Investigating the potential mechanism of Pioglitazone in Sepsis-Related brain injury through transcriptomics.

Sepsis-related brain injury (SRBI) refers to brain dysfunction and structural damage caused by sepsis, which is characterized by inflammation, oxidative stress, and destruction of the blood-brain barrier. Pioglitazone is a PPAR-γ agonist in which PPAR-γ acts as an inflammatory modulator, determining the relationship between PPAR-γ and SRBI and inflammatory state is critical for the disease. This study aimed to construct a drug-target-disease network for SRBI and Pioglitazone based on network pharmacology, and to investigate the therapeutic effect and potential mechanism of Pioglitazone in SRBI induced by lipopolysaccharide (LPS) in rats through transcriptomics. To establish a rat Model of SRBI by intraperitoneal injection of LPS (10 mg/kg): SD rats were divided into Control, Model (LPS), Pioglitazone, (LPS + Pioglitazone) and GW9662 group (LPS+GW9662). The effects and potential mechanisms of Pioglitazone in the treatment of SRBI were studied using biochemical indexes, pathological changes and transcriptome-sequencing (RNA-seq). RNA-seq results showed 620 DEGs between the Model and the Pioglitazone groups. Enrichment analysis involved multiple inflammatory response processes and chemokine receptor binding functions. TLR4 and CXCL10 in the Toll signaling pathway may play an important role in SRBI as important targets. Pioglitazone may ameliorate SRBI through the PPAR-γ/TLR4/CXCL10 pathway.

Atorvastatin combined with dexamethasone in chronic subdural haematoma (ATOCH II): study protocol for a randomized controlled trial.

BACKGROUND: Chronic subdural haematoma (CSDH) is a common condition in the elderly that often requires neurosurgical management. For small CSDH, evidence has emerged that statins may reduce haematoma volume and improve outcomes, presumably by reducing local inflammation and promoting vascular repair. We wish to extend this evidence in a study that aims to determine the efficacy and safety of atorvastatin combined with low-dose dexamethasone in patients with CSDH. METHODS: The second ATorvastatin On Chronic subdural Hematoma (ATOCH-II) study is a multi-centre, randomized, placebo-controlled, double-blind trial which aims to enrol 240 adult patients with a conservative therapeutic indication for CSDH, randomly allocated to standard treatment with atorvastatin 20 mg combined with low-dose dexamethasone (or matching placebos) daily for 28 days, and with 152 days of follow-up. The primary outcome is a composite good outcome defined by any reduction from baseline in haematoma volume and survival free of surgery at 28 days. Secondary outcomes include functional outcome on the modified Rankin scale (mRS) and modified Barthel Index at 28 days, surgical transition and reduction in haematoma volumes at 14, 28 and 90 days. DISCUSSION: This multi-centre clinical trial aims to provide high-quality evidence on the efficacy and safety of the combined treatment of atorvastatin and low-dose dexamethasone to reduce inflammation and enhance angiogenesis in CSDH. TRIAL REGISTRATION: ChiCTR, ChiCTR1900021659 . Registered on 3 March 2019, http://www.chictr.org.cn/showproj.aspx?proj=36157 .

Multiple-Coated PLGA Nanoparticles Loading Triptolide Attenuate Injury of a Cellular Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, which is associated with extracellular deposition of amyloid-ß proteins (Aß). It has been reported that triptolide (TP), an immunosuppressive and anti-inflammatory agent extracted from a Chinese herb Tripterygium wilfordii, shows potential neuroprotective effects pertinent to AD. However, the clinical use of TP for AD could be hampered due to its high toxicity, instability, poor water solubility, and nonspecific biodistribution after administration. In this paper, we reported a kind of multiple-coated PLGA nanoparticle with the entrapment of TP and surface coated by chitosan hydrochloride, Tween-80, PEG20000, and borneol/mentholum eutectic mixture (MC-PLGA-TP-NP) as a novel nasal brain targeting preparation for the first time. The obtained MC-PLGA-TP-NP was 147.5 ± 20.7 nm with PDI of 0.263 ± 0.075, zeta potential of 14.62 ± 2.47 mV, and the entrapment efficiency and loading efficiency of 93.14% ± 4.75% and 1.17 ± 0.08%, respectively. In comparison of TP, MC-PLGA-TP-NP showed sustained-release profile and better transcellular permeability to Caco-2 cells in vitro. In addition, our data showed that MC-PLGA-TP-NP remarkably reduced the cytotoxicity, attenuated the oxidative stress, and inhibited the increase of the intracellular Ca2+ influx in differentiated PC12 cells induced by Aß 1-42. Therefore, it can be concluded that MC-PLGA-TP-NP is a promising preparation of TP, which exerts a better neuroprotective activity in the AD cellular model.

Instantaneous Respiratory Response of Gamer with High-Risk Internet Gaming Disorder during Game-Film Stimuli by Using Complementary Ensemble Empirical Mode Decomposition.

Gamers with Internet gaming disorder (IGD) dynamically regulate their psychophysiological responses during playing; however, analyzing instantaneous psychophysiological responses in these gamers has been limited by a lack of appropriate methods. We propose combining the Complementary Ensemble Empirical Mode Decomposition and Direct Quadrature methods to overcome this limitation. The related effect of abdominal breathing (AB) training (as a relaxing psychology method) on the distribution of instantaneous frequency (IF) was investigated by calculating median (IFmed), kurtosis (IFkurt) and skewness (IFskew), and 19 participants with high-risk IGD (HIGD) were found to have increased IFmed [massively multiplayer online role-playing game (MMORPG): 0.36 ± 0.08; first-person shooter game (FPSG): 0.34 ± 0.08] but decreased IFkurt (MMORPG: 5.98 ± 2.31; FPSG: 6.84 ± 4.61) and IFskew (MMORPG: 0.40 ± 0.69; FPSG: 0.64 ±1.04) during game-film stimuli compared with baseline and recovery states. After AB training, IFmed of these 19 participants (MMORPG: 0.24 ± 0.11; FPSG: 0.18 ± 0.06) decreased significantly. This study is firstly to observe the IF distribution of respiratory signal in gamers with HIGD; thus, this distribution may be used as a respiratory physiological marker of IGD risk.

Nimodipine Improves Cognitive Impairment After Subarachnoid Hemorrhage in Rats Through IncRNA NEAT1/miR-27a/MAPT Axis.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a cerebral hemorrhage disease that severely damages the brain and causes cognitive impairment (CI). Therefore, accurate and appropriate treatment strategies are urgently needed. The application of nimodipine can not only improve blood circulation in patients with SAH but also repair ischemic neuron injury. PURPOSE: To investigate the effects of nimodipine and lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1)/miR-27a/microtubule-associated protein tau (MAPT) axis on CI after SAH. METHODS: One hundred and twenty healthy male rats were selected and equally divided into control group, sham operation group, model group, PBS group, nimodipine group (drug group), NC siRNA group, NC mimics group, NEAT1 siRNA, miR-27a mimics, MAPT siRNA, drug + NEAT1-ad, and drug + NC-ad groups by random number table. Rats in the model group were constructed by double-hemorrhage model, and expression vectors were injected into the tail to regulate the expression of lncRNA NEAT1, miR-27a and MAPT. In addition, Western blot was employed to detect brain tissue protein, flow cytometry was applied to measure brain tissue apoptosis, and MTT was utilized to determine cell activity, so as to evaluate brain damage and cognitive function in each group. RESULTS: Nimodipine, down-regulated lncRNA NEAT1, up-regulated miR-27a and down-regulated MAPT all improved brain damage and CI, inhibited brain tissue cell apoptosis, and enhanced brain cell activity. The common binding sites of lncRNA NEAT1 and MAPT were found on the miR-27a sequence fragment, and miR-27a could be paired with the former two. Nimodipine was found to cause the down-regulation of lncRNA NEAT1 and MAPT, as well as the up-regulation of miR-27a. CONCLUSION: Nimodipine can improve CI after SAH in rats through the lncRNA NEAT1/miR-27a/MAPT axis.

Characteristics of the isocitrate dehydrogenase gene and telomerase reverse transcriptase promoter mutations in gliomas in Chinese patients.

OBJECTIVES: To explore the characteristics of IDH and TERT promoter mutations in gliomas in Chinese patients. METHODS: A total of 124 Chinese patients with gliomas were enrolled to study the frequencies of mutations in isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase promoter (TERTp). Among the 124 patients, 59 patients were enrolled to study the classification of gliomas based on mutations in IDH and TERTp. RESULTS: Isocitrate dehydrogenase mutations are positively correlated with a good prognosis but mutations in TERTp cannot predict prognoses independently. The combined analysis of the mutations of IDH and TERTp can predict the prognosis more accurately. Patients with IDH and TERTp glioma mutations have the best prognosis, followed by only IDH mutation patients and only TERTp mutation patients, which have the worst prognosis. IDH and TERTp mutations occur frequently in males, younger patients or lower-grade patients. In contrast, only TERTp mutations occur frequently in females, older patients or higher-grade patients. CONCLUSIONS: Patients with IDH and TERTp glioma mutations have the best prognosis, and only IDH mutation patients and only TERTp mutation patients have the worst prognosis. Moreover, the molecular classification of gliomas by mutations of IDH and TERTp is not suitable for pediatric patients.

A Novel Cue-Induced Abdominal Reaction Analysis for Internet Gaming Disorder.

Individuals with Internet gaming disorder (IGD) frequently play online games to achieve satisfaction. Numerous signal processing questions regarding the negative consequences and characteristic respiration in a long-term sitting posture remain unanswered. This study recruited 50 individuals with high-risk and low-risk IGD (HIGD and LIGD); these participants were taught to perform a specific respiration during game-film stimuli. The instantaneous frequencies on abdominal movement (fDF) were calculated with ensemble empirical mode decomposition (EEMD). The difference value (ΔfDF) between rest and stimulus statuses was calculated and found that HIGD showed ΔfDF values of 0.060 during positive stimuli and 0.055 during negative stimuli before the exercise but 0.020 and 0.016, respectively, after the exercise. However, the ΔfDF value for those with LIGD during negative stimuli before the exercise was 0.013, and it increased to 0.025 after the exercise. This is the first approach to IGD discrimination toward abdominal response with EEMD.

Protective effect of isoliquiritigenin against cerebral injury in septic mice via attenuation of NF-κB.

BACKGROUND: The study was conducted to scrutinize the outcome of isoliquiritigenin (ISL) against cerebral injury in septic mice. METHODS: The sepsis was introduced using cecal ligation and puncture (CLP) method in experimental mice. The effect of ISL was quantified using the content of brain water and blood brain barrier (BBB) permeability. The effect on the levels of myeloperoxidase (MPO), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) in brain homogenates was also determined. The effect of ISL on the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in serum was also estimated. The levels of various inflammatory biomarkers (COX-2 and PGE2) were also studied. The expression of NF-κB signalling cascade and inducible nitric oxide synthase (iNOS) was estimated by Western blot. RESULTS: Compared with CLP group, the brain water content was found to be reduced significantly together with the enhanced BBB integrity in ISL treated group. The level of MDA was reduced together with enhanced level of SOD and GSH in the ISL treated group. The levels of TNF-α, IL-1ß, and IL-6 were also found to be modulated in ISL group. The level of COX-2 and PGE2 was reduced to near normal after ISL administration together with increase in the IκBα expression and reduction of p65 and p-p65 expression in a concentration-dependent manner. The expression of iNOS was also found to be reduced in ISL group. CONCLUSION: These results demonstrate that ISL causes protection of CLP-induced sepsis in experimental mice via multiple pathways.

Linarin suppresses glioma through inhibition of NF-κB/p65 and up-regulating p53 expression in vitro and in vivo.

Glioma is the most common form of malignant brain cancer with high mortality rate in human. Therefore, finding effective therapeutic strategy and revealing the underlying molecular mechanism is necessary. Plant-extracted flavonoid glycosides have been suggested to be bioactive compounds with pleiotropic functions, such as anti-cancer, anti-inflammatory, antioxidant and effects. Our study was attempted to explore the anti-cancer role of linarin (acacetin-7-O-ß-d-rutinoside) in glioma in vitro and in vivo. Nuclear factor kappa-B (NF-κB) activity is a common phenomenon in various cancers, resulting in abnormal cell proliferation, malignant transformation, or resistance to cell death. P53, an essential tumor suppressor, plays an important role in preventing tumor progression. Our data indicated that linarin suppressed glioma cell proliferation and migration by inducing apoptosis, which was through reducing cell cycle-related signals, including Survivin, p-Rb, and Cyclin D1, while promoting p21, Bax, Caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Also, we found that linarin-reduced cellular proliferation of glioma was dependent on p53 up-regulation and Nuclear factor kappa-B (NF-κB)/p65-down-regulation, thereby inhibiting glioma cell growth. We further conformed the inhibitory effect of linarin in vivo using xenograft tumor model. Linarin significantly triggered apoptosis as well as the tumor growth in animals, accompanied with p53 increase and p65 decrease. Our data illustrated that linarin could be used as a promising candidate against glioma progression.

Significance of Vestibular Testing on Distinguishing the Nerve of Origin for Vestibular Schwannoma and Predicting the Preservation of Hearing.

BACKGROUND: Determining the nerve of origin for vestibular schwannoma (VS), as a method for predicting hearing prognosis, has not been systematically considered. The vestibular test can be used to investigate the function of the superior vestibular nerve (SVN) and the inferior vestibular nerve (IVN). This study aimed to preoperatively distinguish the nerve of origin for VS patients using the vestibular test, and determine if this correlated with hearing preservation. METHODS: A total of 106 patients with unilateral VS were enrolled in this study prospectively. Each patient received a caloric test, vestibular-evoked myogenic potential (VEMP) test, and cochlear nerve function test (hearing) before the operation and 1 week, 3, and 6 months, postoperatively. All patients underwent surgical removal of the VS using the suboccipital approach. During the operation, the nerve of tumor origin (SVN or IVN) was identified by the surgeon. Tumor size was measured by preoperative magnetic resonance imaging. RESULTS: The nerve of tumor origin could not be unequivocally identified in 38 patients (38/106, 35.80%). These patients were not subsequently evaluated. In 26 patients (nine females, seventeen males), tumors arose from the SVN and in 42 patients (18 females, 24 males), tumors arose from the IVN. Comparing with the nerve of origins (SVN and IVN) of tumors, the results of the caloric tests and VEMP tests were significantly different in tumors originating from the SVN and the IVN in our study. Hearing was preserved in 16 of 26 patients (61.54%) with SVN-originating tumors, whereas hearing was preserved in only seven of 42 patients (16.67%) with IVN-originating tumors. CONCLUSIONS: Our data suggest that caloric and VEMP tests might help to identify whether VS tumors originate from the SVN or IVN. These tests could also be used to evaluate the residual function of the nerves after surgery. Using this information, we might better predict the preservation of hearing for patients.

[Neuroendoscopic management of tethered spinal cord syndrome].

OBJECTIVE: To investigate the methods and efficacy of neuroendoscopic operation in the treatment of tethered spinal cord syndrome (TSCS). METHODS: A total of 21 cases were recruited. There were 13 males and 8 females with an average age of 12.5 years old. TSCS was diagnosed by magnetic resonance imaging (MRI). They were operated under neuroendoscope. RESULTS: No complication was found during a follow-up period of 0.5 - 3 years. The symptoms improved in 18 cases. Neither obvious improvement nor aggravation was found in 3 cases. The total effective rate was 85.71%. CONCLUSION: Neuroendoscopic treatment of TSCS is both safe and effective.

[The clinical significance of the relationship between serum lost goodwill target proteome and the acute physiology and chronic health evaluation II score of patient with critical illness].

OBJECTIVE: To investigate the expression of serum lost goodwill target (LGT) proteome, and to analyze its clinical significance in evaluating prognosis of patient with critical illness on the basis of acute physiology and chronic health evaluation II (APACHEII) score. METHODS: The serum samples were collected from 96 patients with critical illness and 30 healthy volunteers as healthy control. The expression of serum LGT proteome was detected by surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) protein chip technology. The abundance value of LGT proteome in patients at admission was measured, and at the same time APACHE II score was estimated, in order to analyze its clinical significance in patients with critical illness. RESULTS: The amount of LGT proteome in APACHEII≥15 group [n =35, (9.26 ± 7.51)%] was significantly higher than that of APACHEII and it;15 group [n=61, (4.19 ± 4.07)%], and the LGT proteome amount in both groups was significantly higher than that of the healthy control group [(1.52 ± 0.47)%, both P <0.01]. Spearman correlation analysis showed that there was significant positive correlation between the abundance of LGT proteome and the APACHE II score (r =0.317 ,P =0.002). The abundance of LGT proteome in death group[n =23, (10.14 ± 9.23)%] was significantly higher than that in survival group [ n =73, (5.8 3 ± 3.57)%, P <0.01]. The fatality rate of the LGT proteome group with average abundance exceeding 5% [68.0% (17/25)] was significantly higher than that of the LGT proteome group with average abundance lower than 5% [8.5% (6/71), P<0.01]. According to the LGT proteome abundance to evaluate the prognosis of the patients,the positive predict rate was 68.0 %,the negative predict rate was 91.5 %, the false positive rate was 32.0%, the false negative rate was 8.5%. CONCLUSION: The LGT proteome was intimately correlated with the severity degree of disease condition and prognosis in patients with critical illness. The determination of LGT proteome combined with APACHE IIscore evaluation can probably be an important indicator in evaluating the prognosis of patient with critical illness. Further research on LGT proteome is warranted to facilitate the prognostication and clinical decision making.

Investigation of a plasmid containing a novel immunotoxin VEGF165-PE38 gene for antiangiogenic therapy in a malignant glioma model.

Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. Our previous studies have shown the effect of VEGF165-PE38 recombinant immunotoxin on proliferation and apoptosis in human umbilical vein endothelial cells in vitro. In this study, we explored the direct inhibition of angiogenesis in chick chorioallantoic membrane and antiangiogenic therapy in a malignant glioma model. HEK293 cells were transfected with the pVEGF165PE38-IRES2-EGFP plasmid. ELISA was used to confirm the expression of VEGF165-PE38 in the transfected cells. These cells released 1396 + or - 131.9 pg VEGF165-PE38/1x10(4) cells/48 h into the culture medium and the supernatant was capable of inhibiting the growth of capillary-like structures in chick chorioallantoic membrane assay. In a murine malignant glioma model, plasmid was directly administered via multiple local intratumoral delivery. After day 16 the tumor volume in mice treated with pVEGF165PE38-IRES2-EGFP was significantly lower than that in mice in the control groups. Immunohistochemistry studies showed that the treated group had decreased expression of CD31. Quantitative analysis of microvessel density in the treated group was 1.99 + or - 0.69/0.74 mm(2), and was significantly lower than that in the control groups (9.33 + or - 1.99/0.74 mm(2), 8.09 + or - 1.39/0.74 mm(2) and 8.49 + or - 1.69/0.74 mm(2)). Immunohistochemistry analysis indicated that immunotoxin VEGF165-PE38 was distributed in the treated group in malignant glioma tissue. Our findings provide evidence that the in vivo production of VEGF165-PE38 through gene therapy using a eukaryotic expression plasmid had potential antiangiogenic activity in malignant glioma in vivo.

In vivo magnetic resonance tracking of Feridex-labeled bone marrow-derived neural stem cells after autologous transplantation in rhesus monkey.

Bone marrow stroma cells-derived neural stem cells (BMSCs-D-NSCs) transplantation is a promising strategy for the treatment of nervous system disorders. The development of a non-invasive method to follow the fate of BMSCs-D-NSCs in vivo is very important for the future application of this treatment. In this paper, we show for the first time, that BMSCs-D-NSCs from rhesus monkeys can be labeled in vitro with the superparamagnetic iron oxide (SPIO) contrast agent Feridex and Poly-L-lysine (PLL) without affecting morphology, cell cycle, telomerase activity, proliferation and differentiation ability of the labeled cells. Furthermore, when autografted into the striatum, these cells survived, differentiated and were incorporated into the brain, and could be reliably tracked using MRI, as confirmed by histological examination of the grafting sites with PKH(67) fluorescence. These results suggest that Feridex labeling of BMSCs-D-NSCs is feasible, efficient and safe for MRI tracing following autografting into the rhesus monkey nervous system.