Ketamine and Propofol Protect Neuron Cells from Oxygen-Glucose Deprivation-Induced Injury through SAPK/JNK Signalling Pathway.

Ketamine and propofol are commonly used anaesthetic reagents. Recent research revealed that ketamine and propofol have an important role in cell survival. However, it remains unknown whether they affect the outcome of hypoxic-ischemic brain injury. To address this issue, we in this study investigated the effects of ketamine and propofol on the survival and proliferation of neuronal PC12 cells after exposure to oxygen-glucose deprivation- (OGD-) induced injury. PC12 cells were maintained under a 3-dimensional (3D) culture system to mimic a real physiological microenvironment. The cell injury was induced by 5% CO2 and 95% N2 for a different time point. MTT assay was used for the cell proliferation assay. The cell apoptosis was evaluated by annexin V and propidium iodide (PI) labeling, immunofluorescence staining, transmission electron microscopy (TEM), flow cytometry, and Western blot, respectively. Our results showed that PC12 cell apoptosis was significantly increased for up to 70% after the cells were treated with OGD for 24 hours and reduced to baseline at the 72-hour time point. However, pretreatment with ketamine and propofol significantly protected the cells from OGD-induced cell apoptosis, as evidenced by more expression of antiapoptotic Bcl-2 and lower expression of proapoptotic cleaved caspase-3, phosphor-SAPK/JNK, and phosphor-c-Jun than those of untreated control cells. Thus, we conclude that ketamine and propofol protected PC12 cells from OGD-induced cell apoptosis, at least partially through the SAPK/JNK signalling pathway.

Neurofilament degradation is involved in laparotomy-induced cognitive dysfunction in aged rats.

Excessive neuroinflammatory responses play important roles in the development of postoperative cognitive dysfunction (POCD). Neurofilaments (NFs) were essential to the structure of axon and nerve conduction; and the abnormal degradation of NFs were always accompanied with degenerative diseases, which were also characterized by excessive neuroinflammatory responses in brain. However, it is still unclear whether the NFs were involved in the POCD. In this study, the LC-MS/MS method was used to explore the neuroinflammatory response and NFs of POCD in aged rats. Moreover, trichostatin A (TSA), an inflammation-related drug, was selected to test whether it could improve the surgery-induced cognitive dysfunction, inflammatory responses and NFs. Evident cognitive dysfunction, excessive microglia activation, neuroinflammatory responses and upregulated NFs in hippocampus were observed in the POCD group. TSA pretreatment could significantly mitigate these changes. The KEGG analysis revealed that nine pathways were enriched in the TSA + surgery group (versus the surgery group). Among them, two signaling pathways were closely related with the changes of NFs proteins. In conclusion, surgery could impair the cognitive function and aggravate neuroinflammation and NFs. The TSA could significantly improve these changes which might be related to the activation of the "focal adhesion" and "ECM-receptor interaction" pathways.

Effects of the ALX/FPR2 receptors of lipoxin A4 on lung injury induced by fat embolism syndrome in rats.

This study was designed to investigate the inflammatory responses in fat embolism syndrome (FES) and the relationship of ALX/FPR2 receptors and lipoxin A4 (LXA4) in FES models. In this model, lung injury score, lung tissue wet-to-dry (W/D) ratio and total protein concentration in bronchoalveolar lavage fluid (BALF) were increased compared with those of the control group. Meanwhile, the number of leukocytes and neutrophils was significantly increased in the FES group, as was the myeloperoxidase (MPO) activity and mRNA expression. In addition, the release of TNF-α and IL-1ß was increased. Then, we explored whether LXA4 and ALX/FPR2 were involved in the pathological process of FES. The LXA4 concentration in the experimental groups was markedly higher than that in the control group. At the same time, the protein and mRNA levels of ALX/FPR2 were upregulated in the rat model of FES. Moreover, rats treated with BML-111, an agonist for the ALX/FPR2 receptor of LXA4, showed a lower inflammatory response than mice treated with fat alone. However, the role of BML-111 in fat emboli (FE)-induced acute lung injury (ALI) was attenuated by BOC-2, an antagonist of the ALX/FPR2 receptor of LXA4. Our results demonstrated that the inflammatory response may play an important role in the pathogenesis of FES and that the activation of the ALX/FPR2 receptor for LXA4 can decrease the inflammatory response and may be a therapeutic target for FE-induced ALI.

Idarubicin-loaded methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) nanoparticles for enhancing cellular uptake and promoting antileukemia activity.

PURPOSE: Nanoparticle (NP)-based drug delivery approaches have tremendous potential for enhancing treatment efficacy and decreasing doses of chemotherapeutics. Idarubicin (IDA) is one of the most common chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). However, severe side effects and drug resistance markedly limit the application of IDA. METHODS: In this study, we encapsulated IDA in polymeric NPs and validated their antileukemia activity in vitro and in vivo. RESULTS: NPs with an average diameter of 84 nm was assembled from a methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) (mPEG-PLGA). After loading of IDA, IDA-loaded mPEG-PLGA NPs (IDA/mPEG-PLGA NPs) were formed. The in vitro release data showed that the IDA/mPEG-PLGA NPs have excellent sustained release property. IDA/mPEG-PLGA NPs had exhibited the lower IC50 than pure IDA. Moreover, IDA/mPEG-PLGA NPs in the same concentration substantially induced apoptosis than did pure IDA. Most importantly, IDA/MPEG-PLGA NPs significantly decreased the infiltration of leukemia blasts and improved the overall survival of MLL-AF9-induced murine leukemia compared with free IDA. However, the blank NPs were nontoxic to normal cultured cells in vitro, suggesting that NPs were the safe carrier. CONCLUSION: Our data suggest that IDA/mPEG-PLGA NPs might be a suitable carrier to encapsulate IDA. Low dose of IDA/mPEG-PLGA NPs can be used as a conventional dosage for antileukemia therapy to reduce side effect and improve survival.

S100A11 regulates renal carcinoma cell proliferation, invasion, and migration via the EGFR/Akt signaling pathway and E-cadherin.

S100A11 is a S100 protein family member that contributes to cancer progression. Upregulated in human renal cancer tissues, S100A11 may be a prognostic marker for clear cell renal cell carcinoma, but how it functions in cancer is uncertain. Thus, we studied S100A11 and noted knockdown of S100A11 using short hairpin RNA, which inhibited proliferation, invasion, and migration of renal carcinoma cells as well as increased expression of E-cadherin and decreased expression of epidermal growth factor receptor/Akt in renal carcinoma cells. Therefore, S100A11 may be a key molecular target for treating renal carcinoma.

Overexpression of a Chinese cabbage BrERF11 transcription factor enhances disease resistance to Ralstonia solanacearum in tobacco.

Ethylene-responsive factors (ERFs) play diverse roles in plant growth, developmental processes and stress responses. However, the roles and underlying mechanism of ERFs remain poorly understood, especially in non-model plants. In this study, a full length cDNA of ERF gene was isolated from the cDNA library of Chinese cabbage. According to sequence alignment, we found a highly conservative AP2/ERF domain, two nuclear localization signals, and an ERF-associated Amphiphilic Repression (EAR) motif in its C-terminal region. It belonged to VIIIa group ERFs sharing the highest sequence identity with AtERF11 in all of the ERFs in Arabidopsis and designated BrERF11. BrERF11-green fluorescence protein (GFP) transient expressed in onion epidermis cells localized to the nucleus. The transcript levels of BrERF11 were induced by exogenous salicylic acid (SA), methyl jasmonate (MeJA), ethephon (ETH), and hydrogen peroxide (H(2)O(2)). Constitutive expression of BrERF11 enhanced tolerance to Ralstonia solanacearum infection in transgenic tobacco plants, which was coupled with hypersensitive response (HR), burst of H(2)O(2) and upregulation of defense-related genes including HR marker genes, SA-, JA-dependent pathogen-related genes and ET biosynthesis associated genes and downregulation of CAT1, suggesting BrERF11 may participate in pathogen-associated molecular pattern (PAMP)- and effector-triggered immunity (PTI and ETI) mediated by SA-, JA- and ET-dependent signaling mechanisms.

Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats.

BACKGROUND: Propofol exerts protective effects on neuronal cells, in part through the inhibition of programmed cell death. Autophagic cell death is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. We therefore studied whether propofol could attenuate the formation of autophagosomes, and if so, whether the inhibition of autophagic cell death mediates the neuroprotective effects observed with propofol. METHODOLOGY/PRINCIPAL FINDINGS: The cell model was established by depriving the cells of oxygen and glucose (OGD) for 6 hours, and the rat model of ischemia was introduced by a transient two-vessel occlusion for 10 minutes. Transmission electron microscopy (TEM) revealed that the formation of autophagosomes and autolysosomes in both neuronal PC12 cells and pyramidal rat hippocampal neurons after respective OGD and ischemia/reperfusion (I/R) insults. A western blot analysis revealed that the autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 (LC3-II), Beclin-1 and class III PI3K, were also increased accordingly, but cytoprotective Bcl-2 protein was decreased. The negative effects of OGD and I/R, including the formation of autophagosomes and autolysosomes, the increase in LC3-II, Beclin-1 and class III PI3K expression and the decline in Bcl-2 production were all inhibited by propofol and specific inhibitors of autophagy, such as 3-methyladenine (3-MA), LY294002 and Bafilomycin A1 (Baf),. Furthermore, in vitro OGD cultures and in vivo I/R rats showed an increase in cell survival following the administration of propofol, as assessed by an MTT assay or histochemical analyses. CONCLUSIONS/SIGNIFICANCE: Our data suggest that propofol can markedly attenuate autophagic processes via the decreased expression of autophagy-related proteins in vitro and in vivo. This inhibition improves cell survival, which provides a novel explanation for the pleiotropic effects of propofol that benefit the nervous system.