Abstract Propofol (2,6-diisopropylphenol) is one of the most commonly used anesthetics in clinical surgery. However, its role and relevant mechanisms in post-traumatic stress disorder (PTSD)-like behavioral deficits remain largely unknown. In this study, the PTSD-like phenotype was constructed in rats using the modified single prolonged stress (MSPS) procedure. Propofol and GABAergic system antagonist bicuculline alone or combined administration were performed in rats after MSPS. SH-SY5Y cells were treated with different dosages of BDNF (1, 2, 5, 7 and 10 ng/ml), followed by treated with 25 µmol propofol. We first observed that propofol inhibited the protein level of activity regulated cytoskeleton protein (Arc) in the hippocampus of rats exposed to the MSPS procedure and BDNF-induced Arc upregulation in SH-SY5Y cells. Further analysis showed that administration of propofol alleviated fear memory formation in rats exposed to the MSPS procedure using open field, light dark box and contextual fear conditioning tests, accompanied with increased neurons cells in the hippocampal CA3 region by Nissl staining. Finally, administration of bicuculline to the basolateral amygdala (BLA) can significantly reverse the effect of propofol on the Arc expression and behavioral improvement of the modeling rats. In conclusions, our data suggested that propofol could alleviates fear memory formation in rats underwent MSPS by inhibiting Arc expression in the hippocampus in association with GABAergic activation in the basolateral amygdala GABAergic system.
Global cerebral ischemia induced by cardiac arrest usually leads to poor neurological outcomes. Numerous studies have focused on ways to prevent ischemic damage in the brain, however clinical therapies are still limited. Our previous studies revealed that delta opioid receptor (DOR) activation with [d-Ala2, d-Leu5] enkephalin (DADLE), a DOR agonist, not only significantly promotes neuronal survival on day 3, but also improves spatial memory deficits on days 5-9 after ischemia. However, the neurological mechanism underlying DADLE-induced cognitive recovery remains unclear. This study first examined the changes in neuronal survival in the CA1 region at the advanced time point (day 7) after ischemia/reperfusion (I/R) injury and found a significant amelioration of damaged CA1 neurons in the rats treated with DADLE (2.5 nmol) when administered at the onset of reperfusion. The structure and function of CA1 neurons on days 3 and 7 post-ischemia showed significant improvements in both the density of the injured dendritic spines and the basic transmission of the impaired CA3-CA1 synapses following DADLE treatment. The molecular changes involved in DADLE-mediated synaptic modulation on days 3 and 7 post-ischemia implied the time-related differential regulation of PKCα-MARCKS on the dendritic spine structure and of BDNF- ERK1/2-synapsin I on synaptic function, in response to ischemic/reperfusion injury as well as to DADLE treatment. Importantly, all the beneficial effects of DADLE on ischemia-induced cellular, synaptic, and molecular deficits were eliminated by the DOR inhibitor naltrindole (2.5 nmol). Taken together, this study suggested that DOR activation-induced protective signaling pathways of PKCα-MARCKS involved in the synaptic morphology and BDNF-ERK-synapsin I in synaptic transmission may be engaged in the cognitive recovery in rats suffering from advanced cerebral ischemia.
Ischemic stroke poses a severe risk to human health worldwide, and currently, clinical therapies for the disease are limited. Delta opioid receptor (DOR)-mediated neuroprotective effects against ischemia have attracted increasing attention in recent years. Our previous studies revealed that DOR activation by [d-Ala2, d-Leu5] enkephalin (DADLE), a selective DOR agonist, can promote hippocampal neuronal survival on day 3 after ischemia. However, the specific molecular and cellular mechanisms underlying the DOR-induced improvements in ischemic neuronal survival remain unclear.We first detected the cytoprotective effects of DADLE in an oxygen-glucose deprivation/reperfusion (OGD/R) model and observed increased viability of OGD/R SH-SY5Y neuronal cells. We also evaluated changes in the DOR level following ischemia/reperfusion (I/R) injury and DADLE treatment and found that DADLE increased DOR levels after ischemia in vivo and vitro. The effects of DOR activation on postischemic autophagy were then investigated, and the results of the animal experiment showed that DOR activation by DADLE enhanced autophagy after ischemia, as indicated by elevated LC3 II/I levels and reduced P62 levels. Furthermore, the DOR-mediated protective effects on ischemic CA1 neurons were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Moreover, the results of the cell experiments revealed that DOR activation not only augmented autophagy after OGD/R injury but also alleviated autophagic flux dysfunction. The molecular pathway underlying DOR-mediated autophagy under ischemic conditions was subsequently studied, and the in vivo and vitro data showed that DOR activation elevated autophagy postischemia by triggering the AMPK/mTOR/ULK1 signaling pathway, while the addition of the AMPK inhibitor compound C eliminated the protective effects of DOR against I/R injury.DADLE-evoked DOR activation enhanced neuronal autophagy through activating the AMPK/mTOR/ULK1 signaling pathway to improve neuronal survival and exert neuroprotective effects against ischemia.
Pseudomonas aeruginosa PAO1 is a Gram-negative, opportunistic bacterial human pathogen which infects immunocompromised individuals.The bacterium carries a type III secretion system (T3SS) as a major virulence determinant.The strategy of T3SS inhibitors is to prevent the bacterium from injecting effector proteins into the host, and causing a change in the pathophysiology of the host cells.Based on the structure of a known T3SS inhibitor of P. aeruginosa, 20 new α-phenoxyacetamide derivatives have been designed and synthesized, and the structure-activity relationship results for these new derivatives have been discussed.Five derivatives have shown strong inhibitory effect against exoS gene expression of P. aeruginosa, and among them, N-(2-pyridylmethyl)-2-(2,4-dichlorophenoxy)-butanamide (5r) has not only exhibited stronger potency than the known T3SS inhibitor, but also better solubility in aqueous solution.
With the process of European economic integration,European higher education are increasingly merging into a whole.Within the framework of emerging European higher education area,European higher education played an important role in facilitating student mobility and developing international curriculum.This article can be divided into eight parts,it starts from the historical evolution of European credit transfer system,then introduces its major characteristics,its basic documents,ECTS counselors,the rights and obligations no matter which institution wants to get the ECTS recognition,the role that the universities play in the ECTS,the current situation of ECTS,in the end,summarizes some meaningful practices to our country.
Drug-resistant pathogens have presented increasing challenges to the discovery and development of new antibacterial agents. The type III secretion system (T3SS), existing in bacterial chromosomes or plasmids, is one of the most complicated protein secretion systems. T3SSs of animal and plant pathogens possess many highly conserved main structural components comprised of about 20 proteins. Many Gram-negative bacteria carry T3SS as a major virulence determinant, and using the T3SS, the bacteria secrete and inject effector proteins into target host cells, triggering disease symptoms. Therefore, T3SS has emerged as an attractive target for antimicrobial therapeutics. In recent years, many T3SS-targeting small-molecule inhibitors have been discovered; these inhibitors prevent the bacteria from injecting effector proteins and from causing pathophysiology in host cells. Targeting the virulence of Gram-negative pathogens, rather than their survival, is an innovative and promising approach that may greatly reduce selection pressures on pathogens to develop drug-resistant mutations. This article summarizes recent progress in the search for promising small-molecule T3SS inhibitors that target the secretion and translocation of bacterial effector proteins.
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