Circular RNA CircPDS5B impairs angiogenesis following ischemic stroke through its interaction with hnRNPL to inactivate VEGF-A.

BACKGROUND: Ischemic stroke (IS) is the primary cause of mortality and disability worldwide. Circular RNAs (circRNAs) have been proposed as crucial regulators in IS. This study focused on the role of circPDS5B in IS and its underlying mechanism. METHOD: Transient middle cerebral artery occlusion (tMCAO) mice and glucose deprivation/reoxygenation (OGD/R)-exposed human brain microvascular endothelial cells (BMECs) were used as IS models. Expression levels of circPDS5B, heterogenous nuclear ribonucleoprotein L (hnRNPL), runt-related transcription factor-1 (Runx1), and Zinc finger protein 24 (ZNF24) were quantified by qRT-PCR. MTT, wound healing, transwell and tube formation assays were employed to evaluate the cell proliferation, migration, and angiogenesis, respectively. Moreover, RNA pull-down, and RIP assay were performed to investigate the interaction among circPDS5B, hnRNPL and vascular endothelial growth factor-A (VEGF-A). RESULTS: circPDS5B was significantly up-regulated in IS patients and tMCAO mice. Deficiency of circPDS5B relieved brain infarction and neuronal injury of tMCAO mice. OGD/R-induced apoptosis, inhibition in viability, migration, and angiogenesis in BMECs were dramatically abrogated by circPDS5B knockdown. Mechanistically, circPDS5B stabilized Runx1 and ZNF24 via recruiting hnRNPL, thereby suppressing the transcription and expression of VEGFA. hnRNPL silencing strengthened circPDS5B knockdown-mediated beneficial effect on IS. CONCLUSION: Altogether, our study showed that high expression of circPDS5B exacerbated IS through recruitment of hnRNPL to stabilize Runx1/ZNF24 and subsequently inactivate VEGFA. Our findings suggest circPDS5B may be a novel therapeutic target for IS.

LncRNA PVT1 Promotes Neuronal Cell Apoptosis and Neuroinflammation by Regulating miR-488-3p/FOXD3/SCN2A Axis in Epilepsy.

It is vital to understand the mechanism of epilepsy onset and development. Dysregulated lncRNAs are closely associated with epilepsy. Our work probed the role of lncRNA PVT1/miR-488-3p/FOXD3/SCN2A axis in epilepsy. The mRNA and protein expressions were assessed using qRT-PCR and western blot. MTT assay and TUNEL staining were conducted to assess cell viability and apoptosis, respectively. TNFα, IL-1ß and IL-6 levels were analyzed using ELISA. LDH level was tested by Assay Kit. The binding relationship between PVT1, miR-488-3p and FOXD3 were verified using dual luciferase reporter gene assay. The epilepsy model of rats was established by lithium-pilocarpine injection. Nissl staining was performed to evaluate neuronal damage. PVT1 was markedly upregulated in epilepsy model cells. Knockdown of PVT1 increased the viability, while repressed the apoptosis and inflammatory cytokines secretion as well as LDH level in epilepsy cell model. MiR-488-3p alleviated neuronal injury and neuroinflammation in model cells. MiR-488-3p functioned as the direct target of PVT1, and its inhibition neutralized the effects of PVT1 silencing on neuronal cell injury and neuroinflammation in model cells. Furthermore, miR-488-3p inhibited neuronal cell injury and neuroinflammation in model cells by regulating FOXD3/SCN2A pathway. Finally, animal experiments proved that PVT1 promoted epilepsy-induced neuronal cell injury and neuroinflammation by regulating miR-488-3p-mediated FOXD3/SCN2A pathway. PVT1 promoted neuronal cell injury and inflammatory response in epilepsy via inhibiting miR-488-3p and further regulating FOXD3/SCN2A pathway.

Blueberry extracts antagonize Aß25-35 neurotoxicity and exert a neuroprotective effect through MEK-ERK-BDNF/UCH-L1 signaling pathway in rat and mouse hippocampus.

BACKGROUND: The neuroprotective potential of blueberry (BB) extracts against Alzheimer's disease (AD) has been previously hinted at, while its exact mechanism has remained largely enigmatic. OBJECTIVE: Our study endeavored to unravel the impacts and mechanisms by which BB extracts ameliorated the learning and memory prowess of AD-afflicted mice, with a specific focus on the MEK-ERK pathway. METHODS: We employed 3-month-old APP/PS1 transgenic mice and stratified them into three distinct groups: AD+BB, AD, and control (CT). The Morris Water Maze Test (MWMT) was then administered to gauge their learning and memory faculties. In vitro experiments were executed on Aß25-35-afflicted rat hippocampal neurons, which were subsequently treated with varying concentrations of BB extracts. We then assessed the expression levels of genes and proteins integral to the MEK-ERKBDNF/UCH-L1 pathway. RESULTS: The data showed that the AD mice demonstrated compromised learning and memory faculties in MWMT. However, the AD+BB cohort showcased marked improvements in performance. Furthermore, in the AD subset, significant elevations in the expressions of MEK2 and ERK1/2 were observed, both at the mRNA and protein levels. Conversely, UCH-L1 mRNA expressions exhibited a decline, while BDNF expressions surged significantly. However, post BB extract treatment, the expressions of MEK2 and ERK1/2 were subdued, with UCH-L1 and BDNF mRNA expressions reverting to control levels. CONCLUSIONS: Our findings propounded that BB extracts could offer therapeutic promise for AD by bolstering learning and memory capacities. The unwarranted activation of the MEK-ERK pathway, coupled with the aberrant expressions of BDNF and UCH-L1, might underpin AD's pathogenesis.

Prognostic factors in patients with thymoma who underwent surgery.

PURPOSE: Thymoma is the most common primary tumor in the anterior mediastinum. The prognostic factors of patients with thymoma still need to be clarified. In this study, we aimed to investigate the prognostic factors of patients with thymoma who received radical resection and establish the nomogram to predict the prognosis of these patients. MATERIALS AND METHODS: Patients who underwent radical resection for thymoma with complete follow-up data between 2005 and 2021 were enrolled. Their clinicopathological characteristics and treatment methods were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the independent prognostic factors. According to the results of the univariate analysis in the Cox regression model, the predictive nomograms were created. RESULTS: A total of 137 patients with thymoma were enrolled. With a median follow-up of 52 months, the 5-year and 10-year PFS rates were 79.5% and 68.1%, respectively. The 5-year and 10-year OS rates were 88.4% and 73.1%, respectively. Smoking status (P = 0.022) and tumor size (P = 0.039) were identified as independent prognostic factors for PFS. Multivariate analysis showed that a high level of neutrophils (P = 0.040) was independently associated with OS. The nomogram showed that the World Health Organization (WHO) histological classification contributed more to the risk of recurrence than other factors. Neutrophil count was the most important predictor of OS in patients with thymoma. CONCLUSION: Smoking status and tumor size are risk factors for PFS in patients with thymoma. A high level of neutrophils is an independent prognostic factor for OS. The nomograms developed in this study accurately predict PFS and OS rates at 5 and 10 years in patients with thymoma based on individual characteristics.

Subclinical hemorrhagic nonfunctionning pituitary adenoma: pituitary gland function status, endoscopic endonasal transsphenoidal surgery, and outcomes.

OBJECTIVE: How do subclinical hemorrhages into nonfunctioning pituitary adenomas (NFPAs) influence the hormonal status and surgical outcomes remains unclear, our study aim at evaluating its definite effects on pituitary gland function and surgical outcomes. METHODS: All 103 consecutive patients who underwent initial endoscopic endonasal approach (EEA) for NFPAs resection from June 2016 to June 2018 were retrospectively reviewed, depending on magnetic resonance imaging (MRI), operative and pathological findings, patients were divided into the non-hemorrhagic NFPAs group and the subclinical hemorrhagic NFPAs group. A comparative analysis was conducted between these two groups to investigate the effects of subclinical hemorrhages in NFPAs on pituitary endocrine function and surgical outcomes. RESULTS: The incidence of subclinical hemorrhage on NFPAs was 22.3% (23/103), which was more frequently observed in larger adenomas (28.9 ± 9.6 mm vs 19.2 ± 9.2 mm, p = 0.001). The incidence of preoperative hypopituitarism was 69.6% (16/23) for subclinical hemorrhagic NFPAs group and 31% (25/80) for non-hemorrhagic NFPAs group (p = 0.001), a high incidence of hypopituitarism for subclinical hemorrhagic NFPAs finally was found to be owing to the large tumor rather than the intratumoral hemorrhage. All those NFPAs were resected via EEA with the technology of extra-pseduocapusual dissection in a standard elective fashion. Postoperatively, there were more than 75.6% of patients with preoperative hypopituitarism had at least one axis recovered, with hyperprolactinemia resolved in 91.7% of patients, 94.7% headaches and 90% visual symptoms resolved or improved after surgery, there was no significant difference between these two groups (p > 0.05), indicates there was no any surgical outcome difference between NFPAs with or without subclinical hemorrhage. A very low postoperative complication was achieved with new postoperative anterior pituitary failure occurred in 9.7% of patients and permanent diabetes insipidus (DI) occurred in 9.7% of patients, which advocated that EEA can be chosen as a safe surgical treatment for subclinical hemorrhagic NFPAs. Furthermore, with the technology of extra-pseduocapusual dissection, more than 87% subclinical hemorrhagic NFPAs had achieved gross total resection (GTR) with a low incidence of new postoperative hypopituitarism (14%). CONCLUSION: Subclinical hemorrhage in NFPAs does not aggravate pituitary gland function. A surgical management strategy by EEA with the technology of extra-pseduocapusual dissection for the subclinical hemorrhagic NFPAs usually yields satisfactory endocrine and surgical outcomes, but it does not necessitate emergent tumor decompression.

5 kHz, 4.2mJ, 900 ps end-pumped Nd:YVO4 MOPA laser system.

A 5 kHz sub-nanosecond master oscillator power amplifier (MOPA) laser system was reported in this paper. The master oscillator was an electro-optically Q-switched Nd:YVO4 laser directly pumped at 879 nm, yielding a pulse energy of 520 µJ and a pulse width of 900 ps at 5 kHz. With two Nd:YVO4 amplifiers directly pumped at 914 nm, the pulse energy was further scaled up. Under the absorbed pump energy of 11.0 mJ, the pulse energy was amplified to 4.2 mJ, corresponding to a peak power of 4.7 MW. The optical-to-optical efficiency of the amplifiers reached 33.5%.

Acute exposure to simulated high-altitude hypoxia alters gut microbiota in mice.

Gut microbiota bears adaptive potential to different environments, but little is known regarding its responses to acute high-altitude exposure. This study aimed to evaluate the microbial changes after acute exposure to simulated high-altitude hypoxia. C57BL/6 J mice were divided into hypoxia and normoxia groups. The hypoxia group was exposed to a simulated altitude of 5500 m for 24 h above sea level. The normoxia group was maintained in low altitude of 10 m above sea level. Colonic microbiota was analyzed using 16S rRNA V4 gene sequencing. Compared with the normoxia group, Shannon, Simpson and Akkermansia were significantly increased, while Firmicutes-to-Bacteroidetes ratio and Bifidobacterium were significantly decreased in the hypoxia group. The hypoxia group exhibited lower mobile element containing and higher potentially pathogenic and stress-tolerant phenotypes than those in the normoxia group. Functional analysis indicated that environmental information processing was significantly lower, metabolism, cellular processes and organismal systems were significantly higher in the hypoxia group than those in the normoxia group. In conclusion, acute exposure to simulated high-altitude hypoxia alters gut microbiota diversity and composition, which may provide a potential target to alleviate acute high-altitude diseases.

Effects of early-life zinc deficiency on learning and memory in offspring and the changes in DNA methylation patterns.

OBJECTIVE: To investigate the effect of maternal zinc deficiency on learning and memory in offspring and the changes in DNA methylation patterns. METHODS: Pregnant rats were divided into zinc adequate (ZA), zinc deficient (ZD), and paired fed (PF) groups. Serum zinc contents and AKP activity in mother rats and offspring at P21 (end of lactation) and P60 (weaned, adult) were detected. Cognitive ability of offspring at P21 and P60 were determined by Morris water maze. The expression of proteins including DNMT3a, DNMT1, GADD45ß, MeCP2 and BDNF in the offspring hippocampus were detected by Western-blot. The methylation status of BDNF promoter region in hippocampus of offspring rats was detected by MS-qPCR. RESULTS: Compared with the ZA and PF groups, pups in the ZD group had lower zinc levels and AKP activity in the serum, spent more time finding the platform and spent less time going through the platform area. Protein expression of DNMT1 and GADD45b were downregulated in the ZD group during P0 and P21 but not P60 compared with the ZA and PF group, these results were consistent with a reduction in BDNF protein at P0 (neonate), P21. However, when pups of rats in the ZD group were supplemented with zinc ion from P21 to P60, MeCP2 and GADD45b expression were significantly downregulated compared with the ZA and PF group. CONCLUSION: Post-weaning zinc supplementation may improve cognitive impairment induced by early life zinc deficiency, whereas it may not completely reverse the abnormal expression of particular genes that are involved in DNA methylation, binding to methylated DNA and neurogenesis.

Building roof extraction from ASTIL echo images applying OSA-YOLOv5s.

Light detection and ranging (LiDAR) is a type of essential tool for urban planning and geoinformation extraction. Airborne streak tube imaging LiDAR (ASTIL) is a new system with great advantages in the rapid collection of remote sensing data. To the best of our knowledge, a new method to extract a building roof from the echo images of ASTIL is proposed. We improve YOLOv5s with a one-shot aggregation (OSA) module to improve efficiency. The experimental results show that the mean average precision of the OSA-YOLOv5s algorithm can reach 95.2%, and the frames per second can reach 11.74 using a CPU and 39.39 using a GPU. The method proposed can extract building objects efficiently from the echo images of ASTIL and acquire the building roof point cloud.

A Steep-Slope MoS2/Graphene Dirac-Source Field-Effect Transistor with a Large Drive Current.

In the continuous transistor feature size scaling down, the scaling of the supply voltage is stagnant because of the subthreshold swing (SS) limit. A transistor with a new mechanism is needed to break through the thermionic limit of SS and hold the large drive current at the same time. Here, by adopting the recently proposed Dirac-source field-effect transistor (DSFET) technology, we experimentally demonstrate a MoS2/graphene (1.8 nm/0.3 nm) DSFET for the first time, and a steep SS of 37.9 mV/dec at room temperature with nearly free hysteresis is observed. Besides, by bringing in the structure of gate-all-around (GAA), the MoS2/graphene DSFET exhibits a steeper SS of 33.5 mV/dec and a 40% increased normalized drive current up to 52.7 µA·µm/µm (VDS = 1 V) with a current on/off ratio of 108, which shows potential for low-power and high-performance electronics applications.

High-pulse-energy passively Q-switched sub-nanosecond MOPA laser system operating at kHz level.

A passively Q-switched sub-nanosecond master oscillator power amplifier (MOPA) laser system at 1064 nm has been reported in this paper. The master oscillator was a passively Q-switched YAG/Nd:YAG/Cr4+:YAG microchip laser, yielding a pulse energy of 0.14 mJ and a pulse width of ∼490 ps at repetition rates of 500 Hz and 1 kHz. After passing a double-pass side-pumped Nd:YAG amplification system, the pulse energy reached 7.6 mJ and 1.7 mJ at 500 Hz and 1 kHz, respectively. The spatial beam deformation caused by the thermally induced birefringence was investigated numerically and experimentally.

Generation and amplification of a multi-beam sub-nanosecond laser.

In this paper, a methodology to produce a multi-beam sub-nanosecond laser is proposed. Laser pulses with a pulse energy of 0.14 mJ and a pulse width of 490 ps are generated in a YAG/Nd:YAG/Cr4+:YAG microchip laser at a repetition rate of 200 Hz. After amplification with a laser diode (LD) side-pumped Nd:YAG module, four laser beams are generated because of the thermally induced birefringence. With a double-pass LD side-pumped amplifier, the single pulse energy of the four laser beams is amplified to 5.23 mJ with a peak power of ∼10.67 MW, and air breakdown with four points is achieved with a 2 × 2 lens array.

LncRNA LIFR-AS1 promotes proliferation and invasion of gastric cancer cell via miR-29a-3p/COL1A2 axis.

BACKGROUND: LncRNA was known to be closely associated with the progression of human tumors. The role of lncRNA LIFR-AS1 in the pathogenesis and progression of gastric tumor is still unclear. The aim of this study was to investigate the function of LIFR-AS1 and the underlying mechanism in the pathogenesis and progression of gastric cancer. METHODS: QRT-PCR was used to evaluate the expression of LIFR-AS1, miR-29a-3p and COL1A2 in gastric tumor tissues and cells. Western blotting was used to evaluate the protein expression of COL1A2 in gastric tumor cells. CCK-8 assay, transwell assay and flow cytometry were used to evaluate the roles of LIFR-AS1, miR-29a-3p and COL1A2 in cell proliferation, invasion, migration and apoptosis. The relationship among LIFR-AS1, miR-29a-3p and COL1A2 was assessed by bioinformatics analyses and luciferase reporter assay. RESULTS: The expression levels of LIFR-AS1 were significantly increased in gastric tumor tissues and cells, while the expression levels of miR-29a-3p were decreased. The expression of miR-29a-3p was negatively correlated with the expression of LIFR-AS1 in gastric cancer tumor tissues. Knocking down of LIFR-AS1 inhibited proliferation, invasion and migration of gastric tumor cells, and induced apoptosis of gastric tumor cells. Bioinformatics analyses and integrated experiments revealed that LIFR-AS1 elevated the expression of COL1A2 through sponging miR-29a-3p, which further resulted in the progression of gastric tumor. CONCLUSION: LIFR-AS1 plays an important role as a competing endogenous RNA in gastric tumor pathogenesis and may be a potential target for the diagnosis and treatment of gastric tumor.

High ligation of the inferior mesenteric artery and anastomotic leakage in anterior resection for rectal cancer: a systematic review and meta-analysis of randomized controlled trial studies.

AIM: Surgeons have concerns whether high ligation (HL) of the inferior mesenteric artery (IMA) increases the incidence of anastomotic leakage (AL). This meta-analysis aimed to evaluate the influence of HL of the IMA on AL compared with low ligation (LL). METHODS: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov databases were searched. Randomized controlled trial studies that compared HL with LL of the IMA in anterior resection for rectal cancer and reported AL outcomes were eligible for inclusion. The odds ratios and mean differences were analysed by a random-effects model. Trial sequential analysis was performed to minimize the risk of random errors. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence for outcomes. RESULTS: Of the 531 records screened, five randomized controlled trials with 779 patients were selected for analysis. The pooled incidence of AL was 12.1% (95% Cl 7.77-18.26) in the HL group and 9.7% (95% Cl 5.79-15.82) in the LL group (OR 1.20, 95% CI 0.77-1.87, P = 0.42). In trial sequential analysis, the cumulative Z-score curve exceeded the futility boundary, although the required information size of 1060 had not been reached. The quality of evidence was judged to be high according to the GRADE approach. CONCLUSIONS: This meta-analysis shows that HL of the IMA does not increase the incidence of AL in anterior resection for rectal cancer.

MKP1 reduces neuroinflammation via inhibiting endoplasmic reticulum stress and mitochondrial dysfunction.

MAP kinase phosphatase 1 (MKP1) has been identified as an antiapoptotic protein via sustaining mitochondrial function. However, the role of MKP1 in neuroinflammation has not been fully understood. The aim of this study is to figure out the influence of MKP1 in lipopolysaccharide (LPS)-treated microglia BV-2 cells and investigate whether MKP1 reduces BV-2 cell death via modulating endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The results of this study demonstrated that MKP1 was rapidly downregulated after exposure to LPS. However, the transfection of MKP1 adenovirus could reverse cell viability and attenuate LPS-mediated BV-2 cell apoptosis. Mechanistically, MKP1 overexpression alleviated ER stress and corrected LPS-induced calcium overloading. Besides, MKP1 adenovirus transfection also reversed mitochondrial bioenergetics, maintained mitochondrial membrane potential, and blocked mitochondria-initiated apoptosis signals. Furthermore, we found that MKP1 overexpression is associated with inactivation of mitogen-activated protein kinase-c-Jun N-terminal kinase (MAPK-JNK) pathway. Interestingly, the activation of MAPK-JNK pathway could abolish the protective effects of MKP1 on BV-2 cells survival and mitochondrial function in the presence of LPS. Altogether, our results identified MKP1 as a primary defender of neuroinflammation via modulating ER stress and mitochondrial function in a manner dependent on MAPK-JNK pathway. These findings may open a new window for the treatment of neuroinflammation in the clinical setting.

Sphingosine kinase 1 promotes cerebral ischemia-reperfusion injury through inducing ER stress and activating the NF-κB signaling pathway.

Endoplasm reticulum stress and inflammation response have been found to be linked to cerebral ischemia-reperfusion (IR) injury. Sphingosine kinase 1 (SPHK1) has been reported to be a novel endoplasm reticulum regulator. The aim of our study is to figure out the role of SPHK1 in cerebral IR injury and verify whether it has an ability to regulate inflammation and endoplasm reticulum stress. Hydrogen peroxide was used to induce cerebral IR injury. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, western blots, and immunofluorescence were used to measure the alterations of cell viability, inflammation response, and endoplasm reticulum stress. The results demonstrated that after exposure to hydrogen peroxide, cell viability was reduced whereas SPHK1 expression was significantly elevated. Knockdown of SPHK1 attenuated hydrogen peroxide-mediated cell death and reversed cell viability. Our data also demonstrated that SPHK1 deletion reduced endoplasm reticulum stress and alleviated inflammation response in hydrogen peroxide-treated cells. In addition, we also found that SHPK1 modulated endoplasm reticulum stress and inflammation response to through the NF-κB signaling pathway. Inhibition of NF-κB signaling pathway has similar results when compared with the cells with SPHK1 deletion. Altogether, our results demonstrated that SPHK1 upregulation, induced by hydrogen peroxide, is responsible for cerebral IR injury through inducing endoplasm reticulum stress and inflammation response in a manner working through the NF-κB signaling pathway. This finding provides new insight into the molecular mechanism to explain the neuron death induced by cerebral IR injury.

Cerebral ischemia-reperfusion is modulated by macrophage-stimulating 1 through the MAPK-ERK signaling pathway.

Cerebral ischemia-reperfusion (IR) injury is associated with mitochondrial damage. Macrophage-stimulating 1 (MST1) reportedly stimulates mitochondrial apoptosis by suppressing BCL-2. We investigated whether MST1 promotes the progression of cerebral IR injury by inducing mitochondrial dysfunction in vivo and in vitro. Western blot analysis, quantitative polymerase chain reaction, immunofluorescence, and mitochondrial function assays were conducted in cells from wild-type and Mst1-knockout mice subjected to cerebral IR injury. MST1 expression in wild-type glial cells increased following cerebral IR injury. Cerebral IR injury reduced the mitochondrial membrane potential and mitochondrial metabolism in glial cells, while it enhanced mitochondrial reactive oxygen species generation and mitochondrial calcium levels in these cells. The deletion of Mst1 attenuated cerebral IR injury by improving mitochondrial function and reducing mitochondrial damage. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway was suppressed in wild-type glial cell upon cerebral IR injury but was reactivated in Mst1-knockout glial cell. Accordingly, blocking the MAPK/ERK pathway abolished the beneficial effects of Mst1 deletion during cerebral IR injury by inducing mitochondrial damage in glial cells. Our results suggest that cerebral IR injury is associated with MST1 upregulation in the brain, while the genetic ablation of Mst1 can attenuate mitochondrial damage and sustain brain function following cerebral IR injury.

HSP90 inhibitor 17AAG attenuates sevoflurane-induced neurotoxicity in rats and human neuroglioma cells via induction of HSP70.

BACKGROUND: 17AAG has been extensively studied for its antitumor effects that protect cells from lethal stress by maintaining protein stability. The role of 17AAG in sevoflurane-induced neuronal injury has never been studied. We aim to investigate the effect of 17AAG on sevoflurane-induced neurotoxicity in vivo and in vitro. METHODS: Sevoflurane-induced hippocampal neuron injury model was established in aged Sprague-Dawley rats. Pretreatment of vehicle or 17AAG was administered prior to sevoflurane inhalation. H4 neuroglioma cells were pretreated with vehicle or 17AAG and exposed to sevoflurane. Apoptosis, oxidative stress, expression of interleukin-6 (IL-6), and activation of the nuclear factor-κB (NF-κB) signaling pathway in H4 cells were examined by Hoechst assay, flow cytometry, Western blot, and immunofluorescent staining. RNA interference against HSPA1A was performed to test the function of HSP70 in neuroprotection. RESULTS: Exogenous 17AAG reduced sevoflurane-induced apoptosis and oxidative stress in rat hippocampal neurons and in H4 cells. In H4 cells, 17AAG suppressed sevoflurane-induced upregulation of IL-6 and activation of NF-κB signaling. 17AAG enhanced sevoflurane-induced upregulation of HSP70 in rat hippocampal neurons and in H4 cells. Conversely, silencing of HSPA1A in H4 cells blocked the cytoprotective effect of 17AAG against sevoflurane-induced apoptosis and oxidative stress, and prevented upregulation of IL-6 and activation of NF-κB signaling. CONCLUSIONS: 17AAG protects against sevoflurane-induced neurotoxicity in vivo and in vitro via HSP70-dependent inhibition of apoptosis, oxidative stress, and pro-inflammatory signaling pathway.

Changes of hippocampus proteomic profiles after blueberry extracts supplementation in APP/PS1 transgenic mice.

Objective: To examine protein changes in the hippocampus of APP/PS1 transgenic mice after blueberry extracts (BB) intervention.Methods: Eight APP/PS1 transgenic mice were randomly assigned to Alzheimer's disease (AD)+BB group (n=4) and AD+control group (n=4). After a 16-week treatment, 2-DE and MALDI-TOF-MS were used to compare the proteomic profiles of the hippocampus in the two groups and Western blot was used to confirm the important differentially expressed proteins.Results: Twelve proteins were differentially expressed between the two groups. Nine of them were identified. Cytochrome b-c1 complex subunit 6, beta-actin, dynamin 1, and heat shock cognate 71 were up-regulated in AD+BB group, while a-enolase, stress-induced-phosphoprotein 1, malate dehydrogenase (MDH), MDH 1, and T-complex protein 1 subunit beta were down-regulated, respectively. Importantly, some of the identified proteins (e.g. dynamin 1) are known to be involved in cognitive impairment. Western blot analysis of hippocampus dynamin 1 expression confirmed the proteomic findings.Conclusions: The consumption of BB modulates the expression of proteins that are linked to the improvements of cognitive dysfunction in hippocampus of APP/PS1 transgenic mice.

Mitochonic acid-5 attenuates TNF-α-mediated neuronal inflammation via activating Parkin-related mitophagy and augmenting the AMPK-Sirt3 pathways.

Mitochondrial dysfunction has been found to be associated with neuronal inflammation; however, no effective drug is available to attenuate neuroinflammation via sustaining mitochondrial function. In the current study, experiments were performed to understand the beneficial effects of mitochonic acid 5 (MA-5) on tumor necrosis factor-α (TNF-α)-mediated neuronal injury and mitochondrial damage. Our data illustrated that MA-5 pretreatment reduced inflammation response induced by TNF-α in CATH.a cells. Molecular investigations demonstrated that MA-5 pretreatment repressed oxidative stress, inhibited endoplasmic reticulum stress, sustained cellular energy metabolism, and blocked cell apoptosis induced by TNF-α stress. Further, we found that MA-5 treatment elevated the expression of Sirtuin 3 (Sirt3) and this effect was dependent on the activation of AMP-activated protein kinase (AMPK) pathway. Blockade of AMPK abolished the promotive action of MA-5 on Sirt3 and thus mediated mitochondrial damage and cell death. Besides, we also found that MA-5 treatment augmented Parkin-related mitophagy and increased mitophagy promoted CATH.a cells survival via improving mitochondrial function. Knockdown of Parkin abolished the beneficial action of MA-5 on mitochondrial homeostasis and CATH.a cell survival. Altogether, our results confirm that MA-5 is an effective drug to attenuate neuroinflammation via sustaining mitochondrial damage and promoting CATH.a cell survival. The protective action of MA-5 on neuronal damage is associated with Parkin-related mitophagy and the activation of AMPK-Sirt3 pathways.