonates. Methods: The clinical data of 1071 cesarean section women admitted to The Affiliated Jiangning Hospital of Nanjing Medical University from January 2021 to December 2021 were retrospectively analyzed. They were divided into hypotension group (n = 472) and normal control group (n = 599) according to whether there was hypotension during operation. The correlations between the clinical data of cesarean section and the occurrence of intraoperative hypotension and poor prognosis of neonates were analyzed by logistic regression analysis. Receiver operating curve (ROC) was drawn and the area under the curve (AUC) was calculated. Results: Logistic regression analysis results showed that BMI ≥30 kg/m2, infant weight ≥3500 g, spinal anesthesia, puncture site L2-3, bupivacaine dose>10 mg, ropivacaine dose>50 mg, and perfusion index≥4 were the risk factor for intraoperative hypotension in cesarean section (p < 0.01) and BMI ≥30 kg/m2, umbilical cord around neck, spinal anesthesia, and perfusion index≥4 were risk factors for poor prognosis of neonates (p < 0.01). The AUC of ROC for BMI to diagnose intraoperative hypotension in cesarean section women was 0.6240 (95% CI: 0.59-0.66, p < 0.01), the sensitivity was only 30.20% (95% CI: 26.73%-35.02%), and the specificity was 87.65% (84.77%-90.04%), and the AUC of BMI for the diagnosis of poor prognosis of neonates was 0.5647 (95% CI: 0.5013-0.6280, p = 0.049), and the sensitivity was 51.19% (95% CI: 40.69%-61.59%), and the specificity was 64.34% (61.30%-67.26%). The AUC of perfusion index for the diagnosis of intraoperative hypotension in cesarean section women was 0.8333 (95% CI: 0.8081-0.8584, p < 0.01), the sensitivity was 94.49% (95% CI: 92.05%-96.21%), and the specificity was 73.12% (69.43%-76.52%); the AUC of perfusion index for the diagnosis of ROC with poor prognosis of neonates was 0.6164 (95% CI: 0.5538-0.6791, p < 0.01), the sensitivity was 70.24% (95% CI: 59.75%-78.96%), and the specificity was 50.86% (47.75%-53.97%). Conclusion: The prediction model established by BMI, infant weight, anesthesia method, puncture site, anesthetic drug dose, and perfusion index has guiding value for clinical prediction of cesarean section maternal hypotension. The prediction model established by BMI, umbilical cord around neck, anesthesia method, and perfusion index has guiding value for clinical prediction of poor prognosis of neonates.

Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner.

Background: The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the "first responders", play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified. Methods: In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed KitW-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again. Results: Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate. Conclusion: Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD.

Bidirectional communication between mast cells and the gut-brain axis in neurodegenerative diseases: Avenues for therapeutic intervention.

Although the global incidence of neurodegenerative diseases has been steadily increasing, especially in adults, there are no effective therapeutic interventions. Neurodegeneration is a heterogeneous group of disorders that is characterized by the activation of immune cells in the central nervous system (CNS) (e.g., mast cells and microglia) and subsequent neuroinflammation. Mast cells are found in the brain and the gastrointestinal tract and play a role in "tuning" neuroimmune responses. The complex bidirectional communication between mast cells and gut microbiota coordinates various dynamic neuro-cellular responses, which propagates neuronal impulses from the gastrointestinal tract into the CNS. Numerous inflammatory mediators from degranulated mast cells alter intestinal gut permeability and disrupt blood-brain barrier, which results in the promotion of neuroinflammatory processes leading to neurological disorders, thereby offsetting the balance in immune-surveillance. Emerging evidence supports the hypothesis that gut-microbiota exert a pivotal role in inflammatory signaling through the activation of immune and inflammatory cells. Communication between inflammatory cytokines and neurocircuits via the gut-brain axis (GBA) affects behavioral responses, activates mast cells and microglia that causes neuroinflammation, which is associated with neurological diseases. In this comprehensive review, we focus on what is currently known about mast cells and the gut-brain axis relationship, and how this relationship is connected to neurodegenerative diseases. We hope that further elucidating the bidirectional communication between mast cells and the GBA will not only stimulate future research on neurodegenerative diseases but will also identify new opportunities for therapeutic interventions.

Neuroimmune connections between corticotropin-releasing hormone and mast cells: novel strategies for the treatment of neurodegenerative diseases.

Corticotropin-releasing hormone is a critical component of the hypothalamic-pituitary-adrenal axis, which plays a major role in the body's immune response to stress. Mast cells are both sensors and effectors in the interaction between the nervous and immune systems. As first responders to stress, mast cells can initiate, amplify and prolong neuroimmune responses upon activation. Corticotropin-releasing hormone plays a pivotal role in triggering stress responses and related diseases by acting on its receptors in mast cells. Corticotropin-releasing hormone can stimulate mast cell activation, influence the activation of immune cells by peripheral nerves and modulate neuroimmune interactions. The latest evidence shows that the release of corticotropin-releasing hormone induces the degranulation of mast cells under stress conditions, leading to disruption of the blood-brain barrier, which plays an important role in neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder and amyotrophic lateral sclerosis. Recent studies suggest that stress increases intestinal permeability and disrupts the blood-brain barrier through corticotropin-releasing hormone-mediated activation of mast cells, providing new insight into the complex interplay between the brain and gastrointestinal tract. The neuroimmune target of mast cells is the site at which the corticotropin-releasing hormone directly participates in the inflammatory responses of nerve terminals. In this review, we focus on the neuroimmune connections between corticotropin-releasing hormone and mast cells, with the aim of providing novel potential therapeutic targets for inflammatory, autoimmune and nervous system diseases.

Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway.

OBJECTIVE: Neuroinflammation plays a critical role in central nervous system diseases. Exosomal miRNAs released from various cells are implicated in cell-to-cell communication. Prior studies have placed substantial emphasis on the role of cytokines in mast cell-microglia interactions during neuroinflammation. However, it has never been clearly determined whether exosomal miRNAs participate in the interaction between mast cells and microglia and thus mediate neuroinflammation. METHODS: The characteristics of exosomes isolated from cell culture supernatants were confirmed by transmission electron microscopy (TEM), nanoparticle-tracking analysis (NTA) and Western blot. The transfer of PKH67-labelled exosomes and Cy3-labelled miR-409-3p was observed by fluorescence microscopy. Migration and activation of murine BV-2 microglial cells were evaluated through Transwell assays and immunofluorescence staining for Iba1 and CD68. CD86, IL-1ß, IL-6 and TNF-α were assessed via qRT-PCR and ELISA. MiR-409-3p was detected by qRT-PCR. Nr4a2 and NF-κB levels were measured by western blot. Regulatory effects were identified by luciferase reporter assays. RESULTS: Lipopolysaccharide (LPS)-stimulated murine P815 mast cells secreted exosomes that were efficiently taken up by murine BV-2 cells, which promoted murine BV-2 cell migration and activation. LPS-P815 exosomes increased the CD86, IL-1ß, IL-6 and TNF-α levels in murine BV-2 microglia. Furthermore, activated mast cells delivered exosomal miR-409-3p to murine BV-2 microglia. Upregulated miR-409-3p promoted murine BV-2 microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway. CONCLUSION: Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway, which provides evidence that not only cytokines but also exosomal miRNAs participate in neuroinflammation. In the future, targeting exosomal miRNAs may provide new insights into neuroinflammation.

Corrigendum to "Protective Effects of Pretreatment with Oleanolic Acid in Rats in the Acute Phase of Hepatic Ischemia-Reperfusion Injury: Role of the PI3K/Akt Pathway".

[This corrects the article DOI: 10.1155/2014/451826.].

Activation of PI3K/Akt/HIF-1α Signaling is Involved in Lung Protection of Dexmedetomidine in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Pilot Study.

BACKGROUND: Lung resection and one lung ventilation (OLV) during video-assisted thoracoscopic surgery (VATS) may lead to acute lung injury. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, improves arterial oxygenation in adult patients undergoing thoracic surgery. The aim of this pilot study was to explore possible mechanism related to lung protection of DEX in patients undergoing VATS. PATIENTS AND METHODS: Seventy-four patients scheduled for VATS were enrolled in this study. Three timepoints (before anesthesia induction (T0), 40 min after OLV (T1), and 10 min after two-lung ventilation (T2)) of arterial blood gas were obtained. Meanwhile, lung histopathologic examination, immunohistochemistry analysis (occludin and ZO-1), levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in lung tissue and plasma, and activation of phosphoinositide-3-kinase (PI3K)/AKT/hypoxia-inducible factor (HIF)-1α signaling were detected. Postoperative outcomes including duration of withdrawing the pleural drainage tube, length of hospital stay, hospitalization expenses, and postoperative pulmonary complications (PPCs) were also recorded. RESULTS: Sixty-seven patients were randomly divided into DEX group (group D, n=33) and control group (group N, n=34). DEX improved oxygenation at T1 and T2 (group D vs group N; T1: 191.8 ± 49.8 mmHg vs 159.6 ± 48.1 mmHg, P = 0.009; T2: 406.0 mmHg [392.2-423.7] vs 374.5 mmHg [340.2-378.2], P = 0.001). DEX alleviated the alveolar capillary epithelial structure damage, increased protein expression of ZO-1 and occludin, inhibited elevation of the expression of TNF-α and IL-6 in lung tissue and plasma, and increased protein expression of p-PI3K, p-AKT and HIF-1α. Dex administered had better postoperative outcomes with less risk of PPCs and hospitalization expenses as well as shorter duration of withdrawing the pleural drainage tube and length of hospital stay. CONCLUSION: Activation of PI3K/Akt/HIF-1α signaling might be involved in lung protection of DEX in patients undergoing VATS.

Correction to: Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization.

An amendment to this paper has been published and can be accessed via the original article.

Histamine 2/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway in aged rats.

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.

The Mast Cell Is an Early Activator of Lipopolysaccharide-Induced Neuroinflammation and Blood-Brain Barrier Dysfunction in the Hippocampus.

Neuroinflammation contributes to or even causes central nervous system (CNS) diseases, and its regulation is thus crucial for brain disorders. Mast cells (MCs) and microglia, two resident immune cells in the brain, together with astrocytes, play critical roles in the progression of neuroinflammation-related diseases. MCs have been demonstrated as one of the fastest responders, and they release prestored and newly synthesized mediators including histamine, ß-tryptase, and heparin. However, temporal changes in MC activation in this inflammation process remain unclear. This study demonstrated that MC activation began at 2 h and peaked at 4 h after lipopolysaccharide (LPS) administration. The number of activated MCs remained elevated until 24 h after LPS administration. In addition, the levels of histamine and ß-tryptase in the hippocampus markedly and rapidly increased within 6 h and remained higher than the baseline level within 24 h after LPS challenge. Furthermore, mast cell-deficient KitW-sh/W-sh mice were used to investigate the effects of MCs on microglial and astrocytic activation and blood-brain barrier (BBB) permeability at 4 h after LPS stimulation. Notably, LPS-induced proinflammatory cytokine secretion, microglial activation, and BBB damage were inhibited in KitW-sh/W-sh mice. However, no detectable astrocytic changes were found in WT and KitW-sh/W-sh mice at 4 h after LPS stimulation. Our findings indicate that MC activation precedes CNS inflammation and suggest that MCs are among the earliest participants in the neuroinflammation-initiating events.

Propofol protects human cardiac cells against chemical hypoxiainduced injury by regulating the JNK signaling pathways.

Propofol is a widely used intravenous anesthetic shown to exert a cardioprotective role against oxidative stress and ischemia/reperfusion injury in rat cardiac H9c2 cells. However, the regulatory mechanisms and functions of propofol in human cardiomyocytes remain unknown. The present study chemically induced hypoxia with cobalt chloride (CoCl2) to mimic cardiomyocyte ischemic injury in human cardiac AC16 and HCM cells. To investigate its underlying mechanisms, propofol was added to the cells before the chemical hypoxia phase. The present results suggested that, in response to hypoxia, mitochondrial membrane potential was lost, and cardiomyocyte viability and superoxide dismutase levels decreased. However, the present results showed that reactive oxygen species and malondialdehyde levels increased. The present results suggested that these effects were significantly reversed following propofol treatment. Additionally, the present results suggested that the protective effect of propofol against CoCl2-induced injury may be inhibited by the activation of the JNK signaling pathways. The present results indicated that propofol pre-treatment inhibited CoCl2-induced myocardial injury by preventing mitochondrial dysfunction, which may be partially due to the activation of the JNK signaling pathways. Therefore, propofol may exert anti-oxidative effects in human cardiac cells. The present results suggested that propofol may be used as a treatment for oxidative stress-related cardiac disorders.

Pro-inflammatory role of high-mobility group box-1 on brain mast cells via the RAGE/NF-κB pathway.

High-mobility group box-1 (HMGB-1) acts as a pro-inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro-inflammatory effects of HMGB-1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB-1 and explored whether this process is involved in the pro-inflammatory effects of HMGB-1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB-1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague-Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB-1. Increased levels of tumor necrosis factor and IL-1ß were observed in the P815 cells, as well as in the rats' brains, after HMGB-1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)-siRNA inhibited the HMGB-1-induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor-κB (NF-κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB-1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood-brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB-1-induced pro-inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro-inflammatory effect of HMGB-1 on the CNS, probably via activating the RAGE/NF-κB pathway.

Stabilization of Brain Mast Cells Alleviates LPS-Induced Neuroinflammation by Inhibiting Microglia Activation.

BACKGROUND: The functional aspects of mast cell-microglia interactions are important in neuroinflammation. Our previous studies have demonstrated that mast cell degranulation can directly induce microglia activation. However, the role of mast cells in Lipopolysaccharide (LPS)-induced microglia activation, neuroinflammation and cognitive impairment has not been clarified. METHODS: This study investigated the interaction between brain microglia and mast cells in vivo through site-directed injection of cromolyn into rat right hypothalamus using stereotaxic techniques. Cognitive function was subsequently assessed using trace fear conditioning and Y maze tests. Mast cells in rat brain were stained with toluidine blue and counted using Cell D software. Microglia activation was assessed by Iba1 immunohistochemistry both in rat brain and in mast cell-deficient KitW-sh/W-sh mice. Receptor expression in rat microglia was determined using flow cytometry analysis. Cytokine levels in rat brain tissue and cell supernatant were measured using high-throughput ELISA. Western blotting was used to analyze Cell signaling proteins. RESULTS: In this study, intraperitoneal injection of 1 mg/kg LPS induced mast cell activation in hypothalamus and cognitive dysfunction in rats, and that this process can be repressed by the mast cell stabilizer cromolyn (200 µg). Meanwhile, in mice, LPS IP injection induced significant microglia activation 24 h later in the hypothalamus of wild-type (WT) mice, but had little effect in KitW-sh/W-sh mice. The stabilization of mast cells in rats inhibited LPS-induced microglia activation, inflammatory factors release, and the activation of MAPK, AKT, and NF-κB signaling pathways. We also found that LPS selectively provokes upregulation of H1R, H4R, PAR2, and TLR4, but downregulation of H2R and H3R, in ipsilateral hypothalamus microglia; these effects were partially inhibited by cromolyn. In addition, LPS was also found to induce activation of P815 cells in vitro, consistent with findings from in vivo experiments. These activated P815 cells also induced cytokine release from microglia, which was mediated by the MAPK signaling pathway. CONCLUSION: Taken together, our results demonstrate that stabilization of mast cells can inhibit LPS-induced neuroinflammation and memory impairment, suggesting a novel treatment strategy for neuroinflammation-related diseases.