ABSTRACT
Mercury (Hg) emitted from East Asian has increased the risk of Hg in China Marginal Seas for decades. However, the speciation of Hg (especially the bioavailable Hg) in these regions remains unclear. To address this problem, we analyzed total Hg (THg) and methylmercury (MeHg) in the sediment and porewater of Yellow sea (YS) and East China Sea (ECS) and determined the speciation of Hg using both improved BCR sequential extraction and isotope dilution (ID) techniques. Nearshore areas of YS and ECS exhibited higher THg levels in sediments and porewater, suggesting the significant contribution of terrestrial inputs. The spatial distribution of MeHg showed similar trends with THg, but the sites with higher MeHg concentrations did not align with those of THg. The improved BCR sequential extraction method showed the residual fraction dominated Hg content (â¼44 %) in both systems, with a minor bioavailable carbonate fraction (1 %). The Spearman correlation analysis indicates that Eh and pH are the two factors significantly affected Hg bioavailability in the sediment. The bioavailability of Hg (estimated by the BCR method) showed a significant positive correlation with MeHg levels in the sediment (R²=0.47, P < 0.05), suggesting that BCR can be used to estimate the potential of Hg methylation in the sediment. However, the extent of bioavailable Hg in BCR and ID method were 1.15 ± 0.38 % and 29.5 ± 14.8 %, respectively, implying that Hg bioavailability may be underestimated by BCR techniques compared to ID methods (T-test, P < 0.01).
Subject(s)
Geologic Sediments , Mercury , Methylmercury Compounds , Water Pollutants, Chemical , Geologic Sediments/chemistry , Mercury/analysis , China , Water Pollutants, Chemical/analysis , Environmental Monitoring/methods , Biological Availability , Oceans and SeasABSTRACT
Coastal seas contribute the majority of human methylmercury (MeHg) exposure via marine fisheries. The terrestrial area surrounding the Bohai Sea and Yellow Sea (BS and YS) is one of the mercury (Hg) emission "hot spots" in the world, resulting in high concentrations of Hg in BS and YS seawater in comparison to other marine systems. However, comparable or even lower Hg levels were detected in seafood from the BS and YS than other coastal regions around the word, suggesting a low system bioaccumulation of Hg. Reasoning a low system efficiency of MeHg production (represented by MeHg/THg (total Hg) in seawater) may be present in these two systems, seven cruises were conducted in the BS and YS to test this hypothesis. MeHg/THg ratios in BS and YS seawater were found to be lower than that in most coastal systems, indicating that the system efficiency of MeHg production is relatively lower in the BS and YS. The low system efficiency of MeHg production reduces the risk of Hg in the BS and YS with high Hg discharge intensity. By measuring in situ production and degradation of MeHg using double stable isotope addition method, and MeHg discharge flux from various sources and its exchange at various interfaces, the budgets of MeHg in the BS and YS were estimated. The results indicate that in situ methylation and demethylation are the major source and sink of MeHg in the BS and YS. By comparing the potential controlling processes and environmental parameters for MeHg/THg in the BS and YS with the other coastal seas, estuaries and bays, lower transport efficiency of inorganic Hg from water column to the sediment, slower methylation of Hg, and rapid demethylation of MeHg were identified to be major reasons for the low system efficiency of MeHg production in the BS and YS. This study highlights the necessity of monitoring the system efficiency of MeHg production, associated processes, and controlling parameters to evaluate the efficiency of reducing Hg emissions in China as well as the other countries.
Subject(s)
Environmental Monitoring , Methylmercury Compounds , Seawater , Water Pollutants, Chemical , Seawater/chemistry , Oceans and Seas , China , MercuryABSTRACT
In the past few decades, mercury (Hg) discharged into the coastal bays of China has significantly increased; however, long-term trends regarding the pollution status and sources of Hg in these bays have yet to be clear. Focusing on this issue, surface sediments and core sediments were collected in the Jiaozhou Bay (JZB), a typical bay highly affected by human activities in China, to analyze the concentrations and stable isotopic composition of Hg. Total mercury (THg) concentrations in surface sediment varied from 7 to 163 ng/g, with higher levels located in the eastern JZB, possibly attributed to intensive industrial and population density. THg in sediment cores 14 and 20 displayed fluctuating increasing trends from 1936 to 2019, reflecting the deterioration of Hg pollution. In contrast, THg in sediment core 28 near the river mouth exhibited a declining trend, possibly due to the river dam construction. Using a stable isotope mixing model, contributions of various sources (atmospheric, riverine, and industrial emissions) to Hg in the JZB were estimated. The results showed that industrial emissions were the main source (over 50%) of mercury in the JZB in 2019. Sediment cores recorded an increase in industrial Hg due to early industrialization and Reform and Opening-up before 2000. In addition, sediment core 20 demonstrated a rise in the percentage of riverine Hg due to land reclamation at the bay's mouth during 2000-2007.
Subject(s)
Mercury , Water Pollutants, Chemical , Humans , Mercury/analysis , Bays , Water Pollutants, Chemical/analysis , Environmental Monitoring/methods , Geologic Sediments , Isotopes , ChinaABSTRACT
BACKGROUND: Caffeic acid tablets (CFA) are a proprietary Chinese medicine in treating thrombocytopenia. The efficacy and safety of CFA compared with other platelet-raising drugs for the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation. Therefore, we designed this meta-analysis to further establish the efficacy and safety of CFA in treating thrombocytopenia. METHODS: A computerized search was conducted in the Chinese biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journal Database (VIP), PubMed, and Web of Science databases using the keywords "caffeic acid tablets" and "thrombocytopenia." All randomized controlled trials were selected for the timeframe of build to 02/2023 and then screened and analyzed using RevMan 5.4 and stata17.0 software. RESULTS: A total of 35 publications with an overall 2533 patients were included in the study. The results of the meta-analysis showed that CFA were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [standardized mean difference (SMD) = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and CFA reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02]. CONCLUSION: CFA can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and are worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Drugs, Chinese Herbal , Thrombocytopenia , Humans , Drugs, Chinese Herbal/adverse effects , Caffeic Acids/adverse effects , Thrombocytopenia/drug therapyABSTRACT
Mercury (Hg) has seven stable isotopes that can be utilized to trace the sources of Hg and evaluate the importance of transport and transformation processes in the cycling of Hg in the environment. The ocean is an integral part of the Earth and plays an important role in the global mercury cycle. However, there is a lack of a systematic review of Hg stable isotopes in marine environments. This review is divided into four sections: a) advances in Hg stable isotope analysis, b) the isotope ratios of Hg in various marine environmental matrices (seawater, sediment, and organisms), c) processes governing stable Hg isotope ratios in the ocean, and d) application of Hg stable isotopes to understand biotic uptake and migration. Mercury isotopes have provided much useful information on marine Hg cycling that cannot be given by Hg concentrations alone. This includes (i) sources of Hg in coastal or estuarine environments, (ii) transformation pathways and mechanisms of different forms of Hg in marine environments, (iii) trophic levels and feeding guilds of marine fish, and (iv) migration/habitat changes of marine fish. With the improvement of methods for seawater Hg isotope analysis (especially species-specific methods) and the measurement of Hg isotope fractionation during natural biogeochemical processes in the ocean, Hg stable isotopes will advance our understanding of the marine Hg cycle in the future, e.g., mercury exchange at the sea-atmosphere interface and seawater-sediment interface, contributions of different water masses to Hg in the ocean, fractionation mechanisms of Hg and MeHg transformation in seawater.
ABSTRACT
Phosphate is considered to be an important biogenic element and responsible for eutrophication in aquatic ecosystems, existing in both dissolved and absorbed forms. Due to the complex matrix of coastal seawater, a high sensitivity and anti-interference method for phosphate detection is required for environmental protection. In this study, a novel electrochemical method was proposed based on reduced graphene oxide-ordered mesoporous carbon screen-printed electrode (rGO-OMC/SPE) analysis, allowing sensitivity and reliable determination of phosphate in turbid coastal waters. Combining the good absorption capacity of OMC with the excellent electroconductivity of rGO, the fabricated electrode exhibits improved signal responses, enhanced by up to 43-fold. The platform was evaluated using turbidity interference test with good recovery percentages comprised between 96% and 105% in different phosphate concentration, and salinity interference test between 92% and 105%, respectively. A linear range from 0.2 to 150 µM phosphate was achieved, with a detection limit of 0.05 µM (s/nâ¯=â¯3). The fabricated platform was successfully used for on-site analysis of phosphate in turbid coastal waters. This reliable and effective method for the analysis of phosphate in turbid coastal waters allows for sensitivity and anti-interference determination, while also representing a significant step towards comprehensive and convenient analysis of phosphorus species.
Subject(s)
Electrochemical Techniques , Environmental Monitoring/methods , Phosphates/analysis , Carbon/chemistry , Electrodes , Eutrophication , Graphite/chemistry , Water Pollutants, Chemical/analysisABSTRACT
The present study explored the mechanisms by which fragile X mental retardation 1 (fmr1) overexpression inhibits lipopolysaccharide (LPS)-induced cardiomyocyte injury. Factors including oxidative stress reaction, mitochondrial membrane potential variation and cell apoptosis were evaluated. The viability of H9c2 cells was evaluated with a Cell Counting Kit-8 assay after cells were treated with LPS at different concentrations (0, 1, 3, 6 and 9 µg/ml) for various durations (4, 12 and 24 h). Flow cytometry was used to determine variations in reactive oxygen species (ROS), mitochondrial membrane potential and cell apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to detect the levels of apoptosis-associated factors, and western blot analysis was used to determine the phosphorylation levels of phosphoinositide-3 kinase (PI3K), Akt and forkhead box (Fox)O3a. The results indicated that LPS decreased the viability of H9c2 cells in a dose- and time-dependent manner. Overexpression of fmr1 inhibited the LPS-induced decrease in the mitochondrial membrane potential and the production of ROS as well as apoptosis in H9c2 cells. Fmr1 also inhibited LPS-induced reductions in antioxidant enzyme activities, including those of superoxide dismutase and reduced/oxidized glutathione ratio, and decreased LPS-associated increases in the lipid peroxidation product malondialdehyde. Apoptosis-associated factors were identified to be involved in the effects of Fmr1. Overexpression of Fmr1 attenuated LPS-associated increases in the apoptosis-activating factors B-cell lymphoma 2 (Bcl-2)-associated X protein and caspase-3 and decreases in apoptosis inhibitors, including Bcl-2 and X-linked inhibitor of apoptosis protein. Fmr1 overexpression also reduced LPS-induced increases in the phosphorylation levels of PI3K, Akt and FoxO3a. In conclusion, fmr1 overexpression alleviated oxidative stress and apoptosis in H9c2 cardiomyocytes injured by LPS via regulating oxidative stress and apoptosis-associated factors, as well as the PI3K/Akt pathway. This information may provide a novel and effective therapeutic strategy for heart diseases.
ABSTRACT
Apigenin, a flavonoid with multiple physiological and pharmacological activities, is associated with the prevention of cardiovascular diseases. The present study aimed to examine the roles and mechanisms of apigenin in the apoptosis of H9C2 rat cardiomyocytes, which were subjected to myocardial ischemiareperfusion (MI/R) injury. Cell viability, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and cellular apoptosis were evaluated using cell counting kit8 assays and flow cytometry. The content/activity of oxidative stress markers was determined using commercial kits. Western blot analysis and reverse transcriptionquantitative polymerase chain reaction assays were used to measure protein and mRNA expression, respectively. The results demonstrated that apigenin had limited cytotoxicity on the viability of H9C2 rat cardiomyocytes. Apigenin reduced the oxidative stress, ROS production and cellular apoptotic capacity of MI/Rinduced H9C2 cells. Apigenin additionally increased the MMP level of MI/Rinduced H9C2 cells. Furthermore, apigenin modulated apoptosisassociated protein expression and phosphatidylinositol 3'-kinase (PI3K)/RACα serine/threonineprotein kinase (Akt) signaling in MI/Rinduced H9C2 cells. Treatment with LY294002 reversed the antiapoptotic effect of apigenin. In conclusion, apigenin suppressed the apoptosis of H9C2 cells that were subjected to MI/R injury by activating the PI3K/Akt pathway. It was suggested that apigenin may be effective as an MI/R therapy.
Subject(s)
Apigenin/pharmacology , Cardiotonic Agents/pharmacology , Myocytes, Cardiac/drug effects , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Animals , Apoptosis/drug effects , Cell Hypoxia/drug effects , Cell Line , Cell Survival/drug effects , Chromones/pharmacology , Gene Expression Regulation , Glucose/deficiency , Membrane Potential, Mitochondrial/drug effects , Models, Biological , Morpholines/pharmacology , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/agonists , Proto-Oncogene Proteins c-akt/metabolism , Rats , Reactive Oxygen Species/agonists , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
Symptomatic internal carotid artery (ICA) occlusion with hemodynamic impairment remains a dismal disease when untreated. In this prospective, single-center, controlled study, we investigated the feasibility, safety, and long-term outcome of stenting by endovascular recanalization for patients with chronic ICA occlusion. Forty patients with symptomatic chronically occluded ICA were assigned to receive endovascular recanalization (group A, n = 18) or conservative management (group B, n = 22). The primary end point was 100% complete recanalization of the primary occlusion at 60 minutes, and secondary end points were improvement in neurologic function and cognitive function. Patients in the 2 groups were comparable in demographic and baseline characteristics. Successful recanalization was achieved in 88.9% (16 of 18) of patients with the restoration of Thrombolysis in Myocardial Ischemia/Thrombolysis in Cerebral Ischemia 2 or 3 flow. There was no procedural or new cerebral ischemic event. Improvement in brain perfusion was observed in 12 (12 of 18, 75%) patients on single-photon emission computed tomography. Improvement in neurologic function defined as a reduction of ≥4 points on the National Institutes of Health Stroke Scale (NIHSS) at 6 months was observed in group A (baseline, 6.83 ± 3.01 vs 6 months, 2.61 ± 1.20; P < .01) and group B (baseline, 6.05 ± 2.75 vs 6 months, 4.77 ± 1.69; P < .05). A significant difference in NIHSS scores was noted between group A and B at 1, 3, and 6 months (P < .05 or .001). Improvement in cognitive function defined as an increase of ≥8 on the Montreal Cognitive Assessment (MoCA) was observed in group A at 3 and 6 months (baseline, 14.67 ± 3.56 vs 3 months, 24.17 ± 3.55 and 6 months, 24.72 ± 2.85; P < .01). Significant improvement in MoCA was also observed in group B (P < .01). Furthermore, a significant difference in MoCA scores was noted between group A and B at 1, 3, and 6 months (P < .05 or .001). Endovascular recanalization is feasible and safe for patients with symptomatic chronic carotid artery occlusion. Successful carotid artery stenting can improve neurological function and global cognitive function than nonrevascularization.
Subject(s)
Brain Ischemia/prevention & control , Carotid Stenosis/surgery , Cognition Disorders/prevention & control , Stents , Aged , Carotid Artery, Internal , Carotid Stenosis/diagnostic imaging , Chronic Disease , Feasibility Studies , Female , Humans , Male , Patient Safety , Prospective Studies , Radiography , Treatment OutcomeABSTRACT
BACKGROUND: Algorithm evaluation provides a means to characterize variability across image analysis algorithms, validate algorithms by comparison with human annotations, combine results from multiple algorithms for performance improvement, and facilitate algorithm sensitivity studies. The sizes of images and image analysis results in pathology image analysis pose significant challenges in algorithm evaluation. We present an efficient parallel spatial database approach to model, normalize, manage, and query large volumes of analytical image result data. This provides an efficient platform for algorithm evaluation. Our experiments with a set of brain tumor images demonstrate the application, scalability, and effectiveness of the platform. CONTEXT: The paper describes an approach and platform for evaluation of pathology image analysis algorithms. The platform facilitates algorithm evaluation through a high-performance database built on the Pathology Analytic Imaging Standards (PAIS) data model. AIMS: (1) Develop a framework to support algorithm evaluation by modeling and managing analytical results and human annotations from pathology images; (2) Create a robust data normalization tool for converting, validating, and fixing spatial data from algorithm or human annotations; (3) Develop a set of queries to support data sampling and result comparisons; (4) Achieve high performance computation capacity via a parallel data management infrastructure, parallel data loading and spatial indexing optimizations in this infrastructure. MATERIALS AND METHODS: WE HAVE CONSIDERED TWO SCENARIOS FOR ALGORITHM EVALUATION: (1) algorithm comparison where multiple result sets from different methods are compared and consolidated; and (2) algorithm validation where algorithm results are compared with human annotations. We have developed a spatial normalization toolkit to validate and normalize spatial boundaries produced by image analysis algorithms or human annotations. The validated data were formatted based on the PAIS data model and loaded into a spatial database. To support efficient data loading, we have implemented a parallel data loading tool that takes advantage of multi-core CPUs to accelerate data injection. The spatial database manages both geometric shapes and image features or classifications, and enables spatial sampling, result comparison, and result aggregation through expressive structured query language (SQL) queries with spatial extensions. To provide scalable and efficient query support, we have employed a shared nothing parallel database architecture, which distributes data homogenously across multiple database partitions to take advantage of parallel computation power and implements spatial indexing to achieve high I/O throughput. RESULTS: Our work proposes a high performance, parallel spatial database platform for algorithm validation and comparison. This platform was evaluated by storing, managing, and comparing analysis results from a set of brain tumor whole slide images. The tools we develop are open source and available to download. CONCLUSIONS: Pathology image algorithm validation and comparison are essential to iterative algorithm development and refinement. One critical component is the support for queries involving spatial predicates and comparisons. In our work, we develop an efficient data model and parallel database approach to model, normalize, manage and query large volumes of analytical image result data. Our experiments demonstrate that the data partitioning strategy and the grid-based indexing result in good data distribution across database nodes and reduce I/O overhead in spatial join queries through parallel retrieval of relevant data and quick subsetting of datasets. The set of tools in the framework provide a full pipeline to normalize, load, manage and query analytical results for algorithm evaluation.
ABSTRACT
Epidermal growth factor (EGF) is a known mitogen for neural stem and progenitor cells (NS/NPCs) in the central nervous system (CNS). In vitro, EGF maintains NS/NPCs in the proliferative state, whereas in the normal rodent brain it promotes their proliferation and migration in the subventricular zone (SVZ). Additionally, EGF administration can augment neuronal replacement in the ischemic-injured adult striatum. Recently we found that the SVZ and the hippocampus display an injury-induced proliferative response following traumatic brain injury (TBI) that is linked to increased EGF expression. As adult neurogenesis is associated with cognitive function, we hypothesized that post-TBI administration of EGF could affect neurogenesis and cognitive recovery. Adult rats were intraventricularly infused with EGF or vehicle for 7 days following TBI. 5-Bromo-2-deoxyuridine (BrdU) was administered to label proliferating cells and the animals were sacrificed at 1 or 4 weeks post-injury. Using immunohistochemistry and stereology, we found that at 1 week post-injury, compared to vehicle-infused animals EGF-infused animals had significantly more BrdU-positive cells in the SVZ and hippocampus concomitant with enhanced EGF receptor expression. At 4 weeks post-injury, the number of BrdU-positive cells in the hippocampus was similar in both groups, suggesting that EGF does not support long-term survival of newly generated cells. Furthermore, we found that the EGF-induced proliferative population differentiated preferentially toward astroglial phenotype. Nevertheless, animals treated with EGF showed significant improvement in cognitive function, which was accompanied by reduced hippocampal neuronal cell loss. Collectively, the data from this study demonstrate that EGF exerts a neuroprotective rather than neurogenic effect in protecting the brain from injury.
Subject(s)
Brain Injuries/metabolism , Brain Injuries/therapy , Epidermal Growth Factor/therapeutic use , Neuronal Plasticity/physiology , Animals , Brain Injuries/pathology , Cell Proliferation/drug effects , Disease Models, Animal , Epidermal Growth Factor/administration & dosage , Humans , Injections, Intraventricular , Male , Neurogenesis/physiology , Neuronal Plasticity/drug effects , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/therapeutic use , Rats , Rats, Sprague-Dawley , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Stem Cells/drug effects , Stem Cells/physiology , Treatment OutcomeABSTRACT
Stem/progenitor cells reside throughout the adult CNS and are actively dividing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. This neurogenic capacity of the SVZ and DG is enhanced following traumatic brain injury (TBI) suggesting that the adult brain has the inherent potential to restore populations lost to injury. This raises the possibility of developing strategies aimed at harnessing the neurogenic capacity of these regions to repair the damaged brain. One strategy is to enhance neurogenesis with mitogenic factors. As basic fibroblast growth factor (bFGF) is a potent stem cell mitogen, we set out to determine if an intraventricular administration of bFGF following TBI could affect the levels of injury-induced neurogenesis in the SVZ and DG, and the degree to which this is associated with cognitive recovery. Specifically, adult rats received a bFGF intraventricular infusion for 7 days immediately following TBI. BrdU was administered to animals daily at 2-7 days post-injury to label cell proliferation. At 1 or 4 weeks post-injury, brain sections were immunostained for BrdU and neuronal or astrocytic markers. We found that injured animals infused with bFGF exhibited significantly enhanced cell proliferation in the SVZ and the DG at 1 week post-TBI as compared to vehicle-infused animals. Moreover, following bFGF infusion, a greater number of the newly generated cells survived to 4 weeks post-injury, with the majority being neurons. Additionally, animals infused with bFGF showed significant cognitive improvement. Collectively, the current findings suggest that bFGF-enhanced neurogenesis contributes to cognitive recovery following TBI.
Subject(s)
Brain Injuries/drug therapy , Cognition Disorders/drug therapy , Fibroblast Growth Factor 2/pharmacology , Neurogenesis/drug effects , Neuronal Plasticity/drug effects , Recovery of Function/drug effects , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Brain Injuries/complications , Brain Injuries/physiopathology , Bromodeoxyuridine , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Proliferation/drug effects , Cerebrum/cytology , Cerebrum/drug effects , Cerebrum/metabolism , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Disease Models, Animal , Fibroblast Growth Factor 2/metabolism , Fibroblast Growth Factor 2/therapeutic use , Injections, Intraventricular , Male , Neurogenesis/physiology , Neuronal Plasticity/physiology , Neurons/drug effects , Neurons/metabolism , Rats , Recovery of Function/physiology , Stem Cells/cytology , Stem Cells/drug effects , Stem Cells/metabolism , Treatment OutcomeABSTRACT
OBJECTIVE: Perfluorocarbon emulsions have been shown to improve outcomes in stroke models. This study examined the effect of Oxycyte, a third-generation perfluorocarbon emulsion (04RD33; Synthetic Blood International, Inc., Costa Mesa, CA) treatment on cognitive recovery and mitochondrial oxygen consumption after a moderate lateral fluid percussion injury (LFPI). METHODS: Adult male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allocated to 4 groups: 1) LFPI treated with a lower dose of Oxycyte (4.5 mL/kg); 2) LFPI with a higher dose of Oxycyte (9.0 mL/kg); 3) LFPI with saline infusion; and 4) sham animals treated with saline. Fifteen minutes after receiving moderate LFPI or sham surgery, animals were infused intravenously with Oxycyte or saline within 30 minutes while breathing 100% O2. Animals breathed 100% O2 continuously for a total of 4 hours after injury. At 11 to 15 days after LFPI, animals were assessed for cognitive deficits using the Morris water maze test. They were sacrificed at Day 15 after injury for histology to assess hippocampal neuronal cell loss. In a parallel study, mitochondrial oxygen consumption values were measured by the Cartesian diver microrespirometer method. RESULTS: We found that injured animals treated with a lower or higher dose of Oxycyte had significant improvement in cognitive function when compared with injured saline-control animals (P < 0.05). Moreover, injured animals that received either dose of Oxycyte had significantly less neuronal cell loss in the hippocampal CA3 region compared with saline-treated animals (P < 0.05). Furthermore, a lower dose of Oxycyte significantly improved mitochondrial oxygen consumption levels (P < 0.05). CONCLUSION: The current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.
Subject(s)
Brain Injuries/drug therapy , Cognition Disorders/drug therapy , Fluorocarbons/therapeutic use , Neuroprotective Agents/therapeutic use , Animals , Blood Pressure/drug effects , Brain Injuries/complications , Brain Injuries/physiopathology , Cell Count , Cognition Disorders/etiology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/injuries , Hippocampus/pathology , Male , Maze Learning/drug effects , Neurons/drug effects , Neurons/pathology , Oxygen Consumption/drug effects , Oxygen Inhalation Therapy , Rats , Rats, Sprague-Dawley , Recovery of Function/drug effects , Wounds, NonpenetratingABSTRACT
OBJECT: Hyperbaric oxygen (HBO2) has been shown to improve outcome after severe traumatic brain injury, but its underlying mechanisms are unknown. Following lateral fluid-percussion injury (FPI), the authors tested the effects of HBO2 treatment as well as enhanced normobaric oxygenation on mitochondrial function, as measured by both cognitive recovery and cellular adenosine triphosphate (ATP) levels. METHODS: Adult male Sprague-Dawley rats were subjected to moderate lateral FPI or sham injury and were allocated to one of four treatment groups: 1) FPI treated with 4 hours of normobaric 30% O2; 2) FPI treated with 4 hours of normobaric 100% O2; 3) FPI treated with 1 hour of HBO2 plus 3 hours of normobaric 100% O2; and 4) sham-injured treated with normobaric 30% O2. Cognitive outcome was assessed using the Morris water maze (MWM) on Days 11 to 15 after injury. Animals were then killed 21 days postinjury to assess hippocampal neuronal loss. Adenosine triphosphate was extracted from the neocortex and measured using high-performance liquid chromatography. The results showed that injured animals treated with HBO2 or normobaric 100% O2 alone had significantly higher levels of cerebral ATP as compared with animals treated using normobaric 30% O2 (p < or = 0.05). The injured animals treated with HBO2 had significant improvements in cognitive recovery, as characterized by a shorter latency in MWM performance (p < or = 0.05), and decreased neuronal loss in the CA2/3 and hilar regions as compared with those treated with 30% or 100% O2, (p < or = 0.05). CONCLUSIONS: Both hyperbaric and normobaric hyperoxia increased cerebral ATP levels after lateral FPI. In addition, HBO2 treatment improved cognitive recovery and reduced hippocampal neuronal cell loss after brain injury in the rat.
Subject(s)
Brain Injuries/therapy , Cognition/physiology , Hyperbaric Oxygenation , Mitochondria/physiology , Adenosine Triphosphate/metabolism , Animals , Brain Injuries/metabolism , Brain Injuries/psychology , Chromatography, High Pressure Liquid , Free Radicals/metabolism , Hippocampus/pathology , Male , Maze Learning , Rats , Rats, Sprague-Dawley , Recovery of Function/physiologyABSTRACT
The hippocampus is particularly vulnerable to traumatic brain injury (TBI), the consequences of which are manifested as learning and memory deficits. Following injury, substantive spontaneous cognitive recovery occurs, suggesting that innate repair mechanisms exist in the brain. However, the underlying mechanism contributing to this is largely unknown. The existence of neural stem cells in the adult hippocampal dentate gyrus (DG) and their proliferative response following injury led us to speculate that neurogenesis may contribute to cognitive recovery following TBI. To test this, we first examined the time course of cognitive recovery following lateral fluid percussion injury in rats. Cognitive deficits were tested at 11-15, 26-30 or 56-60 days post-injury using Morris Water Maze. At 11-15 and 26-30 days post-injury, animals displayed significant cognitive deficits, which were no longer apparent at 56-60 days post-TBI, suggesting an innate cognitive recovery at 56-60 days. We next examined the proliferative response, maturational fate and integration of newly generated cells in the DG following injury. Specifically, rats received BrdU at 2-5 days post-injury followed by Fluorogold (FG) injection into the CA3 region at 56 days post-TBI. We found the majority of BrdU+ cells which survived for 10 weeks became dentate granule neurons, as assessed by NeuN and calbindin labeling, approximately 30% being labeled with FG, demonstrating their integration into the hippocampus. Additionally, some BrdU+ cells were synaptophysin-positive, suggesting they received synaptic input. Collectively, our data demonstrate the extensive anatomical integration of new born dentate granule neurons at the time when innate cognitive recovery is observed.
Subject(s)
Brain Injuries/pathology , Brain Injuries/psychology , Cognition Disorders/etiology , Cognition Disorders/psychology , Dentate Gyrus/pathology , Neurons/pathology , Animals , Brain Injuries/physiopathology , Bromodeoxyuridine , Calbindins , Cell Proliferation , Cell Survival , Cellular Senescence , Fluorescent Dyes , Male , Maze Learning , Rats , Rats, Sprague-Dawley , Recovery of Function , S100 Calcium Binding Protein G/metabolism , Stilbamidines , Swimming , Synaptophysin/metabolism , Time FactorsABSTRACT
OBJECTIVE: Failure of energy metabolism after traumatic brain injury may be a major factor limiting outcome. Although glucose is the primary metabolic substrate in the healthy brain, the well documented surge in tissue lactate after traumatic brain injury suggests that lactate may provide an energy need that cannot be met by glucose. We hypothesized, therefore, that administration of lactate or the combination of lactate and supraphysiological oxygen may improve mitochondrial oxidative respiration in the brain after rat fluid percussion injury. We measured oxygen consumption (VO2) to determine what effects glucose, lactate, oxygen, and the combination of lactate and oxygen have on mitochondrial respiration in both injured and uninjured rat brain tissue. METHODS: Anesthetized Sprague-Dawley rats were intubated and ventilated with either 0.21 or 1.0 fraction of inspired oxygen (FIO2). Brain tissue from acute sham animals was subjected in vitro to 1.1 mM, 12 mM and 100 mM concentrations of glucose and L-lactate. In another group, injury (fluid percussion injury of 2.5 +/- 0.02 atmospheres) was induced over the left hemisphere. The VO2 of mug amounts of brain tissues were measured in a microrespirometry system (Cartesian diver). RESULTS: The VO2 was found to be independent of glucose concentrations, but dose-dependent for lactate. Moreover, the lactate dependent VO2s were all significantly higher than those generated by glucose. Injured rats on FIO2 0.21 had brain tissue VO2 rates that were significantly lower than those of shams or preinjury levels. In injured rats treated with FIO2 1.0, the reduction in VO2 levels was prevented. Injured rats that received an intravenous infusion of 100 mM lactate had VO2 rates that were significantly higher than those obtained with FIO2 1.0. Combined treatment further boosted the lactate generated VO2 rates by approximately 15%. CONCLUSION: Glucose sustains mitochondrial respiration at a low level "fixed" rate because, despite increasing its concentration nearly 100-fold, it cannot up-regulate VO2 after fluid percussion injury. Lactate produces a dose-dependent VO2 response, possibly enabling mitochondria to meet the increased energy needs of the injured brain.