Jue Jiang

Perineural dexmedetomidine attenuates inflammation in rat sciatic nerve via the NF-κB pathway.

Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-α. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF-α at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-κB to the nucleus and the binding activity of NF-κB. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF-α and the activation of NF-κB. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-κB, thus reducing inflammatory cytokines.

Neuronal apoptosis may not contribute to the long-term cognitive dysfunction induced by a brief exposure to 2% sevoflurane in developing rats

BACKGROUND Sevoflurane is an inhaled anesthetic commonly used in the pediatric. Recent animal studies suggest that early exposure to high concentration of sevoflurane for a long duration can induce neuroapoptosis and later cognitive dysfunction. However, the neurodevelopmental impact induced by lower concentration and shorter exposure duration of sevoflurane is unclear. To investigate whether early exposure to 2% concentration of sevoflurane for a short duration (clinically relevant usage of sevoflurane) can also induce neuroapoptosis and later cognitive dysfunction. METHODS Rat pups were subjected to control group, 2% sevoflurane for 3h and 3% sevoflurane for 6h. TUNEL assay and apoptotic enzyme cleaved caspase-3 measured by western blot were used for detection of neuronal apoptosis in frontal cortex and CA1 region of hippocampus 24 after sevoflurane treatment. Long-term cognitive function was evaluated by Morris water maze and passive avoidance test as the rats grew up. RESULTS The apoptotic levels in frontal cortex and CA1 region were significantly increased after rats exposed to 3% sevoflurane for 6h (P<0.05), but not 2% sevoflurane for 3h (P>0.05). Exposure to both 2% sevoflurane for 3h and 3% sevoflurane for 6h could cause long-term cognitive dysfunction and animals exposed to 3% sevoflurane for 6h exhibited worse neurodevelopmental outcomes (P<0.05). CONCLUSION It was suggested that neuronal apoptosis might not contribute to long-term cognitive dysfunction induced by 2% concentration and short exposure time of sevoflurane. Our findings also suggested that the mechanisms of sevoflurane-induced neurodevelopmental impact might be various, depending on the concentration and exposure duration.

The change of circulating insulin like growth factor binding protein 7 levels may correlate with postoperative cognitive dysfunction.

Insulin-like growth factor binding protein (IGFBP) 7 may be a critical regulator of memory consolidation. This study was performed to assess the relationship between circulating IGFBP7 levels and postoperative cognition dysfunction (POCD) in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. Among one hundred and two patients included in this study, forty-four patients completed collection of all four blood samples and thirty-five patients were diagnosed with POCD. The results of Mini-Mental State Examination (MMSE) test and enzyme-linked immunosorbent assay showed that postoperative MMSE score and circulating insulin-like growth factor (IGF)-1 level were lower and circulating IGFBP7 level was higher than preoperative level. Circulating IGF-1 level was significantly lower and D-value of preoperative and postoperative day 1 circulating IGFBP7 levels (ΔIGFBP7(1)) was significantly higher in the POCD group. Age preoperative MMSE, IGF-1 level and ΔIGFBP7(1) significantly correlated with POCD, but preoperative IGFBP7 level not. Logistic regression analysis revealed that older patients, lower preoperative MMSE score, IGF-1 level and higher IGFBP7 level significantly increased the risk of POCD, but ΔIGFBP7(1) not. Hence, circulating IGF-1 and IGFBP7 levels and their changes during operation under general anesthesia may correlate with POCD, but further investigation in larger samples is needed.

Downregulation of circulating insulin-like growth factor 1 contributes to memory impairment in aged mice after sevoflurane anesthesia

Insulin-like growth factor 1 (IGF-1) is a neuroprotective hormone and a decrease in levels of circulating IGF-1 contributes toward cognitive decline. The aim of this study was to investigate the effect of sevoflurane on the level of circulating IGF-1 and cognitive function in aged mice and the role of circulating IGF-1 in the cognitive dysfunction induced by sevoflurane. Aged mice were exposed to 1 or 2 minimal alveolar concentrations of sevoflurane for 4 or 8 h. Before and after the exposure, blood was collected from the tail vein and serum IGF-1 was measured by an enzyme-linked immunosorbent assay. After exposure, spatial learning and memory were tested in the Morris water maze. An intraperitoneal injection of IGF-1 was used to study the role of IGF-1 in the cognitive impairment induced by sevoflurane. Sevoflurane dose dependently decreased the serum IGF-1 concentration, and resulted in aged mice taking significantly longer and traveling significantly further to find the platform. Sevoflurane significantly decreased the times crossing the platform and %time spent in target quadrant relative to the control group. IGF-1 attenuated this effect, but could not completely reverse it. We conclude that downregulation of circulating IGF-1 contributes toward the cognitive impairment induced by sevoflurane.

The cancer pain related factors affected by celecoxib together with cetuximab in head and neck squamous cell carcinoma

Pain is the most disruptive influence on the quality of prognosis among head and neck squamous cell carcinoma (HNSCC) patients. The development of pain is closely associated with tumor growth and inflammation in the cancer patients. Notably, cyclooxygenase-2 (COX-2) is an important mediator during inflammation. Celecoxib, a selective inhibitor of COX-2, was hailed as a promising chemopreventive agent for HNSCC. Dose-dependent cardiac toxicity limits long-term use of celecoxib. However, the toxicity can be diminished by lowering the dosage. In this study, we hypothesized that a combinatory strategy to reduce cancer pain via two distinct pathways, tumor grown inhibition and inflammation blockade, which would enhance analgesia effect induced by HNSCC. We found that treatment of cetuximab (C225), a monoclonal anti-epidermal growth factor receptor (EGFR) antibody, with low-dose celecoxib results in a more pronounced anticancer effect in HNSCC than either agent alone. More noticeably, the combination could downregulate the phosphorylation of constitutively active extracellular signal regulated kinase (ERK) in CAL-27 and Fadu cells. Furthermore, combination therapy enhancing S phase arrest and downregulating cyclin D1 was observed in Fadu cells. The COX-2 expression was significantly blocked by celecoxib combined with C225, and other cancer pain related factors, such as ET-1 and NGF, was also downregulated by combination treatment. Taken together, these results strongly suggest that combination of celecoxib with C225 holds potential as a new therapy strategy in developing cancer pain treatment in HNSCC.

MicroRNA‐27a‐3p Suppression of PPAR‐γ Contributes to Cognitive Impairments Resulting from Sevoflurane Treatment

Sevoflurane is the most widely used anaesthetic administered by inhalation. Exposure to sevoflurane in neonatal mice can induce learning deficits and abnormal social behaviours. MicroRNA (miR)‐27a‐3p, a short, non‐coding RNA that functions as a tumour suppressor, is up‐regulated after inhalation of anaesthetic, and peroxisome proliferator‐activated receptor γ (PPAR‐γ) is one of its target genes. The objective of this study was to investigate how the miR‐27a‐3p–PPAR‐γ interaction affects sevoflurane‐induced neurotoxicity. A luciferase reporter assay was employed to identify the interaction between miR‐27a‐3p and PPAR‐γ. Primary hippocampal neuron cultures prepared from embryonic day 0 C57BL/6 mice were treated with miR‐27a‐3p inhibitor or a PPAR‐γ agonist to determine the effect of miR‐27a‐3p and PPAR‐γ on sevoflurane‐induced cellular damage. Cellular damage was assessed by a flow cytometry assay to detect apoptotic cells, immunofluorescence to detect reactive oxygen species, western blotting to detect NADPH oxidase 1/4 and ELISA to measure inflammatory cytokine levels. In vivo experiments were performed using a sevoflurane‐induced anaesthetic mouse model to analyse the effects of miR‐27a‐3p on neurotoxicity by measuring the number of apoptotic neurons using the Terminal‐deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) method and learning and memory function by employing the Morris water maze test. Our results revealed that PPAR‐γ expression was down‐regulated by miR‐27a‐3p following sevoflurane treatment in hippocampal neurons. Down‐regulation of miR‐27a‐3p expression decreased sevoflurane‐induced hippocampal neuron apoptosis by decreasing inflammation and oxidative stress‐related protein expression through the up‐regulation of PPAR‐γ. In vivo tests further confirmed that inhibition of miR‐27a‐3p expression attenuated sevoflurane‐induced neuronal apoptosis and learning and memory impairment. Our findings suggest that down‐regulation of miR‐27a‐3p expression ameliorated sevoflurane‐induced neurotoxicity and learning and memory impairment through the PPAR‐γ signalling pathway. MicroRNA‐27a‐3p may, therefore, be a potential therapeutic target for preventing or treating sevoflurane‐induced neurotoxicity.

Circulating TNF-α levels increased and correlated negatively with IGF-I in postoperative cognitive dysfunction

Signaling pathways of tumor necrosis factor-α (TNF-α) and insulin-like growth factor-I (IGF-I) are found to be functionally interrelated in some experimental studies. IGF-I may be involved in the pathogenesis of postoperative cognitive dysfunction (POCD). In order to investigate the possible interaction of TNF-α and IGF-I in POCD, the plasma levels of IGF-I and TNF-α were determined in 44 patients under general anesthesia. As compared with non-POCD patients, POCD patients showed increased TNF-α and decreased IGF-I levels in plasma, as well as a significant negative correlation between TNF-α and IGF-I values. The present results suggest that interaction of increased TNF-α levels and decreased IGF-1 levels might lead to a vicious circle, which may contribute to POCD.

Nrf2 protects against acute lung injury and inflammation by modulating TLR4 and Akt signaling

ABSTRACT Lung injury, which is associated with systemic inflammatory responses, is a common problem with significant morbidity and mortality. Here, we examined the involvement of toll‐like receptor 4 (TLR4) and nuclear factor erythroid 2‐related factor 2 (Nrf2) on intestinal ischemia‐reperfusion (I/R)‐induced lung injury in vivo and in vitro. Analysis of lung tissues in Nrf2‐knockout mice by western blotting, immunohistochemistry, and TUNEL assay, and analysis of bronchoalveolar lavage fluid showed that Nrf2 deficiency upregulated TLR4, enhanced I/R‐induced lung injury, apoptosis, inflammation, and autophagy, and increased the I/R‐induced inactivation of Akt. In mouse lung epithelial cells subjected to oxygen and glucose deprivation/reperfusion (OGD/Rep), Nrf2 silencing increased the OGD/Rep‐induced upregulation of TLR4 and MyD88 and downregulation of HO‐1, and exacerbated OGD/Rep‐induced apoptosis, autophagy, and the downregulation of phospho‐Akt. TLR4 silencing and Akt inhibition experiments indicated that OGD/Rep‐induced cell death by suppressing Akt signaling, and Nrf2 protected lung cells by modulating TLR4 and Akt signaling. These results indicated that the Nrf2/TLR4/Akt axis plays a role in inflammation‐associated lung damage, suggesting potential therapeutic targets for the treatment of lung injury. HIGHLIGHTSNrf2 deficiency upregulated TLR4, enhanced I/R‐induced lung injury, apoptosis, inflammation, autophagy.TLR4 silencing and Akt inhibition experiments indicated that OGD/Rep‐induced cell death by suppressing Akt signaling.Nrf2 protected lung cells by modulating TLR4 and Akt signaling.

Propofol inhibits LPS-induced apoptosis in lung epithelial cell line, BEAS-2B

Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells. Compared with control group, LPS up-regulated Pin-1, phosphatase A2 (PP2A) expression, induced p66Shc-Ser36 phosphorylation, and facilitated p66Shc mitochondrial translocation, thus leading to superoxide anion (O2-) generation, mitochondrial cytochrome c release, active caspase 3 over-expression and cell viability inhibition. Importantly, propofol was shown to down-regulate LPS-induced PP2A expression, limit p66Shc mitochondrial translocation, decrease O2- generation, inhibit mitochondrial cytochrome c release, reduce active caspase 3 expression, and recover cells viability, while propofol had no effects on LPS-induced Pin-1 expression and p66Shc-Ser36 phosphorylation. Moreover, the protective effects of propofol on LPS-induced BEAS-2B cells apoptosis were similar to that of calyculin A, which is an inhibitor of PP2A. We also found that FTY720, which is an activator of PP2A, can effectively reverse the protective function of propofol. Our data illustrated that propofol could alleviate LPS-induced BEAS-2B cells oxidation and apoptosis through down-regulating PP2A expression, limiting p66Shc-Ser36 dephosphorylation and p66Shc mitochondrial translocation, decreasing O2- generation, mitochondrial cytochrome c release, activating caspase 3 expression.