Jet Electroforming of High-Aspect-Ratio Microcomponents by Periodically Lifting a Necked-Entrance Through-Mask.

High-aspect-ratio micro- and mesoscale metallic components (HAR-MMMCs) can play some unique roles in quite a few application fields, but their cost-efficient fabrication is significantly difficult to accomplish. To address this issue, this study proposes a necked-entrance through-mask (NTM) periodically lifting electroforming technology with an impinging jet electrolyte supply. The effects of the size of the necked entrance of the through-mask and the jet speed of the electrolyte on electrodeposition behaviors, including the thickness distribution of the growing top surface, deposition defect formation, geometrical accuracy, and electrodeposition rate, are investigated numerically and experimentally. Ensuring an appropriate size of the necked entrance can effectively improve the uniformity of deposition thickness, while higher electrolyte flow velocities help enhance the density of the components under higher current densities, reducing the formation of deposition defects. It was shown that several precision HAR-MMMCs with an AR of 3.65 and a surface roughness (Ra) of down to 36 nm can be achieved simultaneously with a relatively high deposition rate of 3.6 µm/min and thickness variation as low as 1.4%. Due to the high current density and excellent mass transfer effects in the electroforming conditions, the successful electroforming of components with a Vickers microhardness of up to 520.5 HV was achieved. Mesoscale precision columns with circular and Y-shaped cross-sections were fabricated by using this modified through-mask movable electroforming process. The proposed NTM periodic lifting electroforming method is promisingly advantageous in fabricating precision HAR-MMMCs cost-efficiently.

Application Value of Magnetic Resonance Imaging Medical Technology in the Perioperative Management of Brain Gliomas: Impact on Anesthesia and Prognosis.

Objective: To assess the utility of magnetic resonance imaging (MRI) medical technology in the perioperative management of brain gliomas and its impact on anesthesia and prognosis. Methods: An observational, retrospective comparative study was conducted. We selected 60 patients who underwent glioma resection at our hospital from January 2019 to January 2020. Patients were divided into two groups based on admission order: the experimental group (EG) and the control group (CG), with 30 cases each. Patients in the CG underwent conventional intracranial tumor surgery, while those in the EG underwent supratentorial craniotomy for tumor resection with the assistance of MRI medical technology. We compared perioperative parameters, hemodynamic indices, tumor resection outcomes, postoperative complications, and postoperative physical function between the two groups. Results: Compared to the CG, the EG had significantly longer surgery preparation time, anesthesia time, and surgery time (P < .001). However, there were no significant between-group differences in infusion volume and intraoperative blood loss (P > .05). Postoperative hemodynamic indicators were significantly higher in the EG than in the CG (P < .001), and postoperative tumor volume was markedly smaller in the EG (P < .001). The EG also achieved a significantly larger volume of tumor resection and a higher tumor resection rate (P < .001), a significantly lower total incidence of postoperative complications (P < .05), and notably higher Karnofsky Performance Status (KPS) scores (P < .001). Conclusions: Compared to conventional intracranial tumor surgery, the utilization of MRI medical technology in brain glioma surgery, although it prolongs surgery and anesthesia times, enhances the tumor resection rate, and offers significant advantages in improving the prognosis of patients with brain glioma.

Reprogramming of cancer-associated fibroblasts combined with immune checkpoint inhibitors: A potential therapeutic strategy for cancers.

Activated fibroblasts, namely cancer-associated fibroblasts (CAFs), are highly heterogeneous in phenotypes, functions, and origins. CAFs originated from varieties of cell types, including local resident fibroblasts, epithelial cells, mesenchymal stromal cells, or others. These cells participate in tumor angiogenesis, mechanics, drug access, and immune suppression, with the latter being particularly important. It was difficult to distinguish CAFs by subsets due to their complex origins until the use of scRNA-seq. Reprogramming CAFs with TGFß-RI inhibitor, a CXCR4 blocker, or other methods increases T cells activation and infiltration, together with a decrease in CAFs recruitment, thus improving the prognosis. As depletion of CAFs can't bring clinical benefit, the combination of reprogramming CAFs and immune checkpoint inhibitors (ICIs) come into consideration. It has shown better outcomes compared with monotherapy respectively in basic/preclinical researches, and needs more data on clinical trials. Combination therapy may be a promising and expecting method for treatment of cancer.

The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment.

Macrophages are potent immune effector cells in innate immunity and exert dual-effects in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) make up a significant portion of TME immune cells. Similar to M1/M2 macrophages, TAMs are also highly plastic, and their functions are regulated by cytokines, chemokines and other factors in the TME. The metabolic changes in TAMs are significantly associated with polarization towards a protumour or antitumour phenotype. The metabolites generated via TAM metabolic reprogramming in turn promote tumor progression and immune tolerance. In this review, we explore the metabolic reprogramming of TAMs in terms of energy, amino acid and fatty acid metabolism and the potential roles of these changes in immune suppression.

Fabricating Ultra-Narrow Precision Slit Structures with Periodically Reducing Current Over-Growth Electroforming.

An ultra-narrow precision slit with a width of less than ten micrometers is the key structure of some optical components, but the fabrication of these structures is still very difficult to accomplish. To fabricate these slits, this paper proposed a periodically reducing current over-growth electroforming process. In the periodically reducing current over-growth electroforming, the electric current applied to the electrodeposition process is periodically stepped down rather than being constant. Simulations and experimentation studies were carried out to verify the feasibility of the proposed process, and further optimization of process parameters was implemented experimentally to achieve the desired ultra-narrow precision slits. The current values were: I1=Iinitial, I2=0.75Iinitial at Qc=0.5Qt, I3=0.5Iinitial at Qc=0.75Qt,respectively. It was shown that, compared with conventional constant current over-growth electroforming, the proposed process can significantly improve the surface quality and geometrical accuracy of the fabricated slits and can markedly enhance the achievement of the formed ultra-narrow slits. With the proposed process, slits with a width of down to 5 ± 0.1 µm and a surface roughness of less than 62.8 nm can be easily achieved. This can improve the determination sensitivity and linear range of the calibration curves of spectral imagers and food and chemical analysis instruments. Periodically reducing current over-growth electroforming is effective and advantageous in fabricating ultra-narrow precision slits.

Risk factors of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy: A systematic review and meta-analysis.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common and troublesome complication after pancreatoduodenectomy (PD). We conducted a systematic review and meta-analysis to identify the risk factors of CR-POPF after PD. METHODS: We searched PubMed, EMBASE, and Cochrane Library databases for studies related to risk factors of CR-POPF after PD. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were extracted from the included studies, then a meta-analysis was conducted. If necessary, sensitivity analysis would be performed by changing the effect model or excluding 1 study at a time. Publication bias was assessed by funnel plot and Begg test and Egger test. RESULTS: A total of 27 studies with 24,740 patients were included, and CR-POPF occurred in 3843 patients (incidence = 17%, 95% CI: 16%-19%). Male (OR = 1.56, 95% CI: 1.42-1.70), body mass index >25 kg/m2 (OR = 1.98, 95% CI: 1.23-3.18), pancreatic duct diameter <3 mm (OR = 1.87, 95% CI: 1.66-2.12), soft pancreatic texture (OR = 3.49, 95% CI: 2.61-4.67), and blood transfusion (OR = 3.10, 95% CI: 2.01-4.77) can significantly increase the risk of CR-POPF. Pancreatic adenocarcinoma (OR = 0.54, 95% CI: 0.47-0.61), vascular resection (OR = 0.57, 95% CI: 0.39-0.83), and preoperative chemoradiotherapy (OR = 0.68, 95% CI: 0.57-0.81) can significantly decrease the factor of CR-POPF. Diabetes mellitus was not statistically associated with CR-POPF (OR = 0.66, 95% CI: 0.40-1.08). However, the analysis of body mass index, pancreatic texture, and diabetes mellitus had a high heterogeneity, then sensitivity analysis was performed, and the result after sensitivity analysis showed diabetes mellitus can significantly decrease the risk of CR-POPF. There was no significant publication bias in this meta-analysis. CONCLUSIONS: The current review assessed the effects of different factors on CR-POPF. This can provide a basis for the prevention and management of CR-POPF. Effective interventions targeting the above risk factors should be investigated in future studies for decreasing the occurrence of CR-POPF.

Development and validation of a novel N6-methyladenosine (m6A)-related multi- long non-coding RNA (lncRNA) prognostic signature in pancreatic adenocarcinoma.

Accumulating evidence has unveiled the pivotal roles of N6-methyladenosine (m6A) in pancreatic adenocarcinoma (PAAD). However, there are not many researches to predict the prognosis of PAAD using m6A-related long non-coding RNAs (lncRNAs). Raw data from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and the Genotype-Tissue Expression project (GTEx) were utilized to comprehensively analyze the expression and prognostic performances of 145 m6A-related lncRNAs in PAAD and to develop and validate a novel m6A-related multi-lncRNA prognostic signature (m6A-LPS) for PAAD patients. In total, 57 differentially expressed m6A-related lncRNAs with prognostic values were identified. Based on LASSO-Cox regression analysis, m6A-LPS was constructed and verified by using five-lncRNA expression profiles for TCGA and ICGC cohorts. PAAD patients were then divided into high- and low-risKBIE_A_1933868k subgroups with different clinical outcomes according to the median risk score; this was further verified by time-dependent receiver operating characteristic curves. Risk scores were significantly associated with clinical parameters such as histological grade and cancer status among PAAD patients. A nomogram consisting of risk score, grade, and cancer status was generated to predict the survival probability of PAAD patients, as also demonstrated by calibration curves. Discrepancies in cellular processes, signaling pathways, and immune status between the high- and low-risk subgroups were investigated by functional and single-sample gene set enrichment analyses. In conclusion, the novel m6A-LPS for PAAD patients was developed and validated, which might provide new insight into clinical decision-making and precision medicine.

The novel immune-related genes predict the prognosis of patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the main causes of cancer deaths globally. Immunotherapy is becoming increasingly important in the cure of advanced HCC. Thus it is essential to identify biomarkers for treatment response and prognosis prediction. We searched publicly available databases and retrieved 465 samples of genes from The Cancer Genome Atlas (TCGA) database and 115 tumor samples from Gene Expression Omnibus (GEO). Meanwhile, we used the ImmPort database to determine the immune-related genes as well. Weighted gene correlation network analysis, Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis were used to identify the key immune related genes (IRGs) which are closely related to prognosis. Gene set enrichment analysis (GSEA) was implemented to explore the difference of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway between Immune high- and low-risk score groups. Finally, we made a prognostic nomogram including Immune-Risk score and other clinicopathologic factors. A total of 318 genes from prognosis related modules were identified through weighted gene co-expression network analysis (WGCNA). 46 genes were strongly linked to prognosis after univariate Cox analysis. We constructed a seven genes prognostic signature which showed powerful prediction ability in both training cohort and testing cohort. 16 significant KEGG pathways were identified between high- and low- risk score groups using GSEA analysis. This study identified and verified seven immune-related prognostic biomarkers for the patients with HCC, which have potential value for immune modulatory and therapeutic targets.

Pancreatic ductal deletion of S100A9 alleviates acute pancreatitis by targeting VNN1-mediated ROS release to inhibit NLRP3 activation.

Recent studies have proven that the overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also duct cells, however, pancreatic duct contribution in acinar cells homeostasis is poorly known and the molecular mechanisms leading to acinar insult and acute pancreatitis (AP) are unclear. Our previous work also showed that S100A9 protein level was notably increased in AP rat pancreas through iTRAQ-based quantitative proteomic analysis. Therefore, we investigated the actions of injured duct cells on acinar cells and the S100A9-related effects and mechanisms underlying AP pathology in the present paper. Methods: In this study, we constructed S100A9 knockout (s100a9-/-) mice and an in vitro coculture system for pancreatic duct cells and acinar cells. Moreover, a variety of small molecular inhibitors of S100A9 were screened from ChemDiv through molecular docking and virtual screening methods. Results: We found that the upregulation of S100A9 induces cell injury and inflammatory response via NLRP3 activation by targeting VNN1-mediated ROS release; and loss of S100A9 decreases AP injury in vitro and in vivo. Moreover, molecular docking and mutant plasmid experiments proved that S100A9 has a direct interaction with VNN1 through the salt bridges formation of Lys57 and Glu92 residues in S100A9 protein. We further found that compounds C42H60N4O6 and C28H29F3N4O5S can significantly improve AP injury in vitro and in vivo through inhibiting S100A9-VNN1 interaction. Conclusions: Our study showed the important regulatory effect of S100A9 on pancreatic duct injury during AP and revealed that inhibition of the S100A9-VNN1 interaction may be a key therapeutic target for this disease.

Autophagy prevents hippocampal α-synuclein oligomerization and early cognitive dysfunction after anesthesia/surgery in aged rats.

Stress-induced α-synuclein aggregation, especially the most toxic species (oligomers), may precede synaptic and cognitive dysfunction. Under pathological conditions, α-synuclein is degraded primarily through the autophagic/lysosomal pathway. We assessed the involvement of autophagy in α-synuclein aggregation and cognitive impairment following general anesthesia and surgical stress. Autophagy was found to be suppressed in the aged rat hippocampus after either 4-h propofol anesthesia alone or 2-h propofol anesthesia during a laparotomy surgery. This inhibition of autophagy was accompanied by profound α-synuclein oligomer aggregation and neurotransmitter imbalances in the hippocampus, along with hippocampus-dependent cognitive deficits. These events were not observed 18 weeks after propofol exposure with or without surgical stress. The pharmacological induction of autophagy using rapamycin markedly suppressed α-synuclein oligomerization, restored neurotransmitter equilibrium, and improved cognitive behavior after prolonged anesthesia or anesthesia combined with surgery. Thus, both prolonged propofol anesthesia alone and propofol anesthesia during surgery impaired autophagy, which may have induced abnormal hippocampal α-synuclein aggregation and neurobehavioral deficits in aged rats. These findings suggest that the activation of autophagy and the clearance of pathological α-synuclein oligomers may be novel strategies to ameliorate the common occurrence of postoperative cognitive dysfunction.

Isoflurane­induced postoperative cognitive dysfunction is mediated by hypoxia­inducible factor­1α­dependent neuroinflammation in aged rats.

Elderly patients are at high risk of developing postoperative cognitive dysfunction (POCD) after prolonged exposure to inhaled anesthetics. However, the pathogenesis of POCD remains unknown. Hypoxia­inducible factor­1α (HIF­1α) is activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF­1α in isoflurane­induced neuroinflammation and the resulting cognitive impairment. Following a 4­h exposure to 1.5% isoflurane in 20­month­old rats, increased expression of HIF­1α protein, activation of nuclear factor (NF)­κB signaling and increased expression of TNF­1α were observed in the hippocampus of isoflurane­exposed rats compared with the control group. Pharmacological inhibition of HIF­1α activation by 5­[1­(phenylmethyl)­1H­indazol­3­yl]­2­furanmethanol (YC­1) markedly suppressed the enhanced expression of HIF­1α, disrupted NF­κB signaling pathway activity and inhibited the isoflurane­induced increase of TNF­1α expression. YC­1 pretreatment also significantly attenuated isoflurane­induced cognitive deficits according to the results of the Morris water maze task. These results suggest that hippocampal HIF­1α appears to be involved in an upstream mechanism of isoflurane­induced cognitive impairment. Further research is warranted to fully clarify the pathogenesis and investigate HIF­1α as a potential therapeutic target for POCD.

Hypoxia-inducible factor-1α is involved in isoflurane-induced blood-brain barrier disruption in aged rats model of POCD.

Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1α (HIF-1α) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1α in isoflurane-induced blood-brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels. Increases in HIF-1α and VEGF proteins and activation of MMP-2 in the hippocampus were also observed in the hippocamp of isoflurane-exposed rats compared with control rats. Pharmacological inhibition of HIF-1α activation by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) markedly suppressed the expression of HIF-1α, VEGF and MMP-2, and mitigated the severity of BBB disruption.YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits in the Morris water maze task. Overall, our results demonstrate that hippocampal HIF-1α/VEGF signaling seems to be the upstream mechanism of isoflurane-induced cognitive impairment, and provides apotential preventive and therapeutic target for POCD.

Protective effect of dapsone on cognitive impairment induced by propofol involves hippocampal autophagy.

Post-operative cognitive dysfunction (POCD) is a commonly seen postoperative complication in elderly patients and its underlying mechanisms are still unclear. Autophagy, a degradation mechanism of cellular components, is required for cell survival and many physiological processes. Although propofol is one of the most commonly used intravenous anesthetics, investigations into its mechanisms and effects on cognition in aged rodents are relatively scarce. In this study, we evaluate the influence of propofol on learning and memory, and identify the potential role of hippocampal autophagy in propofol-induced cognitive alterations in aged rats. The results demonstrate that 4h propofol exposure significantly impaired cognitive performance through the inhibition of hippocampal autophagy. Diaminodiphenyl sulfone (dapsone, DDS), which was used as an anti-leprosy drug, has been found to have neuroprotective effects. We have previously demonstrated that DDS can improve surgical stress induced depression- and anxiety-like behavior. We therefore aimed to investigate the effects of DDS on propofol-induced cognitive dysfunction and associated hippocampal autophagy responses. Pretreatment with 5mg/kg or 10mg/kg body weight DDS significantly improved the behavioral disorder and upregulated the inhibited autophagic response in aged rats. Our exploration is the first to establish an in vivo link between central autophagy and cognitive dysfunction in aged hippocampus after propofol anesthesia and demonstrate that the prophylactic effect of DDS on the cognitive impairment induced by propofol involves autophagy. These findings may imply a potential novel target for the treatment in patients with propofol anesthesia-induced cognitive impairment.

Increased extrasynaptic GluN2B expression is involved in cognitive impairment after isoflurane anesthesia.

There is increasing concern regarding the postoperative cognitive dysfunction (POCD) in the aging population, and general anesthetics are believed to be involved. Isoflurane exposure induced increased N-methyl-D-aspartic acid receptor (NMDAR) GluN2B subunit expression following anesthesia, which was accompanied by alteration of the cognitive function. However, whether isoflurane affects this expression in different subcellular compartments, and is involved in the development of POCD remains to be elucidated. The aims of the study were to investigate the effects of isoflurane on the expression of the synaptic and extrasynaptic NMDAR subunits, GluN2A and GluN2B, as well as the associated alteration of cognitive function in aged rats. The GluN2B antagonist, Ro25-6981, was given to rats exposed to isoflurane to determine the role of GluN2B in the isoflurane-induced alteration of cognitive function. The results showed that spatial learning and memory tested in the Morris water maze (MWM) was impaired at least 7 days after isoflurane exposure, and was returned to control levels 30 days thereafter. Ro25-6981 treatment can alleviate this impairment. Extrasynaptic GluN2B protein expression, but not synaptic GluN2B or GluN2A, increased significantly after isoflurane exposure compared to non-isoflurane exposure, and returned to control levels approximately 30 days thereafter. The results of the present study indicated that isoflurane induced the prolonged upregulation of extrasynaptic GluN2B expression after anesthesia and is involved in reversible cognitive impairment.

Surgery-Induced Hippocampal Angiotensin II Elevation Causes Blood-Brain Barrier Disruption via MMP/TIMP in Aged Rats.

Reversible blood-brain barrier (BBB) disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD). Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), as well as three of their endogenous tissue inhibitors of MMP (TIMP-1, -2, -3), and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II) and Ang II receptor type 1 (AT1) after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1), as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB) activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.

Duration-dependent regulation of autophagy by isoflurane exposure in aged rats.

Current evidence suggests a central role for autophagy in many inflammatory brain disorders, including Alzheimer's disease (AD). Furthermore, it is also well accepted that some inhalation anesthetics, such as isoflurane, may cause AD-like neuropathogenesis and resultant postoperative cognitive dysfunction, especially in the elderly population. However, the impact of inhalation anesthetics on autophagic components in the brain remains to be documented. Hence, our objective was to investigate the effects of different durations of isoflurane exposure on hippocampus-dependent learning and hippocampal autophagy in aged rats. Aged Sprague-Dawley rats (20 months old) were randomly exposed to 1.5% isoflurane or 100% oxygen for 1 or 4 h. Animals were then trained in the Morris water maze (4 trials/day for 5 consecutive days). Hippocampal phagophore formation markers, beclin 1 and protein microtubule-associated protein 1 light chain-3B (LC3B), as well as p62, an indicator of autophagic flux, were quantified by western blotting. There was no significant difference in the escape latencies and time spent in the target quadrant, as well as hippocampal expression of beclin 1, LC3B-II, and p62 at 24 h post-anesthesia between the 1-h isoflurane-exposed rats and their controls (P >0.05). Four-hour exposure to isoflurane resulted in spatial learning and memory deficits, as evidenced by prolonged escape latencies on days 4 and 5 post-anesthesia and less time spent in the target quadrant than sham-exposed animals (P <0.05). These events were accompanied by a decline in hippocampal expression of LC3B-I, LC3B-II, and beclin 1 24 h after isoflurane (P <0.01 and P <0.05). Nevertheless, no significant change in p62 expression was found. Further kinetics study of autophagic changes induced by 4 h of isoflurane showed a transient upregulation of LC3B-I, LC3B-II, and beclin 1 at the end of exposure and a subsequent striking decrease within 12-24 h post-anesthesia (P <0.05). Hippocampal p62 peaked at 6 h but subsequently resolved. These results from our pilot in vivo study support a duration-dependent relationship between 1.5% isoflurane exposure, and spatial cognitive function as well as hippocampal phagophore formation.

Surgical stress induces brain-derived neurotrophic factor reduction and postoperative cognitive dysfunction via glucocorticoid receptor phosphorylation in aged mice.

AIMS: This study explored whether surgical stress-induced glucocorticoid receptor (GR) phosphorylation is related to postoperative cognitive dysfunction (POCD) in aged individuals. Inhibition of GR activation could be an effective treatment for POCD. METHODS: A laparotomy was given to C57/BL6 mice in POCD group both 20 and 6 months old. Animals in control group were treated in identical manners except for laparotomy. Cognitive function was evaluated by Morris water maze and elevated plus maze. Western blot and Elisa assay were used to detect related molecules. Mifepristone and roscovitine were treated as inhibitions of GR phosphorylation. RESULTS: The cognitive function was impaired, and brain-derived neurotrophic factor (BDNF) was found reduced in aged POCD group. GR translocation into nucleus and elevated GR phosphorylation were found in prefrontal cortex of aged POCD mice. Cyclin-dependent Kinase 5 (CDK5), kinase for GR phosphorylation also elevated in aged POCD mice. With GR antagonist and CDK5 inhibitor, reduction of BDNF and cognitive dysfunction in aged mice were both rescued. CONCLUSION: These results presented a mechanism that surgical stress-induced GR phosphorylation contributes to POCD in aged individuals. Inhibition of GR activation and phosphorylation might be a potential treatment target of POCD.

Surgical stress induced depressive and anxiety like behavior are improved by dapsone via modulating NADPH oxidase level.

Surgical stress induced depression and anxiety like behavior are common complications among aged individuals suffering from surgery. Recent studies proposed that accumulation of oxidative stress is involved in the etiology of stress induced depression and anxiety. Dapsone possesses antioxidant properties, however, whether dapsone is effective in modulating surgical stress induced brain oxidative damage remains uncertain. The present study aimed to investigate the effect of dapsone on surgical stress induced depressive and anxiety like behavior, and brain oxidative stress in a well-established surgical stress model. Depressive and anxiety like behavior accompanied by elevated brain oxidative stress were observed in aged mice underwent abdominal surgery. Pretreatment with 5 mg/kg dapsone significantly improved the behavioral disorder and ameliorated brain oxidative stress in this model. Further investigation, revealed that surgical stress increased brain NADPH oxidase level, while pretreatment with dapsone abrogated the elevation of NADPH oxidase triggered by surgical stress. These findings suggest that dapsone is effective in improving surgical stress induced brain oxidative damage via down-regulating NADPH oxidase level in aged mice.

Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood-brain barrier in aged rats.

The underlying mechanism of isoflurane-induced cognitive dysfunction in older individuals is unknown. In this study, the effects of isoflurane exposure on the hippocampal blood-brain barrier (BBB) in aged rats were investigated because it was previously shown that BBB disruption involves in cognitive dysfunction. Twenty-month-old rats randomly received 1.5% isoflurane or vehicle gas as control. Hippocampal BBB ultrastructure was analyzed by transmission electron microscopy and expression of tight junction proteins was measured by western blot analysis. BBB permeability was detected with sodium fluorescein extravasation and further confirmed by immunoglobulin G immunohistochemistry. Spatial learning and memory were assessed by the Morris water maze test. Isoflurane anesthesia resulted in reversible time-dependent BBB ultrastructure morphological damage and significant decreases in expression of the tight junction proteins occludin, which contributed to sodium fluorescein and IgG leakage. Rats with isoflurane exposure also showed significant cognitive deficits in the Morris water maze test. This in vivo data indicate that occludin down-regulation may be one of the mediators of isoflurane-induced hippocampus BBB disruption, and may contribute to hippocampus-dependent cognitive impairment after isoflurane exposure in aged rats.