Endocannabinoid 2-Arachidonylglycerol Protects Primary Cultured Neurons Against LPS-Induced Impairments in Rat Caudate Nucleus

Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB₁ receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus. However, it is still not clear whether 2-AG is also able to protect CN neurons from proinflammation stimuli. In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response. 2-AG is capable of suppressing elevation of LPS-induced cyclooxygenase-2 expression associated with ERK/p38MAPK/NF-κB signaling pathway in CB₁ receptor-dependant manner in primary cultured CN neurons. Moreover, 2-AG inhibits LPS-induced increase in voltage-gated sodium channel currents and hyperpolarizing shift of activation curves through CB₁ receptor-dependant pathway. Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain.     

mir-300 Promotes Self-Renewal and Inhibits the Differentiation of Glioma Stem-Like Cells

MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells.     

医院感染相关细菌耐药的现状与对策

细菌耐药发展迅猛,严重威胁患者的健康和生命,是全球抗感染领域关注的重点问题.在外科领域,高危患者尤应密切关注.消化道屏障功能不全,条件致病菌异常增多;免疫功能低下或障碍,以致条件致病菌毒性和患者易感性相对增强;重症患者（尤其ICU患者）接受多种医疗护理措施,使得耐药菌易感机会增多;医务人员由于知识不足和对病情严重度的顾虑,不合理应用抗生素等均可导致耐药菌感染性增强,需引起高度关注.应通过对相关知识的认真学习,严格按照各项规定科学用药,杜绝抗生素的滥用,保护患者尤其是危重患者的消化道屏障和免疫功能;注重运用精细手术、通畅引流等专科技术,及时检测、发现感染致病菌给予靶向治疗;加强各项医疗护理技术的无菌操作等综合措施的监控,最大限度地防治、控制耐药菌的产生和传播,促进患者康复.     

Role of IL‐17 and TGF‐β in peritoneal adhesion formation after surgical trauma

Peritoneal adhesions are fibrous tissues formed after surgery. Both cytokines and transforming growth factors (TGFs) are involved in this process. The objective of this study was to investigate the cross talk between these entities. Peritoneal drainage fluid after surgery from patients and rodent models was examined by enzyme‐linked immunosorbent assay and fluorescence‐activated cell sorter. Data showed that the concentrations of interferon (IFN)‐γ and interleukin (IL)‐17 reached their peaks 6–12 hours after surgery, whereas TGF‐β1 concentrations showed two postoperative peak time points at 2 and 72–96 hours. By neutralizing IFN‐γ, IL‐17 6–12 hours, and TGF‐β1 72–96 hours after surgery, the degree of adhesion reduced significantly. However, neutralizing TGF‐β1 2 hours after surgery did not affect adhesion formation. Furthermore, in vitro studies showed that compared with the fibroblasts that were directly stimulated with TGF‐β1, the prestimulation of IL‐17 promoted plasminogen activator inhibitor‐1 production while inhibiting tissue‐type plasminogen activator production. Moreover, additional stimulation with IFN‐γ enhanced this effect. Together, these data indicate that IL‐17 may promote adhesion formation by increasing the reaction of fibroblasts against TGF‐β1. Blocking IL‐17 might have a therapeutic potential in preventing adhesion formation after surgery.     

Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates

Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex.     

Meta-analysis of randomized controlled trials comparing Lichtenstein and totally extraperitoneal laparoscopic hernioplasty in treatment of inguinal hernias

Background

Finding the optimal approach to repair an inguinal hernia is controversial. Therefore, for the scientific evaluation of the total extraperitoneal (TEP) and Lichtenstein mesh techniques for the repair of inguinal hernia, meta-analyses of randomized controlled trials are necessary.

Methods

A complete literature search was conducted in the Cochrane Controlled Trials Register Databases, Pubmed, Embase, International Scientific Institute databases, and Chinese Biomedical Literature Database in various languages.

Results

Randomized controlled trials (13), including 3279 patients, were retrieved from the electronic databases. The Lichtenstein group was associated with a shorter operating time; however, results show that TEP repair enabled patients a shorter time to return to work, less chronic pain compared with Lichtenstein operation. There was no significant difference in seromas, wound infections, or neuralgia. There are no statistically significant difference in terms of hernia recurrence when the follow-up time is ≤3 y. When follow-up time is >3 y, TEP repair shows a higher recurrence rate compared with Lichtenstein repairs.

Conclusions

There was insufficient evidence to determine the greater effectiveness between TEP and Lichtenstein mesh techniques. In future research, it is necessary for subgroup analyses of unilateral primary hernias, recurrent hernias, and simultaneous bilateral repair to be conducted to define the indications for the TEP approach.     

Valproic acid for the treatment of hemorrhagic shock: a dose-optimization study

Background

Valproic acid (VPA) has been shown to improve survival in animal models of hemorrhagic shock at a dose of 300 mg/kg. Our aim was to identify the ideal dose through dose-escalation, split-dosing, and dose de-escalation regimens.

Materials and methods

Rats were subjected to sublethal 40% hemorrhage and treated with vehicle or VPA (dose of 300, 400, or 450 mg/kg) after 30 min of shock. Acetylated histones and activated proteins from the PI3K–Akt–GSK-3β survival pathway at different time points were quantified by Western blot analysis. In a similar model, a VPA dose of 200 mg/kg followed 2 h later by another dose of 100 mg/kg was administered. Finally, animals were subjected to a lethal 50% hemorrhage and VPA was administered in a dose de-escalation manner (starting at dose of 300 mg/kg) until a significant drop in percent survival was observed.

Results

Larger doses of VPA resulted in greater acetylation of histone 3 and increased activation of PI3K pathway proteins. Dose-dependent differences were significant in histone acetylation but not in the activation of the survival pathway proteins. Split-dose administration of VPA resulted in similar results to a single full dose. Survival was as follows: 87.5% with 300 and 250 mg/kg of VPA, 50% with 200 mg/kg of VPA, and 14% with vehicle-treated animals.

Conclusions

Although higher doses of VPA result in greater histone acetylation and activation of prosurvival protein signaling, doses as low as 250 mg/kg of VPA confer the same survival advantage in lethal hemorrhagic shock. Also, VPA can be given in a split-dose fashion without a reduction in its cytoprotective effectiveness.