Search

Studies have found that the phosphatase actin regulatory factor 1 expression can be related to stroke, but it remains unclear whether changes in phosphatase actin regulatory factor 1 expression also play a role in traumatic brain injury. In this study we found that, in a mouse model of traumatic brain injury induced by controlled cortical impact, phosphatase actin regulatory factor 1 expression is increased in endothelial cells, neurons, astrocytes, and microglia. When we overexpressed phosphatase actin regulatory factor 1 by injection an adeno-associated virus vector into the contused area in the traumatic brain injury mice, the water content of the brain tissue increased. However, when phosphatase actin regulatory factor 1 was knocked down, the water content decreased. We also found that inhibiting phosphatase actin regulatory factor 1 expression regulated the nuclear factor kappa B signaling pathway, decreased blood-brain barrier permeability, reduced aquaporin 4 and intercellular adhesion molecule 1 expression, inhibited neuroinflammation, and neuronal apoptosis, thereby improving neurological function. The findings from this study indicate that phosphatase actin regulatory factor 1 may be a potential therapeutic target for traumatic brain injury.

Urolithin A (UA) is a natural metabolite produced from polyphenolics in foods such as pomegranates, berries, and nuts. UA is neuroprotective against Parkinson’s disease, Alzheimer’s disease, and cerebral hemorrhage. However, its effect against traumatic brain injury remains unknown. In this study, we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA. We found that UA greatly reduced brain edema; increased the expression of tight junction proteins in injured cortex; increased the immunopositivity of two neuronal autophagy markers, microtubule-associated protein 1A/B light chain 3A/B (LC3) and p62; downregulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), two regulators of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway; decreased the phosphorylation levels of inhibitor of NFκB (IκB) kinase alpha (IKKα) and nuclear factor kappa B (NFκB), two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway; reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex; and improved mouse neurological function. These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury, and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways, thus reducing neuroinflammation and enhancing autophagy.

Polyurethane vitrimers (PUVs) incorporating urethane reversion covalent adaptable networks are usually limited by the use of aliphatic alcohol for carbamate groups, resulting in high activation energy for bond exchange. In this study, PUVs bearing phenolic carbamate were demonstrated to overcome the low reactivity between phenol and isocyanate in the consumption of polymer wastes. First, poly(carbonate) (PC) was converted to a versatile intermediate mixture of hydroxyl N, N’-diphenylene-isopylidenyl biscarbamates (DP-biscarbamates). Unlike previously developed products with linear structures, the incorporation of a crosslinking agent, trimethylol propane with multiple functional groups would generate crosslinked structures in PUVs with improved mechanical properties. Due to the active sites provided by phenolic carbamate-containing DP-biscarbamate, the PUV products exhibit a gradual viscosity drop that follows the Arrhenius equation and corresponds to the feature of vitrimers with dissociative covalent adaptable networks. These products exhibit activation energies below 100 kJ/mol for topology rearrangement, facilitating the reprocessability for compression molding at mild temperatures of 120 °C. Overall, this study provides a new insight into an efficient material recycling process by the utilization of polymer waste.

Abstract In the petroleum industry, detection of multi-phase fluid flow is very important in both surface and down-hole measurements. Accurate measurement of high rate of water or gas multi-phase flow has always been an academic and industrial focus. NMR is an efficient and accurate technique for the detection of fluids; it is widely used in the determination of fluid compositions and properties. This paper is aimed to quantitatively detect multi-phase flow in oil and gas wells and pipelines and to propose an innovative method for online nuclear magnetic resonance (NMR) detection. The online NMR data acquisition, processing and interpretation methods are proposed to fill the blank of traditional methods. A full-bore straight tube design without pressure drop, a Halbach magnet structure design with zero magnetic leakage outside the probe, a separate antenna structure design without flowing effects on NMR measurement and automatic control technology will achieve unattended operation. Through the innovation of this work, the application of NMR for the real-time and quantitative detection of multi-phase flow in oil and gas wells and pipelines can be implemented.

Alzheimer disease is characterized by a progressive cognitive deficit and may be associated with an aberrant hyperexcitability of the neuronal network. Notoginsenoside R1 (R1), a major activity ingredient from Panax notoginseng, has demonstrated favorable changes in neuronal plasticity and induced neuroprotective effects in brain injuries, resulting from various disorders, however, the underlying mechanisms are still not well understood. In the present study, we aimed to explore the possible neuroprotective effects induced by R1 in a mouse model of AD and the mechanisms underlying these effects. Treatment with R1 significantly improved learning and memory functions and redressed neuronal hyperexcitability in amyloid precursor protein/presenilin-1 mice by altering the numbers and/or distribution of the members of voltage-gated sodium channels (Nav). Moreover, we determined whether R1 contributed to the regulation of neuronal excitability in Aβ-42–injured cells. Results of our study demonstrated that treatment with R1 rescued Aβ1-42–induced injured neurons by increasing cell viability. R1-induced alleviation in neuronal hyperexcitability might be associated with reduced Navβ2 cleavage, which partially reversed the abnormal distribution of Nav1.1α. These results suggested that R1 played a vital role in the recovery of Aβ1-42–induced neuronal injury and hyperexcitability, which is regulated by Nav proteins. Therefore, R1 may be a promising candidate in the treatment of AD.

Abstract Background Oxaliplatin belongs to the platinum-based drug family and has shown promise in treating cancer by binding to DNA to induce cytotoxicity. However, individual patients show diverse therapeutic responses toward oxaliplatin due to yet-unknown underlying mechanisms. We recently established that oxaliplatin also exert its anti-cancer activity in gastric cancer cell lines by targeting tumor-associated NADH oxidase (tNOX), attenuate NAD+ generation and reduce NAD+-dependent sirtuin 1 (SIRT1) deacetylase activity, which in turn enhances p53 acetylation and apoptosis. Methods In this study, differential cellular outcomes in response to oxaliplatin exposure of p53-wild-type versus p53-null HCT116 human colon cancer cells were examined. Cell growth profile was determined by cell impedance measurements and apoptosis was analyzed by flow cytometry. The engagement between oxaliplatin and tNOX protein was studied by cellular thermal shift assay. Furthermore, western blot analysis revealed that p53 was important in regulating tNOX expression in these cell lines. Results In p53-wild-type cells, we found that oxaliplatin inhibited cell growth by inducing apoptosis and concurrently down-regulating tNOX at both the transcriptional and translational levels. In p53-null cells, in contrast, oxaliplatin moderately up-regulated tNOX expression and yielded no apoptosis and much less cytotoxicity. Further experiments revealed that in p53-wild-type cells, oxaliplatin enhanced ROS generation and p53 transcriptional activation, leading to down-regulation of the transcriptional factor, POU3F2, which enhances the expression of tNOX. Moreover, the addition of a ROS scavenger reversed the p53 activation, POU3F2 down-regulation, and apoptosis induced by oxaliplatin in p53-wild-type cells. In the p53-null line, on the other hand, oxaliplatin treatment triggered less ROS generation and no p53 protein, such that POU3F2 and tNOX were not down-regulated and oxaliplatin-mediated cytotoxicity was attenuated. Conclusion Our results show that oxaliplatin mediates differential cellular responses in colon cancer cells depending on their p53 status, and demonstrate that the ROS-p53 axis is important for regulating POU3F2 and its downstream target, tNOX. Notably, the depletion of tNOX sensitizes p53-null cells to both spontaneous and oxaliplatin-induced apoptosis. Our work thus clearly shows a scenario in which targeting of tNOX may be a potential strategy for cancer therapy in a p53-inactivated system.

In the present study, we investigated the role of endogenous neurotrophin-3 in nerve terminal sprouting 2 months after spinal cord dorsal root rhizotomy. The left L 1-5 and L 7 -S 2 dorsal root ganglia in adult cats were exposed and removed, preserving the L 6 dorsal root ganglia. Neurotrophin-3 was mainly expressed in large neurons in the dorsal root ganglia and in some neurons in spinal lamina II. Two months after rhizotomy, the number of neurotrophin-3-positive neurons in the spared dorsal root ganglia and the density of neurite sprouts emerging from these ganglia were increased. Intraperitoneal injection of an antibody against neurotrophin-3 decreased the density of neurite sprouts. These findings suggest that endogenous neurotrophin-3 is involved in spinal cord plasticity and regeneration, and that it promotes axonal sprouting from the dorsal root ganglia after spinal cord dorsal root rhizotomy.

Background/Aims: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. Methods: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN-/-) and measured the behavioral and histopathological features of PD. Results: Aged (15-to 20-month-old) TN-/- mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. Conclusion: The TN-/- mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.

Progressive epidural hematoma (PEDH) after head injury is often observed on serial computerized tomography (CT) scans. Recent advances in imaging modalities and treatment might affect its incidence and outcome. In this study, PEDH was observed in 9.2% of 412 head trauma patients in whom two CT scans were obtained within 24 hours of injury, and in a majority of cases, it developed within 3 days after injury. In multivariate logistic regression, patient gender, age, Glasgow Coma Scale (GCS) score at admission, and skull fracture were not associated with PEDH, whereas hypotension (odds ratio (OR) 0.38, 95% confidence interval (CI) 0.17–0.84), time interval of the first CT scanning (OR 0.42, 95% CI 0.19–0.83), coagulopathy (OR 0.36, 95% CI 0.15–0.85), or decompressive craniectomy (DC) (OR 0.46, 95% CI 0.21–0.97) was independently associated with an increased risk of PEDH. The 3-month postinjury outcome was similar in patients with PEDH and patients without PEDH (χ2=0.07, P=0.86). In conclusion, epidural hematoma has a greater tendency to progress early after injury, often in dramatic and rapid fashion. Recognition of this important treatable cause of secondary brain injury and the associated risk factors may help identify the group at risk and tailor management of patients with TBI.

Background: The reported prevalence of unruptured cerebral aneurysms (UCAs) varies widely. Objective: To measure the prevalence of UCAs by using 3-dimensional time-of-flight magnetic resonance angiography in adults aged 35 to 75 years. Design: Cross-sectional study done between June 2007 and June 2011. Setting: Two communities chosen at random from 2 districts (1 urban and 1 suburban) in Shanghai, China. Participants: 4813 adults aged 35 to 75 years. Measurements: Three-dimensional time-of-flight magnetic resonance angiography, interpreted by 3 observers blinded to the participants' information, was used to identify the location and size of UCAs and to estimate the overall, age-specific, and sex-specific prevalence. Results: 369 UCAs were found in 336 participants (130 men and 206 women); 4477 participants had no evidence of UCAs. The prevalence was 7.0% overall (95% CI, 6.3% to 7.7%), with 5.5% for men (CI, 4.6% to 6.4%) and 8.4% for women (CI, 7.3% to 9.5%). The overall prevalence of UCAs was higher in women than in men (P < 0.001) and peaked at ages 55 to 64 years in men and women. The UCAs were mostly located in the internal carotid artery (81%), and 90.2% had a maximum diameter less than 5 mm. Mean diameter was larger in women than in men (3.7 mm vs. 3.2 mm; P < 0.009). Limitation: Participants were from 2 communities selected from 2 districts in Shanghai, and adults older than 75 years were not studied. Conclusion: The overall prevalence of UCAs was 7.0% in Chinese adults aged 35 to 75 years, and most lesions had a diameter less than 5 mm. Primary Funding Source: National Natural Science Foundation of China. [ABSTRACT FROM AUTHOR]

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a dual-specificity lipid and protein phosphatase. The loss of PTEN was originally discovered in numerous human cancers. PTEN inhibition by bisperoxovanadium (bpV) reduces neurological damage after ischemic brain injury. The purpose of this study was to identify the optimal neuroprotective dose of bpV when administrated after focal ischemia/reperfusion (I/R) injury in rats. Focal I/R injury was induced using the middle cerebral artery occlusion method. bpV at doses of 0.25, 0.50 and 1.0 mg/kg were injected intraperitoneally just after reperfusion, with saline serving as a vehicle control. A maximal reduction in brain injury was observed with 1.0 mg/kg bpV. This dose of bpV also significantly blocked apoptosis in the penumbral cortex of rats. This beneficial effect was associated with the increasing levels of Akt phosphorylation in the penumbral cortex. These results demonstrate that the pharmacological inhibition of PTEN protects against I/R injury in a dose-dependent manner and the protective effect might be induced through upregulation of the phosphoinositide-3 kinase/Akt pro-survival pathway, suggesting a new therapeutic strategy to combat ischemic brain injury. [ABSTRACT FROM AUTHOR]

Posttraumatic cerebral infarction (PTCI) is a severe secondary insult of head injury and often leads to a poor prognosis. Hemocoagulation disorder is recognized to have important effects on hemorrhagic or ischemic damages. We sought to assess if posttraumatic hemocoagulation disorders were associated with cerebral infarction, and evaluate their influence on outcome among patients with moderate or severe head trauma. In this study, PTCI was observed in 28 (10.57%) of the 265 patients within the first week after injury. In multivariate analysis, the thrombocytopenia (odds ratio (OR) 2.210, 95% confidence interval (CI) 1.065-4.674), abnormal prothrombin time (PT) (OR 3.241, 95% CI 1.090-7.648), D-dimer (>2mg/L) (OR 7.260, 95% CI 1.822-28.076), or disseminated intravascular coagulation (DIC) scores (≥5) (OR 4.717, 95% CI 1.778-12.517) were each independently associated with an increased risk of PTCI. Admission Glasgow Coma Scale (GCS) score, abnormal activated partial thromboplastin time (APTT) and fibrinogen, and D-dimer (>2 mg/L) and DIC scores (≥5) showed an independent predictive effect on poor outcome. In conclusion, recognition of this important treatable cause of PTCI and the associated risk factors may help identify the group at risk and tailor management of patients with TBI. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that endogenous angiogenesis inhibitor endostatin/collagen XVIII might play an important role in the secondary brain injury following traumatic brain injury (TBI). In this study, we measured endostatin/collagen XVIII concentrations serially for 1 week after hospitalization by using the enzyme-linked immunosorbent assay method in the cerebrospinal fluid (CSF) of 30 patients with TBI and a Glasgow Coma Scale (GCS) score of 8 or less on admission. There was a significant trend toward increased CSF levels of endostatin after TBI versus control from 72 h after injury. In patients with GCS score of 3-5, CSF endostatin concentration was substantially higher at 72 h after injury than that in patients with GCS score of 6-8 (P < 0.05) and peaked rapidly at day 5 after injury, but decreased thereafter. The CSF endostatin concentration in 12 patients with an unfavorable outcome was significantly higher than that in 18 patients with a favorable outcome at day 5 (P = 0.043) and day 7 (P = 0.005) after trauma. Receiver operating characteristic curve analysis suggested a reliable operating point for the 7-day CSF endostatin concentration predicting poor prognosis to be 67.29 pg/mL. Our preliminary findings provide new evidence that endostatin/collagen XVIII concentration in the CSF increases substantially in patients with sTBI. Its dynamic change may have some clinical significance on the judgment of brain injury severity and the assessment of prognosis. [ABSTRACT FROM AUTHOR]

Aims: The advent of three-dimensional (3D) rotational angiography (3D DSA) challenged the role of digital subtraction angiography (DSA) as a "gold standard" in the diagnosis of intracranial aneurysms. In this study, we report our experiences in diagnosing intracranial aneurysms by using 3D DSA with volume rendering (VR) technique, particularly focusing on its role in depicting additional aneurysms missed by 2D DSA. Materials and Methods: One hundred and thirty-eight consecutive patients with known or suspected aneurysms (54 men, 84 women; median age, 55 years; age range, 18-83 years) underwent both conventional DSA and 3D DSA with VR examination simultaneously. The images of 2D DSA or 3D DSA with VR were evaluated by two observers independently for the presence of aneurysms. Then additional aneurysms were decided and depicted. Results: 3D DSA with VR showed 146 aneurysms in 123 (89.1%) of 138 patients and no aneurysms in 15 patients. 2D DSA showed 115 aneurysms in 110 of 137 patients, with one aneurysm in 106 patients each, 2 in 3 patients each and 3 in 1 patient. After reaching a consensus, there were 31 additional aneurysms detected by 3D DSA with VR. 30 aneurysms were <3 mm in maximum diameter with 3 aneurysms ruptured. These additional aneurysms were located in internal carotid artery (ICA, n = 28, 90.32%), anterior cerebral artery (ACA, n = 3, 9.68%). No additional aneurysms were found in either middle cerebral artery (MCA) or vertebrobasilar and posterior cerebral artery (PCA) systems. Conclusions: 3D DSA, especially VR images, not only clearly reveals aneurysms and aneurysmal morphology, but also detects additional aneurysms missed by 2D DSA, especially small aneurysms less than 3 mm. [ABSTRACT FROM AUTHOR]

This study sought to describe and evaluate any relationship between D-dimer values and progressive hemorrhagic injury (PHI) after traumatic brain injury (TBI). In patients with TBI, plasma D-dimer was measured while a computed tomography (CT) scan was conducted as soon as the patient was admitted to the emergency department. A series of other clinical and laboratory parameters were also measured and recorded. A logistic multiple regression analysis was used to identify risk factors for PHI. A cohort of 194 patients with TBI was evaluated in this clinical study. Eighty-one (41.8%) patients suffered PHI as determined by a second CT scan. The plasma D-dimer level was higher in patients who demonstrated PHI compared with those who did not ( P < 0.001. Using a receiver–operator characteristic curve to predict the possibility by measuring the D-dimer level, a value of 5.00 mg/L was considered the cutoff point, with a sensitivity of 72.8% and a specificity of 78.8%. Eight-four patients had D-dimer levels higher than the cut point value (5.0 mg/L); PHI was seen in 71.4% of these patients and in 19.1% of the other patients ( P < 0.01). Factors with P < 0.2 on bivariate analysis were included in a stepwise logistic regression analysis to identify independent risk factors for TBI coagulopathy. Logistic regression analysis showed that the D-dimer value was a predictor of PHI, and the odds ratio (OR) was 1.341 with per milligram per liter ( P = 0.020). The stepwise logistic regression also identified that time from injury to the first CT shorter than 2 h (OR = 2.118, P = 0.047), PLT counts lesser than 100 × 109/L (OR = 7.853, P = 0.018), and Fg lower than 2.0 g/L (OR = 3.001, P = 0.012) were risk factors for the development of PHI. When D-dimer values were dichotomized at 5 mg/L, time from injury to the first CT scan was no longer a risk factor statistically while the OR value of D-dimer to the occurrence of PHI elevated to 11.850( P < 0.001). The level of plasma D-dimer after TBI can be a useful prognostic factor for PHI and should be considered in the clinical management of patients in combination with neuroimaging and other data. [ABSTRACT FROM AUTHOR]

We examined the incidence and timing of posttraumatic cerebral infarction (PTCI) and provide predictive factors for the development of PTCI in patients with moderate or severe traumatic brain injury. Three hundred and fifty-three consecutive patients with moderate or severe head trauma were retrospectively reviewed to determine the incidence and timing of PTCI and to evaluate the effects of age, gender, admission Glasgow Coma Scores (GCS), decompressive craniectomy, brain herniation, and low systolic blood pressure (BP) on the development of cerebral infarction. Risk factors for posttraumatic cerebral infarction were evaluated using logistic regression analysis. PTCI was observed in 36 (11.96%) of the 353 patients, and in a majority of cases, cerebral infarction developed within 2 weeks after injury. Poor admission GCS ( P < 0.01), low systolic BP ( P < 0.01), brain herniation ( P < 0.05), and decompression craniotomy ( P < 0.05) were significantly associated with the development of PTCI. No relationship was found between PTCI and gender or increased age. Posttraumatic cerebral infarction is a relatively common complication in patients with head trauma that develops early in the clinical course. Low GCS, low systolic BP, brain herniation, and decompression craniotomy may be risk factors for PTCI in patients with moderate or severe traumatic brain injury. [ABSTRACT FROM AUTHOR]