High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance.

PubMed

Frank, James A; Pittet, Jean-Francois; Lee, Hyon; Godzich, Micaela; Matthay, Michael A

2003-05-01

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.

Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status

PubMed Central

Hasselgren, Per-Olof; Glasgow, Allison; Doyle, Ashley N.; Lee, Alice J.; Fox, Peter; Gautam, Shiva; Hennessey, James V.; Kolodny, Gerald M.

2017-01-01

Background: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. Methods: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. Results: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. Conclusions: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function. PMID:27750020

Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

PubMed

Gavrila, Alina; Hasselgren, Per-Olof; Glasgow, Allison; Doyle, Ashley N; Lee, Alice J; Fox, Peter; Gautam, Shiva; Hennessey, James V; Kolodny, Gerald M; Cypess, Aaron M

2017-01-01

In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.

Mechano-Electrochemical Interaction Gives Rise to Strain Relaxation in Sn Electrodes

DOE PAGES

Barai, Pallab; Huang, Bo; Dillon, Shen J.; ...

2016-01-01

Tin (Sn) anode active particles were electrochemically lithiated during simultaneous imaging in a scanning electron microscope. Relationships among the reaction mechanism, active particle local strain rate, particle size, and microcrack formation are elucidated to demonstrate the importance of strain relaxation due to mechano-electrochemical interaction in Sn-based electrodes under electrochemical cycling. At low rates of operation, due to significant creep relaxation, large Sn active particles, of size 1 μm, exhibit no significant surface crack formation. Microcrack formation within Sn active particles occurs due to two different mechanisms: (i)large concentration gradient induced stress at the two-phase interface, and (ii) high volume expansionmore » induced stress at the surface of the active particles. From the present study, it can be concluded that majority of the microcracks evolve at or near the particle surface due to high volume expansion induced tension. Concentration gradient induced damage prevails near the center of the active particle, though significantly smaller in magnitude. Comparison with experimental results indicates that at operating conditions of C/2, even 500 nm sized Sn active particles remain free from surface crack formation, which emphasizes the importance of creep relaxation. A phase map has been developed to demonstrate the preferred mechano-electrochemical window of operation of Sn-based electrodes.« less

Perflurooctanoic Acid Induces Developmental Cardiotoxicity in ...

EPA Pesticide Factsheets

Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxisome proliferator activated receptor alpha (PPAR_). As the cardiovascular system is crucial for embryonic survival, PFOA-induced effects on the heart may partially explain embryonic mortality. To assess impacts of PFOA exposure on the developing heart in an avian model, we used histopathology and immunohistochemical staining for myosin to assess morphological alterations in 19-day-old chicken embryo hearts after PFOA exposure. Additionally, echocardiography and cardiac myofibril ATPase activity assays were used to assess functional alterations in 1-day-old hatchling chickens following developmental PFOA exposure. Overall thinning and thinning of a dense layer of myosin in the right ventricular wall were observed in PFOA-exposed chicken embryo hearts. Alteration of multiple cardiac structural and functional parameters, including left ventricular wall thickness, left ventricular volume, heart rate, stroke volume, and ejection fraction were detected with echocardiography in the exposed hatchling chickens. Assessment of ATPase activity indicated that the ratio of cardiac myofibril calcium-independent ATPase activity to calcium-dependent ATPase activity was not affected, which suggests that d

Hematological variations at rest and during maximal and submaximal exercise in a cold (0°C) environment

NASA Astrophysics Data System (ADS)

Vogelaere, P.; Brasseur, M.; Quirion, A.; Leclercq, R.; Laurencelle, L.; Bekaert, S.

1990-03-01

The affect of negative thermal stress on hematological variables at rest, and during submaximal (sub ex) and maximal exercise (max ex) were observed for young males who volunteered in two experimental sessions, performed in cold (0°C) and in normal room temperature (20°C). At rest, hematological variables such as RBC and derivates Hb and Hct were significantly increased ( P<0.05) during cold stress exposure, while plasma volume decreased. The findings of this study suggest that the major factor inducing hypovolemia during low thermal stress can be imputed to local plasma water-shift mechanisms and especially to a transient shift of plasma water from intrato extravascular compartments. Rest values for WBC and platelets (Pla) were also slightly increased during cold stress exposure. However this increase can partly be related to hemoconcentration but also to the cold induced hyperventilation activating the lung circulation. Maximal exhaustive exercise induced, in both experimental temperatures, significant ( P<0.05) increments of RBC, Hb, Hct, and WBC while plasma volume decreased. However, Pla increase was less marked. On the other hand, cold stress raised slightly the observed variations of the different hematological variables. Submaximal exercise induced a similar, though non-significant, pattern for the different hematological variables in both experimental conditions. Observed plasma volume (Δ PV%) reduction appears during exercise. However cold stress induced resting plasma volume variations that are transferred at every exercise level. Neither exercise nor cold inducement significantly modified the hematological indices (MCH, MCV, MCHC). In conclusion hematological variables are affected by cold stress exposure, even when subjects perform a physical activity.

Effect of norepinephrine on swelling-induced potassium transport in duck red cells. Evidence against a volume-regulatory decrease under physiological conditions

PubMed Central

1985-01-01

Duck red cells exhibit specific volume-sensitive ion transport processes that are inhibited by furosemide, but not by ouabain. Swelling cells in a hypotonic synthetic medium activates a chloride- dependent, but sodium-independent, potassium transport. Shrinking cells in a hypertonic synthetic medium stimulates an electrically neutral co- transport of [Na + K + 2 Cl] with an associated 1:1 K/K (or K/Rb) exchange. These shrinkage-induced modes can also be activated in both hypo- and hypertonic solutions by beta-adrenergic catecholamines (e.g., norepinephrine). Freshly drawn cells spontaneously shrink approximately 4-5% when removed from the influence of endogenous plasma catecholamines, either by incubation in a catecholamine-free, plasma- like synthetic medium, or in plasma to which a beta-receptor blocking dose of propranolol has been added. This spontaneous shrinkage resembles the response of hypotonically swollen cells in that it is due to a net loss of KCl with no change in cell sodium. Norepinephrine abolishes the net potassium transport seen in both fresh and hypotonically swollen cells. Moreover, cells swollen in diluted plasma, at physiological pH and extracellular potassium, show no net loss of KCl and water ("volume-regulatory decrease") unless propranolol is added. Examination of the individual cation fluxes in the presence of catecholamines demonstrates that activation of [Na + K + 2Cl] co- transport with its associated K/Rb exchange prevents, or overrides, swelling-induced [K + Cl] co-transport. These results, therefore, cast doubt on whether the swelling-induced [K + Cl] system can serve a volume-regulatory function under in vivo conditions. PMID:3998706

Volume rather than flow incentive spirometry is effective in improving chest wall expansion and abdominal displacement using optoelectronic plethysmography.

PubMed

Paisani, Denise de Moraes; Lunardi, Adriana Claudia; da Silva, Cibele Cristine Berto Marques; Porras, Desiderio Cano; Tanaka, Clarice; Carvalho, Celso Ricardo Fernandes

2013-08-01

Incentive spirometers are widely used in clinical practice and classified as flow-oriented (FIS) and volume-oriented (VIS). Until recently the respiratory inductive plethysmography used to evaluate the effects of incentive spirometry on chest wall mechanics presented limitations, which may explain why the impact of VIS and FIS remains poorly known. To compare the effects of VIS and FIS on thoracoabdominal mechanics and respiratory muscle activity in healthy volunteers. This cross-sectional trial assessed 20 subjects (12 female, ages 20-40 years, body mass index 20-30 kg/m(2)). All subjects performed 8 quiet breaths and 8 deep breaths with FIS and VIS, in a randomized order. We measured thoracoabdominal chest wall, upper and lower rib-cage, and abdominal volumes with optoelectronic plethysmography, and the muscle activity of the sternocleidomastoid and superior and inferior intercostal muscles with electromyography. VIS increased chest wall volume more than did FIS (P = .007) and induced a larger increase in the upper and lower rib-cages and abdomen (156%, 91%, and 151%, respectively, P < .001). By contrast, FIS induced more activity in the accessory muscles of respiration than did VIS (P < .001). VIS promotes a greater increase in chest wall volume, with a larger abdominal contribution and lower respiratory muscle activity, than does FIS in healthy adults.

Swelling and Eicosanoid Metabolites Differentially Gate TRPV4 Channels in Retinal Neurons and Glia

PubMed Central

Ryskamp, Daniel A.; Jo, Andrew O.; Frye, Amber M.; Vazquez-Chona, Felix; MacAulay, Nanna; Thoreson, Wallace B.

2014-01-01

Activity-dependent shifts in ionic concentrations and water that accompany neuronal and glial activity can generate osmotic forces with biological consequences for brain physiology. Active regulation of osmotic gradients and cellular volume requires volume-sensitive ion channels. In the vertebrate retina, critical support to volume regulation is provided by Müller astroglia, but the identity of their osmosensor is unknown. Here, we identify TRPV4 channels as transducers of mouse Müller cell volume increases into physiological responses. Hypotonic stimuli induced sustained [Ca2+]i elevations that were inhibited by TRPV4 antagonists and absent in TRPV4−/− Müller cells. Glial TRPV4 signals were phospholipase A2- and cytochrome P450-dependent, characterized by slow-onset and Ca2+ waves, and, in excess, were sufficient to induce reactive gliosis. In contrast, neurons responded to TRPV4 agonists and swelling with fast, inactivating Ca2+ signals that were independent of phospholipase A2. Our results support a model whereby swelling and proinflammatory signals associated with arachidonic acid metabolites differentially gate TRPV4 in retinal neurons and glia, with potentially significant consequences for normal and pathological retinal function. PMID:25411497

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berkowitz, L.R.; Orringer, E.P.

Swelling hemoglobin CC erythrocytes stimulates a ouabain-insensitive K flux that restores original cell volume. Studies were performed with the K analog, /sup 86/Rb. This volume regulatory pathway was characterized for its anion dependence, sensitivity to loop diuretics, and requirement for Na. The swelling-induced K flux was eliminated if intracellular chloride was replaced by nitrate and both swelling-activated K influx and efflux were partially inhibited by 1 mM furosemide or bumetanide. K influx in swollen hemoglobin CC cells was not diminished when Na in the incubation medium was replaced with choline, indicating Na independence of the swelling-induced flux. Identical experiments withmore » hemoglobin AA cells also demonstrated a swelling-induced increase in K flux, but the magnitude and duration of this increase were considerably less than that seen with hemoglobin CC cells. The increased K flux in hemoglobin AA cells was likewise sensitive to anion replacement and to loop diuretics and did not require the presence of Na. These data indicate that a volume-activated K pathway with similar transport characteristics exists in both hemoglobin CC and AA red cells.« less

REDUCTION IN INSPIRATORY FLOW ATTENUATES IL-8 RELEASE AND MAPK ACTIVATION OF LUNG OVERSTRETCH

EPA Science Inventory

Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation. Buffer-perfused rabbit lungs were ventilated for 2 h with ...

Hypothyroidism impairs somatovisceral reflexes involved in micturition of female rabbits.

PubMed

Sánchez-García, Octavio; López-Juárez, Rhode; Rodríguez-Castelán, Julia; Corona-Quintanilla, Dora L; Martínez-Gómez, Margarita; Cuevas-Romero, Estela; Castelán, Francisco

2018-04-17

To determine the impact of hypothyroidism on the bladder and urethral functions as well as in the activation of the pubococcygeous (Pcm) and bulbospongiosus (Bsm) during micturition. Age-matched control and methimazole-induced hypothyroid female rabbits were used to simultaneously record cystometrograms, urethral pressure, and the reflex activation of Pcm and Bsm during the induced micturition. Urodynamic and urethral variables were measured. Activation or no activation of the Pcm and Bsm during the storage and voiding phases of micturition were categorized as 1 or 0. Significant differences (P ≤ 0.05) between control and hypothyroid groups were determined with unpaired Student-t or Mann-Whitney tests. One-month induced hypothyroidism increased the residual volume and threshold pressure while the opposite was true for the voided volume, maximal pressure, and voiding efficiency. Urethral pressure was also affected as supported by a notorious augmentation of the urethral resistance, among other changes in the rest of measured variables. Hypothyroidism also affected the reflex activation of the Pcm in the voiding phase of micturition. Our findings demonstrate hypothyroidism impairs the bladder and, urethral functions, and reflex activation of Pcm and Bsm affecting the micturition in female rabbits. © 2018 Wiley Periodicals, Inc.

Implications of Starvation-Induced Change in Right Dorsal Anterior Cingulate Volume in Anorexia Nervosa

PubMed Central

McCormick, Laurie M.; Keel, Pamela K.; Brumm, Michael C.; Bowers, Wayne; Swayze, Victor; Andersen, Arnold; Andreasen, Nancy

2013-01-01

Objective Converging evidence suggests a role for the anterior cingulate cortex (ACC) in the pathophysiology of anorexia nervosa (AN). This study sought to determine whether ACC volume was affected by starvation in active AN and, if so, whether this had any clinical significance. Method Eighteen patients with active AN and age- and gender-matched normal controls underwent magnetic resonance imaging (MRI). Sixteen patients (89%) with AN had intelligence quotients (IQ) testing at intake, 14 (78%) had repeat MRIs after weight normalization, and 10 (56%) had outcome data at 1-year post-hospitalization. Results Right dorsal ACC volume was significantly reduced in active AN patients versus controls and was correlated with lower performance IQ. While ACC normalization occurred with weight restoration, smaller change in right dorsal ACC volume prospectively predicted relapse after treatment. Conclusion Reduced right dorsal ACC volume during active AN relates to deficits in perceptual organization and conceptual reasoning. The degree of right dorsal ACC normalization during treatment is related to outcome. PMID:18473337

Implications of starvation-induced change in right dorsal anterior cingulate volume in anorexia nervosa.

PubMed

McCormick, Laurie M; Keel, Pamela K; Brumm, Michael C; Bowers, Wayne; Swayze, Victor; Andersen, Arnold; Andreasen, Nancy

2008-11-01

Converging evidence suggests a role for the anterior cingulate cortex (ACC) in the pathophysiology of anorexia nervosa (AN). This study sought to determine whether ACC volume was affected by starvation in active AN and, if so, whether this had any clinical significance. Eighteen patients with active AN and age- and gender-matched normal controls underwent magnetic resonance imaging (MRI). Sixteen patients (89%) with AN had intelligence quotients (IQ) testing at intake, 14 (78%) had repeat MRIs after weight normalization, and 10 (56%) had outcome data at 1-year posthospitalization. Right dorsal ACC volume was significantly reduced in active AN patients versus controls and was correlated with lower performance IQ. While ACC normalization occurred with weight restoration, smaller change in right dorsal ACC volume prospectively predicted relapse after treatment. Reduced right dorsal ACC volume during active AN relates to deficits in perceptual organization and conceptual reasoning. The degree of right dorsal ACC normalization during treatment is related to outcome.

Blistering of Graphite/Polymer Composites Galvanically Coupled with Metals in Sea Water

DTIC Science & Technology

1993-01-01

pressure Vi = molar volume of species T Yi = activity coefficient for species T (p = electrical potential Using the flux definition, the conservation...at = aJi/ax ...(11) (b) determine the rate of volume increase of water Vw’ cm3 1s in the blister cavity by the following expression: Vw’ = iVw/at = 1a...induced in the polymer and the fiber/matrix interface region due to the above volume change: The volume increase of the fluid in blister given by

Automation system for measurement of gamma-ray spectra of induced activity for multi-element high volume neutron activation analysis at the reactor IBR-2 of Frank Laboratory of Neutron Physics at the joint institute for nuclear research

NASA Astrophysics Data System (ADS)

Pavlov, S. S.; Dmitriev, A. Yu.; Chepurchenko, I. A.; Frontasyeva, M. V.

2014-11-01

The automation system for measurement of induced activity of gamma-ray spectra for multi-element high volume neutron activation analysis (NAA) was designed, developed and implemented at the reactor IBR-2 at the Frank Laboratory of Neutron Physics. The system consists of three devices of automatic sample changers for three Canberra HPGe detector-based gamma spectrometry systems. Each sample changer consists of two-axis of linear positioning module M202A by DriveSet company and disk with 45 slots for containers with samples. Control of automatic sample changer is performed by the Xemo S360U controller by Systec company. Positioning accuracy can reach 0.1 mm. Special software performs automatic changing of samples and measurement of gamma spectra at constant interaction with the NAA database.

Discrimination and Assessment of Induced Seismicity in Active Tectonic Zones: A Case Study from Southern California

NASA Astrophysics Data System (ADS)

Bachmann, C. E.; Lindsey, N.; Foxall, W.; Robertson, M.

2014-12-01

Earthquakes induced by human activity have become a matter of heightened public concern during recent years. Of particular concern is seismicity associated with wastewater injection, which has included events having magnitudes greater than 5. The causes of the induced events are primarily changes in pore-pressure, fluid volume and perhaps temperature due to injection. Recent research in the US has focused on mid-continental regions having low rates of naturally-occurring seismicity, where induced events can be identified by relatively straightforward spatial and temporal correlation of seismicity with high-volume injection activities. Recent examples include events correlated with injection of wastewater in Oklahoma, Arkansas, Texas and Ohio, and long-term brine injection in the Paradox Valley in Colorado. Even in some of the cases where there appears at first sight to be a clear spatial correlation between seismicity and injection, it has been difficult to establish causality definitively. Here, we discuss methods to identify induced seismicity in active tectonic regions. We concentrate our study on Southern California, where large numbers of wastewater injection wells are located in oil-producing basins that experience moderate to high rates of naturally-occurring seismicity. Using the catalog of high-precision CISN relocations produced by Hauksson et al. (BSSA, 2012), we aim to discriminate induced from natural events based on spatio-temporal patterns of seismicity occurrence characteristics and their relationships to injection activities, known active faults and other faults favorably oriented for slip under the tectonic stress field. Since the vast majority of induced earthquakes are very small, it is crucial to include all events above the detection threshold of the CISN in each area studied. In addition to exploring the correlation of seismicity to injection activities in time and space, we analyze variations in frequency-magnitude distributions, which can be related to differences between the physical conditions at the sources of fluid-induced and natural earthquakes. While induced seismicity often does not show different mechanisms than tectonic earthquakes, an abundance of induced microseismicity causes the slope of the frequency-magnitude distribution to increase locally.

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model.

PubMed

Liu, Feng-Di; Zhao, Rong; Feng, Xiao-Yan; Shi, Yan-Hui; Wu, Yi-Lan; Shen, Xiao-Lei; Li, Ge-Fei; Liu, Yi-Sheng; Zhao, Ying; He, Xin-Wei; Yin, Jia-Wen; Zhuang, Mei-Ting; Zhao, Bing-Qiao; Liu, Jian-Ren

2018-05-09

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.

Evaluation of Caesalpinia bonducella flower extract for anti-inflammatory action in rats and its high performance thin layer chromatography chemical fingerprinting.

PubMed

Arunadevi, Rathinam; Murugammal, Shanmugam; Kumar, Dinesh; Tandan, Surendra Kumar

2015-01-01

The study is aimed to evaluate anti-inflammatory activity of Caesalpinia bonducella Fleming (Caesalpiniaceae) flower extract (CBFE) and to study its effect on radiographic outcome in adjuvant induced arthritis and authentication by high performance thin layer chromatography (HPTLC) chemical fingerprinting. CBFE was administered orally (30, 100, and 300 mg/kg b.wt.) and tested for its anti-inflammatory activity in carrageenan-induced inflammation, cotton pellet induced chronic granulomatous inflammation and autacoids-induced inflammation. Effect on radiographic outcome was tested in adjuvant-induced arthritis. CBFE was HPTLC fingerprinted in suitable solvent system. In carrageenan-induced inflammation, CBFE produced significant inhibition in edema volume at all the doses (30, 100 and 300 mg/kg b.wt.) and percentage of inhibition was 28.68, 31.00, and 22.48, respectively as compared to control at 5 h of its administration. In cotton pellet granuloma assay, CBFE significantly decreased the granuloma weight at 300 mg/kg dose level by 22.53%. CBFE (300 mg/kg) caused significant inhibition by 37.5, 44.44, and 35.29% edema volume, at ½, 1 and 3 h after 5-hydroxytryptamine injection, respectively. Radiographic score of animals treated with 300 mg/kg CBFE was significantly decreased when compared to arthritic control animals. The extract was found to possess significant anti-inflammatory activity. CBFE treatment improved the bony architecture in adjuvant-induced arthritis in rats. The developed HPTLC fingerprint would be helpful in the authentication of C. bonducella flower extract.

Analysis of the pressure-induced potential arising through composite membranes with selective surface layers.

PubMed

Szymczyk, Anthony; Sbaï, Mohammed; Fievet, Patrick

2005-03-01

When a pressure gradient is applied through a charged selective membrane, the transmembrane electrical potential difference, called the filtration potential, results from both the applied pressure and induced concentration difference across the membrane. In this work we investigate the electrokinetic properties relative to both active and support layers of a composite ceramic membrane close to the nanofiltration range. First, the volume charge density of the active layer is obtained by fitting a transport model to experimental rejection rates (which are controlled by the active layer only). Next, the value of the volume charge density is used to compute the theoretical filtration potential through the active layer. For sufficiently high permeate volume fluxes, the concentration difference across the active layer becomes constant, which allows assessing the membrane potential of the active layer. Experimental measurements of the overall filtration potential arising through the whole membrane are performed. The contribution of the support layer to this overall filtration potential is put in evidence. That implies that the membrane potential of the active layer cannot be deduced directly from the overall filtration potential measurements. Finally, the contribution of the support layer is singled out by subtracting the theoretical filtration potential of the active layer from the experimental filtration potential measured across the whole membrane (i.e., support + active layers). The amphoteric behavior of both layers is put in evidence, which is confirmed by electrophoretic measurements carried out with the powdered support layer and by recently reported tangential streaming potential measurements.

Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

PubMed Central

Zhang, Yang; Liu, Gongjian; Dull, Randal O.; Schwartz, David E.

2014-01-01

The inflammatory response is a primary mechanism in the pathogenesis of ventilator-induced lung injury. Autophagy is an essential, homeostatic process by which cells break down their own components. We explored the role of autophagy in the mechanisms of mechanical ventilation-induced lung inflammatory injury. Mice were subjected to low (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for 2 h. Bone marrow-derived macrophages transfected with a scrambled or autophagy-related protein 5 small interfering RNA were administered to alveolar macrophage-depleted mice via a jugular venous cannula 30 min before the start of the ventilation protocol. In some experiments, mice were ventilated in the absence and presence of autophagy inhibitors 3-methyladenine (15 mg/kg ip) or trichostatin A (1 mg/kg ip). Mechanical ventilation with a high tidal volume caused rapid (within minutes) activation of autophagy in the lung. Conventional transmission electron microscopic examination of lung sections showed that mechanical ventilation-induced autophagy activation mainly occurred in lung macrophages. Autophagy activation in the lungs during mechanical ventilation was dramatically attenuated in alveolar macrophage-depleted mice. Selective silencing of autophagy-related protein 5 in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury. Pharmacological inhibition of autophagy also significantly attenuated the inflammatory responses caused by lung hyperinflation. The activation of autophagy in macrophages mediates early lung inflammation during mechanical ventilation via NLRP3 inflammasome signaling. Inhibition of autophagy activation in lung macrophages may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury. PMID:24838752

Stress-induced brain activity, brain atrophy, and clinical disability in multiple sclerosis

PubMed Central

Weygandt, Martin; Meyer-Arndt, Lil; Behrens, Janina Ruth; Wakonig, Katharina; Bellmann-Strobl, Judith; Ritter, Kerstin; Scheel, Michael; Brandt, Alexander U.; Labadie, Christian; Hetzer, Stefan; Gold, Stefan M.; Paul, Friedemann; Haynes, John-Dylan

2016-01-01

Prospective clinical studies support a link between psychological stress and multiple sclerosis (MS) disease severity, and peripheral stress systems are frequently dysregulated in MS patients. However, the exact link between neurobiological stress systems and MS symptoms is unknown. To evaluate the link between neural stress responses and disease parameters, we used an arterial-spin–labeling functional MRI stress paradigm in 36 MS patients and 21 healthy controls. Specifically, we measured brain activity during a mental arithmetic paradigm with performance-adaptive task frequency and performance feedback and related this activity to disease parameters. Across all participants, stress increased heart rate, perceived stress, and neural activity in the visual, cerebellar and insular cortex areas compared with a resting condition. None of these responses was related to cognitive load (task frequency). Consistently, although performance and cognitive load were lower in patients than in controls, stress responses did not differ between groups. Insula activity elevated during stress compared with rest was negatively linked to impairment of pyramidal and cerebral functions in patients. Cerebellar activation was related negatively to gray matter (GM) atrophy (i.e., positively to GM volume) in patients. Interestingly, this link was also observed in overlapping areas in controls. Cognitive load did not contribute to these associations. The results show that our task induced psychological stress independent of cognitive load. Moreover, stress-induced brain activity reflects clinical disability in MS. Finally, the link between stress-induced activity and GM volume in patients and controls in overlapping areas suggests that this link cannot be caused by the disease alone. PMID:27821732

Testosterone and estradiol treatments differently affect pituitary-thyroid axis and liver deiodinase 1 activity in orchidectomized middle-aged rats.

PubMed

Šošić-Jurjević, B; Filipović, B; Renko, K; Miler, M; Trifunović, S; Ajdžanovič, V; Kӧhrle, J; Milošević, V

2015-12-01

We previously reported that orchidectomy (Orx) of middle-aged rats (15-16-month-old; MA) slightly affected pituitary-thyroid axis, but decreased liver deiodinase (Dio) type 1 and pituitary Dio2 enzyme activities. At present, we examined the effects of subsequent testosterone-propionate treatment (5mg/kg; Orx+T), and compared the effects of testosterone with the effects of estradiol-dipropionate (0.06mg/kg; Orx+E) treatment. Hormones were subcutaneously administered, daily, for three weeks, while Orx and sham-operated (SO) controls received only the vehicle. The applied dose of T did not alter serum TSH, T4 and T3 concentrations in Orx- MA, though it increased TSH when administrated to Orx young adults (2.5-month-old; Orx-YA). However, pituitaries of Orx-MA+T rats had higher relative intensity of immunofluorescence (RIF) for TSHβ; in their thyroids we found increased volume and height of follicular epithelium, decreased volume of the colloid and higher RIF for T4-bound to thyroglobulin (Tg-T4). Liver Dio1 activity was increased. E-treatment did not affect serum hormone levels, pituitary RIF for TSHβ, or liver Dio1 activity in Orx-MA rats. Thyroids had decreased relative volume and height of follicular epithelium, increased relative volume of the colloid, decreased volume of sodium-iodide symporter-immunopositive epithelium and lower RIF for Tg-T4. Detected changes were statistically significant. In conclusion, androgenization enhanced pituitary TSHβ RIF, thyroid activation and liver Dio1 enzyme activity in Orx-MA, without elevating serum TSH as in Orx-YA rats. Estrogenization induced pituitary enlargement with no effect on pituitary TSHβ RIF, serum TSH or liver Dio1 activity. E also induced alterations in thyroid histology that indicate mild suppression of its functioning, and contributed to thyroid blood vessel enlargement in Orx-MA rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Oxidation-induced calcium-dependent dehydration of normal human red blood cells.

PubMed

Shcherbachenko, Irina M; Lisovskaya, Irina L; Tikhonov, Vladimir P

2007-05-01

Phenazine-methosulphate (PMS) is a strong oxidant that induces reactive oxygen species (ROS) formation in cells. Though it has been shown that PMS increases the red blood cell (RBC) membrane permeability to K(+), the hypotheses on the mechanism of PMS-induced effects are contradictory and there are no data on volume changes induced by this oxidant. Therefore, the influence of the PMS + ascorbate oxidative system on the volume of normal human RBCs was studied. In a Ca(2 + )-containing medium, PMS + ascorbate caused dehydration (shrinking) of RBCs judged by: (1) changes in the density and osmotic resistance distributions of RBCs, and (2) a decrease in their low-angle scattering assessed by FACS analysis. The dehydration resulted from activation of the Gardos channels, was PMS and ascorbate concentration-dependent, was associated with broadening of the density and osmotic resistance distributions of the RBCs, and decreased in the presence of the taxifolin and rutin antioxidants. These findings contribute to a better understanding of the physiology and pathology of oxidatively-modified RBCs and may be of practical significance in estimating the antioxidant activity of various substances.

Emodin from Polygonum multiflorum ameliorates oxidative toxicity in HT22 cells and deficits in photothrombotic ischemia.

PubMed

Ahn, Sung Min; Kim, Ha Neui; Kim, Yu Ri; Choi, Young Whan; Kim, Cheol Min; Shin, Hwa Kyoung; Choi, Byung Tae

2016-07-21

Polygonum multiflorum Thunb. has been used widely in East Asia in treatment of diseases associated with aging. Emodin, an active component from Polygonum multiflorum Thunb., provides benefits for brain disturbances induced by severe cerebral injury. We investigated the neuroprotective effect of emodin from Polygonum multiflorum Thunb. against glutamate-induced oxidative toxicity and cerebral ischemia. For examination of neuroprotective effects of emodin, cell viability, cytotoxicity, flow cytometry, and Western blot were performed in HT22 cells and infarct volume, behavioral tests and Western blot in a mouse model of photothrombotic ischemic stroke. Pretreatment with emodin resulted in significantly reduced glutamate-induced apoptotic cell death in HT22 cells. However, blocking of phosphatidylinositol-3 kinase (PI3K) activity with LY294002 resulted in significantly inhibited cell survival by emodin. Exposure of glutamate-treated cells to emodin induced an increase in the level of Bcl-2 expression, whereas the expression of Bax and active caspase-3 proteins was significantly reduced. In addition, treatment with emodin resulted in increased phosphorylation of Akt and cAMP response element binding protein (CREB), and expression of mature brain-derived neurotrophic factor (BDNF). This expression by emodin was also significantly inhibited by blocking of PI3K activity. In a photothrombotic ischemic stroke model, treatment with emodin resulted in significantly reduced infarct volume and improved motor function. We confirmed the critical role of the expression levels of Bcl-2/Bax, active caspase-3, phosphorylated (p)Akt, p-CREB, and mature BDNF for potent neuroprotective effects of emodin in cerebral ischemia. These results suggest that emodin may afford a significant neuroprotective effect against glutamate-induced apoptosis through activation of the PI3K/Akt signaling pathway, and subsequently enhance behavioral function in cerebral ischemia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Computational analysis of blood clot dissolution using a vibrating catheter tip.

PubMed

Lee, Jeong Hyun; Oh, Jin Sun; Yoon, Bye Ri; Choi, Seung Hong; Rhee, Kyehan; Jho, Jae Young; Han, Moon Hee

2012-04-01

We developed a novel concept of endovascular thrombolysis that employs a vibrating electroactive polymer actuator. In order to predict the efficacy of thrombolysis using the developed vibrating actuator, enzyme (plasminogen activator) perfusion into a clot was analyzed by solving flow fields and species transport equations considering the fluid structure interaction. In vitro thrombolysis experiments were also performed. Computational results showed that plasminogen activator perfusion into a clot was enhanced by actuator vibration at frequencies of 1 and 5 Hz. Plasminogen activator perfusion was affected by the actuator oscillation frequencies and amplitudes that were determined by electromechanical characteristics of a polymer actuator. Computed plasminogen activator perfused volumes were compared with experimentally measured dissolved clot volumes. The computed plasminogen activator perfusion volumes with threshold concentrations of 16% of the initial plasminogen activator concentration agreed well with the in vitro experimental data. This study showed the effectiveness of actuator oscillation on thrombolysis and the validity of the computational plasminogen activator perfusion model for predicting thrombolysis in complex flow fields induced by an oscillating actuator.

Nrf2 activator ameliorates hemorrhagic transformation in focal cerebral ischemia under warfarin anticoagulation.

PubMed

Imai, Takahiko; Takagi, Toshinori; Kitashoji, Akira; Yamauchi, Keita; Shimazawa, Masamitsu; Hara, Hideaki

2016-05-01

Oxidative stress has been reported to be a main cause of neuronal cell death in ischemia reperfusion injury (IRI). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important factor involved in anti-oxidative responses. We previously reported that bardoxolone methyl (BARD), an Nrf2 activator, prevented damage induced by IRI. In this study, we investigated the effect of BARD on hemorrhagic transformation in the context of blood brain barrier (BBB) protection. Mice received pre-treatment with warfarin (4.0 mg/kg, p.o.). IRI was subsequently induced 18 h after the warfarin administration by transient middle cerebral artery occlusion (MCAO) for 6 h. BARD (0.06, 0.2, 0.6 or 2.0 mg/kg) or saline was injected intravenously immediately after reperfusion. The infarct volume, neurological score, intracranial hemorrhage volume, and BBB permeability were evaluated 24 h after MCAO. The survival rate and behavioral functional recovery were evaluated for 7 days following IRI. Furthermore, the effects of BARD on BBB components were investigated by western blotting and immunostaining analysis. BARD suppressed warfarin-mediated increases in the intracranial hemorrhage volume without affecting the infarct volume. BBB permeability was also suppressed by administration of BARD. Western blotting showed that BARD increased expression of BBB components such as endothelial cells, pericytes, and tight junction proteins. Furthermore, immunostaining showed that BARD induced localization of Nrf2 to endothelial cells and pericytes. BARD suppressed the exacerbation hemorrhage caused by warfarin pretreatment and ameliorated BBB disruption by protecting endothelial cells, pericytes, and tight junction protein expressions. These results indicate that Nrf2 activators may be an effective therapy against hemorrhagic transformation caused by anticoagulant drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-inflammatory effect of selenium nanoparticles on the inflammation induced in irradiated rats.

PubMed

El-Ghazaly, M A; Fadel, N; Rashed, E; El-Batal, A; Kenawy, S A

2017-02-01

Selenium (Se) has been reported to possess anti-inflammatory properties, but its bioavailability and toxicity are considerable limiting factors. The present study aimed to investigate the possible anti-inflammatory and analgesic effects of selenium nanoparticles (Nano-Se) on inflammation induced in irradiated rats. Paw volume and nociceptive threshold were measured in carrageenan-induced paw edema and hyperalgesia model. Leukocytic count, tumor necrosis factor-α (TNF-α), prostaglandin E 2 (PGE 2 ), thiobarbituric acid reactive substances (TBAR), and total nitrate/nitrite (NOx) were estimated in the exudate collected from 6 day old air pouch model. Irradiated rats were exposed to 6 Gy gamma (γ)-irradiation. Nano-Se were administered orally in a dose of 2.55 mg/kg once before carrageenan injection in the first model and twice in the second model. The paw volume but not the nociceptive response produced by carrageenan in irradiated rats was higher than that induced in non-irradiated rats. Nano-Se were effective in reducing the paw volume in non-irradiated and irradiated rats but it did not alter the nociceptive threshold. The inflammation induced in irradiated rats increased all the estimated parameters in the exudate whereas; Nano-Se decreased their elevation in non-irradiated and irradiated rats. Nano-Se possess a potential anti-inflammatory activity on inflammation induced in irradiated rats.

Anatomic and functional properties of bulboglandularis striated muscle support its contribution as sphincter in female rabbit micturition.

PubMed

Corona-Quintanilla, Dora Luz; López-Juárez, Rhode; Zempoalteca, René; Cuevas, Estela; Castelán, Francisco; Martínez-Gómez, Margarita

2016-08-01

To determine anatomic and functional properties of the bulboglandularis muscle (Bgm) for clarifying its role in micturition in female rabbits. Virgin female rabbits were used to describe the gross anatomy and innervation of the Bgm, to determine the effect of the Bgm contraction on urethral pressure, and to evaluate the Bgm activity during the induced-micturition. Both electromyogram and cystometrogram activity were simultaneously recorded in urethane-anesthetized rabbits. Bladder function was assessed measuring standard urodynamic variables before and after blocking the Bgm activity for approaching its contribution to micturition. The relevance of the Bgm activation for micturition was approached applying lidocaine injections. The Bgm was composed of circularly oriented striated fibers enveloping distal urethra and pelvic vagina. Both the venous plexus and urethra were comprised by the Bgm contraction induced by electrical stimulation. The Bgm showed bursts of tonic activity at the storage phase of micturition that gradually decreased until turning off as the onset of the voiding phase. The voided volume, the voiding efficiency, the threshold pressure, and the maximal pressure were decreased after lidocaine injection. Contrastingly, the threshold volume, the residual volume, the voiding duration, and the urethral resistance at voiding were increased. Present anatomical and physiological findings support that the Bgm acts as a sphincter during micturition of female rabbits. Neurourol. Urodynam. 35:689-695, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

The Volumetric Diversity of Misfolded Prion Protein Oligomers Revealed by Pressure Dissociation*

PubMed Central

Torrent, Joan; Lange, Reinhard; Rezaei, Human

2015-01-01

Protein oligomerization has been associated with a wide range of diseases. High pressure approaches offer a powerful tool for deciphering the underlying molecular mechanisms by revealing volume changes associated with the misfolding and assembly reactions. We applied high pressure to induce conformational changes in three distinct β-sheet-rich oligomers of the prion protein PrP, a protein characterized by a variety of infectious quaternary structures that can propagate stably and faithfully and cause diseases with specific phenotypic traits. We show that pressure induces dissociation of the oligomers and leads to a lower volume monomeric PrP state that refolds into the native conformation after pressure release. By measuring the different pressure and temperature sensitivity of the tested PrP oligomers, we demonstrate significantly different void volumes in their quaternary structure. In addition, by focusing on the kinetic and energetic behavior of the pressure-induced dissociation of one specific PrP oligomer, we reveal a large negative activation volume and an increase in both apparent activation enthalpy and entropy. This suggests a transition state ensemble that is less structured and significantly more hydrated than the oligomeric state. Finally, we found that site-specific fluorescent labeling allows monitoring of the transient population of a kinetic intermediate in the dissociation reaction. Our results indicate that defects in atomic packing may deserve consideration as a new factor that influences differences between PrP assemblies and that could be relevant also for explaining the origin of prion strains. PMID:26126829

Gastroprotective activity of polysaccharide from Hericium erinaceus against ethanol-induced gastric mucosal lesion and pylorus ligation-induced gastric ulcer, and its antioxidant activities.

PubMed

Wang, Xiao-Yin; Yin, Jun-Yi; Zhao, Ming-Ming; Liu, Shi-Yu; Nie, Shao-Ping; Xie, Ming-Yong

2018-04-15

The gastroprotective activity of Hericium erinaceus polysaccharide was investigated in rats. The antioxidant activities were also evaluated. Pre-treatment of polysaccharide could reduce ethanol-induced gastric mucosal lesion and pylorus ligation-induced gastric ulcer. The polysaccharide exhibited scavenging activities of 1, 1-diphenyl-2-picryl-hydrozyl and hydroxyl radicals, and ferrous ion-chelating ability. In the pylorus ligation-induced model, gastric secretions (volume of gastric juice, gastric acid, pepsin and mucus) of ulcer rats administrated with polysaccharide were regulated. Levels of tumor necrosis factor-α and interleukins-1β in serum, and myeloperoxidase activity of gastric tissue were reduced, while antioxidant status of gastric tissue was improved. Defensive factors (nitric oxide, prostaglandin E2, epidermal growth factor) in gastric tissue were increased. These results indicate that Hericium erinaceus polysaccharide possess gastroprotective activity, and the possible mechanisms are related to its regulations of gastric secretions, improvements of anti-inflammatory and antioxidant status, as well as increments of defensive factors releases. Copyright © 2018 Elsevier Ltd. All rights reserved.

Evaluation of Caesalpinia bonducella flower extract for anti-inflammatory action in rats and its high performance thin layer chromatography chemical fingerprinting

PubMed Central

Arunadevi, Rathinam; Murugammal, Shanmugam; Kumar, Dinesh; Tandan, Surendra Kumar

2015-01-01

Objective: The study is aimed to evaluate anti-inflammatory activity of Caesalpinia bonducella Fleming (Caesalpiniaceae) flower extract (CBFE) and to study its effect on radiographic outcome in adjuvant induced arthritis and authentication by high performance thin layer chromatography (HPTLC) chemical fingerprinting. Materials and Methods: CBFE was administered orally (30, 100, and 300 mg/kg b.wt.) and tested for its anti-inflammatory activity in carrageenan-induced inflammation, cotton pellet induced chronic granulomatous inflammation and autacoids-induced inflammation. Effect on radiographic outcome was tested in adjuvant-induced arthritis. CBFE was HPTLC fingerprinted in suitable solvent system. Result: In carrageenan-induced inflammation, CBFE produced significant inhibition in edema volume at all the doses (30, 100 and 300 mg/kg b.wt.) and percentage of inhibition was 28.68, 31.00, and 22.48, respectively as compared to control at 5 h of its administration. In cotton pellet granuloma assay, CBFE significantly decreased the granuloma weight at 300 mg/kg dose level by 22.53%. CBFE (300 mg/kg) caused significant inhibition by 37.5, 44.44, and 35.29% edema volume, at ½, 1 and 3 h after 5-hydroxytryptamine injection, respectively. Radiographic score of animals treated with 300 mg/kg CBFE was significantly decreased when compared to arthritic control animals. Conclusion: The extract was found to possess significant anti-inflammatory activity. CBFE treatment improved the bony architecture in adjuvant-induced arthritis in rats. The developed HPTLC fingerprint would be helpful in the authentication of C. bonducella flower extract. PMID:26729956

Ecological risk study on subacute toxicology experiment of streptomycin wastewater for Zebrafish

NASA Astrophysics Data System (ADS)

Shi, Qing; Shen, Hongyan

2017-08-01

An exposure experiment was conducted to study the effect of different volume fraction of effluent streptomycin wastewater on the activity of the peroxidase (POD) activity and the malondialdehyde (MDA) content in muscles of Zebrafish for 20 days. The results show that POD activity is significantly induced on the eighth day. POD activities in the muscles of Zebrafish exposed to the streptomycin wastewater of 20% exposure group were significantly different (0.01

Functional and molecular characterization of multiple K-Cl cotransporter isoforms in corneal epithelial cells

PubMed Central

Capó-Aponte, José E.; Wang, Zheng; Bildin, Victor N.; Iserovich, Pavel; Pan, Zan; Zhang, Fan; Pokorny, Kathryn S.; Reinach, Peter S.

2009-01-01

The dependence of regulatory volume decrease (RVD) activity on potassium–chloride cotransporter (KCC) isoform expression was characterized in corneal epithelial cells (CEC). During exposure to a 50% hypotonic challenge, the RVD response was larger in SV40-immortalized human CEC (HCEC) than in SV40-immortalized rabbit CEC (RCEC). A KCC inhibitor—[(dihydroindenyl)oxy] alkanoic acid (DIOA)—blocked RVD more in HCEC than RCEC. Under isotonic conditions, N-ethylmaleimide (NEM) produced KCC activation and transient cell shrinkage. Both of these changes were greater in HCEC than in RCEC. Immunoblot analysis of HCEC, RCEC, primary human CEC (pHCEC), and primary bovine CEC (BCEC) plasma membrane enriched fractions revealed KCC1, KCC3, and KCC4 isoform expression, whereas KCC2 was undetectable. During a hypotonic challenge, KCC1 membrane content increased more rapidly in HCEC than in RCEC. Such a challenge induced a larger increase and more transient p44/42MAPK activation in HCEC than RCEC. On the other hand, HCEC and RCEC p38MAPK phosphorylation reached peak activations at 2.5 and 15 min, respectively. Only in HCEC, pharmacological manipulation of KCC activity modified the hypotonicity-induced activation of p44/42MAPK, whereas p38MAPK phosphorylation was insensitive to such procedures in both cell lines. Larger increases in HCEC KCC1 membrane protein content correlate with their ability to undergo faster and more complete RVD. Furthermore, pharmacological activation of KCC increased p44/42MAPK phosphorylation in HCEC but not in RCEC, presumably a reflection of low KCC membrane expression in RCEC. These findings suggest that KCC1 plays a role in (i) maintaining isotonic steady-state cell volume homeostasis, (ii) recovery of isotonic cell volume after a hypotonic challenge through RVD, and (iii) regulating hypotonicity-induced activation of the p44/42MAPK signaling pathway required for cell proliferation. PMID:17418819

Sex differences in neural activation following different routes of oxytocin administration in awake adult rats.

PubMed

Dumais, Kelly M; Kulkarni, Praveen P; Ferris, Craig F; Veenema, Alexa H

2017-07-01

The neuropeptide oxytocin (OT) regulates social behavior in sex-specific ways across species. OT has promising effects on alleviating social deficits in sex-biased neuropsychiatric disorders. However little is known about potential sexually dimorphic effects of OT on brain function. Using the rat as a model organism, we determined whether OT administered centrally or peripherally induces sex differences in brain activation. Functional magnetic resonance imaging was used to examine blood oxygen level-dependent (BOLD) signal intensity changes in the brains of awake rats during the 20min following intracerebroventricular (ICV; 1μg/5μl) or intraperitoneal (IP; 0.1mg/kg) OT administration as compared to baseline. ICV OT induced sex differences in BOLD activation in 26 out of 172 brain regions analyzed, with 20 regions showing a greater volume of activation in males (most notably the nucleus accumbens and insular cortex), and 6 regions showing a greater volume of activation in females (including the lateral and central amygdala). IP OT also elicited sex differences in BOLD activation with a greater volume of activation in males, but this activation was found in different and fewer (10) brain regions compared to ICV OT. In conclusion, exogenous OT modulates neural activation differently in male versus female rats with the pattern and magnitude, but not the direction, of sex differences depending on the route of administration. These findings highlight the need to include both sexes in basic and clinical studies to fully understand the role of OT on brain function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Jobelyn® exhibited anti-inflammatory, antioxidant, and membrane-stabilizing activities in experimental models.

PubMed

Umukoro, Solomon; Oluwole, Oluwafemi Gabriel; Eduviere, Anthony T; Adrian, Omogbiya Itievere; Ajayi, Abayomi M

2015-09-01

Jobelyn® (JB) is an African sorghum-based food supplement claimed to be efficacious for the treatment of rheumatoid arthritis (RA). Although in vitro studies confirmed its anti-inflammatory property, no study had shown the effect of JB using in vivo animal models of inflammation. Thus, its effects on acute and chronic inflammation in rats were evaluated in this study. Its effect on rat red blood cell (RBC) lysis was also assessed. Acute inflammation was induced with intraplanter injection of carrageenan and increase in rat paw volume was measured using plethysmometer. The volume of fluid exudates, number of leukocytes, concentrations of malondialdehyde (MDA), and glutathione (GSH) in the fluid were measured on day 5 after induction of chronic inflammation with carrageenan in the granuloma air pouch model. RBC lysis induced by hypotonic medium as determined by release of hemoglobin was measured spectrophotometerically. JB (50-200 mg/kg) given orally produced a significant inhibition of acute inflammation induced by carrageenan in rats. It reduced the volume and number of leukocytes in inflammatory fluid in the granuloma air pouch model of chronic inflammation. It further decreased the levels of MDA in the fluid suggesting antioxidant property. JB elevated the concentrations of GSH in inflammatory exudates indicating free radical scavenging activity. It also significantly inhibited RBC lysis caused by hypotonic medium, suggesting membrane-stabilizing property. JB has in vivo anti-inflammatory activity, which may be related to its antioxidant and membrane-stabilizing properties, supporting its use for the treatment of arthritic disorder.

Supraclavicular skin temperature as a measure of 18F-FDG uptake by BAT in human subjects.

PubMed

Boon, Mariëtte R; Bakker, Leontine E H; van der Linden, Rianne A D; Pereira Arias-Bouda, Lenka; Smit, Frits; Verberne, Hein J; van Marken Lichtenbelt, Wouter D; Jazet, Ingrid M; Rensen, Patrick C N

2014-01-01

Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current 'gold standard' for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans. BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations. Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not. Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects. NTR 2473.

Nicotinamide Adenine Dinucleotide (NAD+) and Nicotinamide: Sex Differences in Cerebral Ischemia

PubMed Central

Siegel, Chad S.; McCullough, Louise D.

2013-01-01

Background Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes. While caspase-dependent mechanisms predominate in the female brain, caspase-independent cell death induced by activation of Poly (ADP-ribose) polymerase (PARP) predominates in the male brain. PARP-1 gene deletion decreases infarction volume in the male brain, but paradoxically increases damage in PARP-1 knockout females. Purpose This study examined stroke induced changes in NAD+, a key energy molecule involved in PARP-1 activation in both sexes. Methods Mice were subjected to Middle Cerebral Artery Occlusion and NAD+ levels were assessed. Caspase-3 activity and nuclear translocation was assessed 6 hours after ischemia. In additional cohorts, Nicotinamide (500mg/kg i.p.) a precursor of NAD+ or vehicle was administered and infarction volume was measured 24 hours after ischemia. Results Males have higher baseline NAD+ levels than females. Significant stroke-induced NAD+ depletion occurred in males and ovariectomized females but not in intact females. PARP-1 deletion prevented the stroke induced loss in NAD+ in males, but worsened NAD+ loss in PARP-1 deficient females. Preventing NAD+ loss with nicotinamide reduced infarct in wild-type males and PARP-1 knockout mice of both sexes, with no effect in WT females. Caspase-3 activity was significantly increased in PARP-1 knockout females compared to males and wild-type females, this was reversed with nicotinamide. Conclusions Sex differences exist in baseline and stroke-induced NAD+ levels. Nicotinamide protected males and PARP knockout mice, but had minimal effects in the wild-type female brain. This may be secondary to differences in energy metabolism between the sexes. PMID:23403179

Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230.

PubMed

Egger, Christine; Gérard, Christelle; Vidotto, Nella; Accart, Nathalie; Cannet, Catherine; Dunbar, Andrew; Tigani, Bruno; Piaia, Alessandro; Jarai, Gabor; Jarman, Elizabeth; Schmid, Herbert A; Beckmann, Nicolau

2014-06-15

Idiopathic pulmonary fibrosis is a progressive and lethal disease, characterized by loss of lung elasticity and alveolar surface area, secondary to alveolar epithelial cell injury, reactive inflammation, proliferation of fibroblasts, and deposition of extracellular matrix. The effects of oropharyngeal aspiration of bleomycin in Sprague-Dawley rats and C57BL/6 mice, as well as of intratracheal administration of ovalbumin to actively sensitized Brown Norway rats on total lung volume as assessed noninvasively by magnetic resonance imaging (MRI) were investigated here. Lung injury and volume were quantified by using nongated or respiratory-gated MRI acquisitions [ultrashort echo time (UTE) or gradient-echo techniques]. Lung function of bleomycin-challenged rats was examined additionally using a flexiVent system. Postmortem analyses included histology of collagen and hydroxyproline assays. Bleomycin induced an increase of MRI-assessed total lung volume, lung dry and wet weights, and hydroxyproline content as well as collagen amount. In bleomycin-treated rats, gated MRI showed an increased volume of the lung in the inspiratory and expiratory phases of the respiratory cycle and a temporary decrease of tidal volume. Decreased dynamic lung compliance was found in bleomycin-challenged rats. Bleomycin-induced increase of MRI-detected lung volume was consistent with tissue deposition during fibrotic processes resulting in decreased lung elasticity, whereas influences by edema or emphysema could be excluded. In ovalbumin-challenged rats, total lung volume quantified by MRI remained unchanged. The somatostatin analog, SOM230, was shown to have therapeutic effects on established bleomycin-induced fibrosis in rats. This work suggests MRI-detected total lung volume as readout for tissue-deposition in small rodent bleomycin models of pulmonary fibrosis. Copyright © 2014 the American Physiological Society.

Maximum magnitude earthquakes induced by fluid injection

USGS Publications Warehouse

McGarr, Arthur F.

2014-01-01

Analysis of numerous case histories of earthquake sequences induced by fluid injection at depth reveals that the maximum magnitude appears to be limited according to the total volume of fluid injected. Similarly, the maximum seismic moment seems to have an upper bound proportional to the total volume of injected fluid. Activities involving fluid injection include (1) hydraulic fracturing of shale formations or coal seams to extract gas and oil, (2) disposal of wastewater from these gas and oil activities by injection into deep aquifers, and (3) the development of enhanced geothermal systems by injecting water into hot, low-permeability rock. Of these three operations, wastewater disposal is observed to be associated with the largest earthquakes, with maximum magnitudes sometimes exceeding 5. To estimate the maximum earthquake that could be induced by a given fluid injection project, the rock mass is assumed to be fully saturated, brittle, to respond to injection with a sequence of earthquakes localized to the region weakened by the pore pressure increase of the injection operation and to have a Gutenberg-Richter magnitude distribution with a b value of 1. If these assumptions correctly describe the circumstances of the largest earthquake, then the maximum seismic moment is limited to the volume of injected liquid times the modulus of rigidity. Observations from the available case histories of earthquakes induced by fluid injection are consistent with this bound on seismic moment. In view of the uncertainties in this analysis, however, this should not be regarded as an absolute physical limit.

Effect of oxotremorine on resting membrane potential and cell volume in skeletal muscle fibers in rats after in vivo blockade of NO-synthase.

PubMed

Khairova, R A; Malomuzh, A I; Naumenko, N V; Urazaev, A Kh

2003-02-01

Denervation of rat phrenic muscle or block of NO-synthase in vivo increased the cross-section area of muscle fibers and decreased membrane resting potential. Oxotremorine prevented the development of denervation-induced or denervation-like (i.e. induced by NO-synthase blockade) membrane depolarization and increase of the cross-sectional area of muscle fibers. Pirenzepine abolished the effects of oxotremorine. It was concluded that non-quantal acetylcholine can be involved in the regulation of skeletal muscle fiber volume via activation of M1 muscarinic receptors followed by NO synthesis.

Role of potassium channels in chlorogenic acid-induced apoptotic volume decrease and cell cycle arrest in Candida albicans.

PubMed

Yun, JiEun; Lee, Dong Gun

2017-03-01

Chlorogenic acid (CRA) is an abundant phenolic compound in the human diet. CRA has a potent antifungal effect, inducing cell death in Candida albicans. However, there are no further studies to investigate the antifungal mechanism of CRA, associated with ion channels. To evaluate the inhibitory effects on CRA-induced cell death, C. albicans cells were pretreated with potassium and chloride channel blockers, separately. Flow cytometry was carried out to detect several hallmarks of apoptosis, such as cell cycle arrest, caspase activation, and DNA fragmentation, after staining of the cells with SYTOX green, FITC-VAD-FMK, and TUNEL. CRA caused excessive potassium efflux, and an apoptotic volume decrease (AVD) was observed. This change, in turn, induced cytosolic calcium uptake and cell cycle arrest in C. albicans. Moreover, CRA induced caspase activation and DNA fragmentation, which are considered apoptotic markers. In contrast, the potassium efflux and proapoptotic changes were inhibited when potassium channels were blocked, whereas there was no inhibitory effect when chloride channels were blocked. CRA induces potassium efflux, leading to AVD and G2/M cell cycle arrest in C. albicans. Therefore, potassium efflux via potassium channels regulates the CRA-induced apoptosis, stimulating several apoptotic processes. This study improves the understanding of the antifungal mechanism of CRA and its association with ion homeostasis, thereby pointing to a role of potassium channels in CRA-induced apoptosis. Copyright © 2016. Published by Elsevier B.V.

Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation.

PubMed

Hoshi, Yutaka; Okabe, Kohki; Shibasaki, Koji; Funatsu, Takashi; Matsuki, Norio; Ikegaya, Yuji; Koyama, Ryuta

2018-06-20

Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice in vivo Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia. SIGNIFICANCE STATEMENT Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which mouse brain slices were treated with oxygen-glucose deprivation. Using this system, we showed that the increase in brain temperature and the following activation of the thermosensitive cation channel TRPV4 (transient receptor potential vanilloid 4) are involved in the pathology of edema. Finally, we confirmed that TRPV4 is involved in brain edema in vivo using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia. Copyright © 2018 the authors 0270-6474/18/385700-10$15.00/0.

Antiaggressive activity of hyperforin: A preclinical study.

PubMed

Kumar, N; Husain, G M; Singh, P N; Kumar, V

2009-08-01

The aim of present study was to investigate the in vivo antiaggressive activity of hyperforin using defensive and offensive behavioral models in rodents. Adult male rats and mice were used for the present study. Animals were divided into three groups, with 6 animals in each. Lorazepam was used as standard antiaggressive agent. Animals were treated once daily, for seven consecutive days. Hyperforin (10 mg/kg, i.p.) was injected in a volume of 10 mL/kg for seven consecutive days. Standard group was treated with lorazepam (2.5 mg/kg, i.p.). The control group was treated with equal volume of vehicle (0.3% carboxy methyl cellulose suspension, i.p.). Animals were screened for aggressive behavior before dividing them into groups. At the end of 7 days, experiments were performed. Antiaggressive activity was evaluated using following validated models of aggression viz. foot shock-induced aggression, isolation-induced aggression, resident-intruder aggression and water competition test. Hyperforin treatment significantly (p < 0.001) reduced various aggressive parameters viz. latency to first attack and number of fights in isolation induced aggression, resident intruder aggression and foot shock induced aggression tests. In water competition test, hyperforin treatment significantly (p < 0.001) reduced the duration of water consumption and frequency of water spout possession. We conclude that hyperforin, the major lipophilic compound contained in extracts of Hypericum perforatum, is thus responsible for the antiaggressive activity, suggesting the therapeutic potential of hyperforin as an antiaggressive agent.

Effect of ischemic cerebral volume changes on behavior.

PubMed

Lyden, P D; Lonzo, L M; Nunez, S Y; Dockstader, T; Mathieu-Costello, O; Zivin, J A

1997-08-01

Ischemia causes long-term effects on brain volume and neurologic function but the relationship between the two is poorly characterized. We studied the relationships between brain volume and three measures of rodent behavior after cerebral ischemia was induced by injecting several thousand microspheres into the internal carotid arteries of rats. Forty eight hours later, each subject was rated using a global neurologic rating scale. Several weeks later, the subjects were tested for open field activity and visual spatial learning. Post-mortem we measured the volume of the cerebral hemispheres and estimated the volume densities of cortex, white matter, hippocampus, basal ganglia, thalamus, ventricle, and visible infarction. Ischemia caused significant impairment, as measured by the global rating scale; the probability of an abnormal rating was correlated with the number of microspheres trapped in the brains. Visual spatial learning was significantly impaired by ischemia, but this deficit was independent of the count of microspheres, whether the subject was abnormal at 48 h, and whether the left or right hemisphere was embolized. Cerebral hemisphere volume was reduced from 430 mm3 to 376 mm3 (P < 0.05). The cortex was reduced from 22 to 19% of cerebrum (P < 0.05) and the white matter compartment was reduced to similar degree. The lesion volume was 6% of cerebrum, comparable to that seen with other ischemia methods. The global outcome rating was significantly related to total cerebral volume, but not to volume changes in any single compartment. On the other hand, visual spatial learning was significantly influenced by volume changes in the cortex and white matter, but not by the topography of the visible infarctions. Open field activity was not altered by infarction. Our data suggests that the total volume of brain tissue lost to infarction may partially determine global neurological rating independently of the topography of the volume loss. Integrative functions such as learning may depend more on the integrity of specific compartments and less on the total volume of intact brain. The volume of visible cystic infarction was not related to long term behavioral outcome. These results should be confirmed using another method of inducing ischemia.

Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats.

PubMed

Mattioli, Theresa-Alexandra M; Milne, Brian; Cahill, Catherine M

2010-04-16

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance. Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration. Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for using ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes.

Near infrared photoimmunotherapy in the treatment of disseminated peritoneal ovarian cancer

PubMed Central

Sato, Kazuhide; Hanaoka, Hirofumi; Watanabe, Rira; Nakajima, Takahito; Choyke, Peter L.; Kobayashi, Hisataka

2014-01-01

Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of disseminated peritoneal ovarian cancer. In vitro and in vivo experiments were conducted with a HER2-expressing, luciferase expressing, ovarian cancer cell line (SKOV-luc). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized (tra-IR700) and cells or tumors were exposed to near infrared (NIR) light. In vitro PIT cytotoxicity was assessed with dead staining and luciferase activity in freely growing cells and in a 3D spheroid model. In vivo NIR-PIT was performed in mice with tumors implanted in the peritoneum and in the flank and these assessed by tumor volume and/or bioluminescence. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. Repeated light exposures induced complete tumor cell killing in the 3D spheroid model. In vivo the anti-tumor effects of NIR-PIT were confirmed by significant reductions in both tumor volume and luciferase activity in the flank model (NIR-PIT vs control in tumor volume changes at day 10; p=0.0001, NIR-PIT vs control in luciferase activity at day 4; p=0.0237), and the peritoneal model (NIR-PIT vs control in luciferase activity at day 7; p=0.0037). NIR-PIT provided effective cell killing in this HER2 positive model of disseminated peritoneal ovarian cancer. Thus, NIR-PIT is a promising new therapy for the treatment of disseminated peritoneal tumors. PMID:25416790

Mucoactive effects of naringin in lipopolysaccharide-induced acute lung injury mice and beagle dogs.

PubMed

Chen, Yan; Wu, Hao; Nie, Yi-chu; Li, Pei-bo; Shen, Jian-gang; Su, Wei-wei

2014-07-01

Our previous study has demonstrated that naringin attenuates EGF-induced MUC5AC hypersecretion in A549 cells by suppressing the cooperative activities of MAPKs/AP-1 and IKKs/IκB/NF-κB signaling pathways. However, the volume of airway mucus is determined by two factors including the number of mucous cells and capacity of mucus secretion. The aim of the present study is to explore the mucoactive effects of naringin in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and beagle dogs. The results demonstrated that naringin of 12.4 mg/kg treatment significantly decreased LPS-induced enhancement of sputum volume and pulmonary inflammation, remarkably increased the subglottic sputum volume and solids content in sputum of lower trachea, while partially, but not fully, significantly increased the elasticity and viscosity of sputum in lower trachea of beagle dogs. Moreover, the MUC5AC content in BALF and goblet-cells in large airways of LPS-induced ALI mice were significantly attenuated by dexamethasone (5 mg/kg), ambroxol (25 mg/kg), and naringin (15, 60 mg/kg). However, the goblet-cells hyperplasia in small airways induced by LPS was only significantly inhibited by dexamethasone and naringin (60 mg/kg). In conclusion, naringin exhibits mucoactive effects through multiple targets which including reduction of goblet cells hyperplasia and mucus hypersecretion, as well as promotion of sputum excretion. Copyright © 2014 Elsevier B.V. All rights reserved.

6-Shogaol inhibits monosodium urate crystal-induced inflammation--an in vivo and in vitro study.

PubMed

Sabina, Evan Prince; Rasool, Mahaboobkhan; Mathew, Lazar; Ezilrani, Panneerselvam; Indu, Haridas

2010-01-01

Gout is a rheumatic disease that is manifestated by an intense inflammation secondary to monosodium urate crystal deposition in joints. In the present study, we assessed the effect of 6-shogaol (isolated active principle from ginger) on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, indomethacin. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-alpha were determined in control and monosodium urate crystal-induced mice. The levels of beta-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL) in vitro. The levels of lysosomal enzymes, lipid peroxidation, and inflammatory mediator tumour necrosis factor-alpha and paw volume were increased significantly and the activities of anti-oxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon 6-shogaol administration. In vitro, 6-shogaol reduced the level of beta-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration dependent manner when compared to control cells. The present results clearly indicated that 6-shogaol exerted a strong anti-inflammatory effect and can be regarded as useful tool for the treatment of acute gouty arthritis. Copyright 2009 Elsevier Ltd. All rights reserved.

Simulations of gravitational stress on normovolemic and hypovolemic men and women.

PubMed

Zhang, Qingguang; Knapp, Charles F; Stenger, Michael B; Patwardhan, Abhijit R; Elayi, Samy C; Wang, Siqi; Kostas, Vladimir I; Evans, Joyce M

2014-04-01

Earth-based simulations of physiologic responses to space mission activities are needed to develop prospective countermeasures. To determine whether upright lower body positive pressure (LBPP) provides a suitable space mission simulation, we investigated the cardiovascular responses of normovolemic and hypovolemic men and women to supine and orthostatic stress induced by head-up tilt (HUT) and upright LBPP, representing standing in lunar, Martian, and Earth gravities. Six men and six women were tested in normovolemic and hypovolemic (furosemide, intravenous, 0.5 mg x kg(-1)) conditions. Continuous electrocardiogram, blood pressure, segmental bioimpedance, and stroke volume (echocardiography) were recorded supine and at lunar, Martian, and Earth gravities (10 degrees, 20 degrees, and 80 degrees HUT vs. 20%, 40%, and 100% bodyweight upright LBPP), respectively. Cardiovascular responses were assessed from mean values, spectral powers, and spontaneous baroreflex parameters. Hypovolemia reduced plasma volume by approximately 10% and stroke volume by approximately 25% at supine, and increasing orthostatic stress resulted in further reductions. Upright LBPP induced more plasma volume losses at simulated lunar and Martian gravities compared with HUT, while both techniques induced comparable central hypovolemia at each stress. Cardiovascular responses to orthostatic stress were comparable between HUT and upright LBPP in both normovolemic and hypovolemic conditions; however, hypovolemic blood pressure was greater during standing at 100% bodyweight compared to 80 degree HUT due to a greater increase of total peripheral resistance. The comparable cardiovascular response to HUT and upright LBPP support the use of upright LBPP as a potential model to simulate activity in lunar and Martian gravities.

Ameliorating effect of an interferon inducer polyinosinic-polycytidylic acid on bleomycin-induced lung fibrosis in hamsters. Morphologic and biochemical evidence.

PubMed Central

Giri, S. N.; Hyde, D. M.

1988-01-01

The effects of polyinosinic-polycytidylic acid (Poly I:C), an inducer of interferons, on bleomycin (Bleo)-induced lung fibrosis was studied in hamsters. Poly I:C (10 mg/kg intraperitoneally) was administered for two days and immediately before intratracheal instillation of bleomycin (7.5 U/kg) or an equivalent volume of saline and thereafter daily for 13 days. The lung hydroxyproline in control, Poly I:C, Bleo, and Bleo + Poly I:C groups averaged 791, 752, 1177, and 766 micrograms/lung. As compared to control, the prolyl hydroxylase activity in the Bleo group was increased by 83% whereas in Bleo + Poly I:C group, the activity was increased by 42%. Protein in the bronchoalveolar lavage supernatant in Poly I:C, Bleo and Bleo + Poly I:C groups were 72, 286, and 206% of the control, respectively. There was no difference in total leukocyte counts between Bleo + Poly I:C and Bleo groups, but the differential cell counts were changed. The numbers of neutrophils, monocytes, lymphocytes, and eosinophils were 50, 84, 91, and 10% of Bleo group, respectively. Morphometric estimates of the volume of parenchymal lesion within the lung showed that hamsters in Bleo + Poly I:C group had significantly less volume of lesion (1.0 cucm) than the Bleo group (1.6 cucm). In addition, the fibrotic lesions in Bleo + Poly I:C group were multifocal and primarily proximal acinar in location, had fewer extracellular fibers, neutrophils and monocytes. Poly I:C treatment ameliorated bleomycin-induced lung collagen accumulation. Images Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:2462354

The Electrophysiologic Effects of Acute Mitral Regurgitation in a Canine Model.

PubMed

Lawrance, Christopher P; Henn, Matthew C; Miller, Jacob R; Kopek, Michael A; Zhang, Andrew J; Schuessler, Richard B; Damiano, Ralph J

2017-04-01

Atrial fibrillation (AF) occurs in 30% of patients with mitral regurgitation referred for surgical intervention. However, the underlying mechanisms in this population are poorly understood. This study examined the effects of acute left atrial volume overload on atrial electrophysiology and the inducibility of AF. Ten canines underwent insertion of an atrioventricular shunt between the left ventricle and left atrium. Shunt and aortic flows were calculated, and the shunt was titrated to a shunt fraction to 40% to 50% of cardiac output. An epicardial plaque with 250 bipolar electrodes was used to determine activation and refractory periods. Biatrial pressures and volumes, conduction times, and atrial fibrillation inducibility were recorded. Data were collected at baseline and 20 minutes after shunt opening and closure. Mean shunt flow was 1.3 ± 0.5 L/min with a shunt fraction of 43% ± 6% simulating moderate to severe mitral regurgitation. Compared with baseline, left atrial volumes and maximum pressures increased by 27% and 29%, respectively, after shunt opening. Biatrial effective refractory periods did not change significantly after shunt opening or closure. Conduction times increased by 9% with shunt opening and returned to baseline after closure. AF duration or inducibility did not change with shunt opening. This canine model of mitral regurgitation demonstrated that acute left atrial volume overload did not increase the inducibility of atrial arrhythmias in contrast with experimental and clinical findings of chronic left atrial volume overload. This suggests that the substrates for AF in patients with mitral regurgitation are a result of chronic remodeling. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Licorice Pretreatment Protects Against Brain Damage Induced by Middle Cerebral Artery Occlusion in Mice.

PubMed

Lim, Chiyeon; Lim, Sehyun; Lee, Byoungho; Kim, Buyeo; Cho, Suin

2018-05-01

Licorice is extracted from the roots of plants in the Glycyrrhiza genus, especially Glycyrrhiza uralensis in China and Korea. It has several pharmacological activities, including neuro-protective, anti-fungal, and anti-cariogenic effects. Ischemia/reperfusion-induced brain injury is a leading cause of adult disability and death; thus, the identification of anti-apoptotic, neuro-protective therapeutic agents is viewed as an attractive drug development strategy. Infarct volumes and the expression of several apoptosis-related proteins, including Bcl-xL, Bcl-2, caspase-8, and caspase-9, were evaluated by western blotting in the brains of mice subjected to middle cerebral artery occlusion (MCAO). Three consecutive days of oral pretreatment with the methanol extract of licorice (GRex) significantly reduced infarct volumes 24 h after MCAO. In addition, GRex effectively inhibited the activation of caspase-9 by upregulating protein expression of Bcl-xL and Bcl-2. The neuro-protective effect of licorice was due to its regulation of apoptosis-related proteins. These data suggest that licorice could be a potential candidate for the treatment of ischemia-induced brain damage.

Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation.

PubMed

Pruimboom, Leo; Raison, Charles L; Muskiet, Frits A J

2015-01-01

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health.

Induced Earthquakes Are Not All Alike: Examples from Texas Since 2008 (Invited)

NASA Astrophysics Data System (ADS)

Frohlich, C.

2013-12-01

The EarthScope Transportable Array passed through Texas between 2008 and 2011, providing an opportunity to identify and accurately locate earthquakes near and/or within oil/gas fields and injection waste disposal operations. In five widely separated geographical locations, the results suggest seismic activity may be induced/triggered. However, the different regions exhibit different relationships between injection/production operations and seismic activity: In the Barnett Shale of northeast Texas, small earthquakes occurred only near higher-volume (volume rate > 150,000 BWPM) injection disposal wells. These included widely reported earthquakes occurring near Dallas-Fort Worth and Cleburne in 2008 and 2009. Near Alice in south Texas, M3.9 earthquakes occurred in 1997 and 2010 on the boundary of the Stratton Field, which had been highly productive for both oil and gas since the 1950's. Both earthquakes occurred during an era of net declining production, but their focal depths and location at the field boundary suggest an association with production activity. In the Eagle Ford of south central Texas, earthquakes occurred near wells following significant increases in extraction (water+produced oil) volumes as well as injection. The largest earthquake, the M4.8 Fashing earthquake of 20 October 2011, occurred after significant increases in extraction. In the Cogdell Field near Snyder (west Texas), a sequence of earthquakes beginning in 2006 followed significant increases in the injection of CO2 at nearby wells. The largest with M4.4 occurred on 11 September 2011. This is the largest known earthquake possibly attributable to CO2 injection. Near Timpson in east Texas a sequence of earthquakes beginning in 2008, including an M4.8 earthquake on 17 May 2012, occurred within three km of two high-volume injection disposal wells that had begun operation in 2007. These were the first known earthquakes at this location. In summary, the observations find possible induced/triggered earthquakes associated with recent increases in injection, recent increases in extraction, with CO2 injection, and with declining production. In all areas, during the 2008-2011 period there were no earthquakes occurring near vast majority of extraction/production wells; thus, the principal puzzle is why these activities sometimes induce seismicity and sometimes do not.

The Search for Fluid Injection-induced Seismicity in California Oilfields

NASA Astrophysics Data System (ADS)

Layland-Bachmann, C. E.; Brodsky, E. E.; Foxall, W.; Goebel, T.; Jordan, P. D.

2017-12-01

During recent years, earthquakes associated with human activity have become a matter of heightened public concern. Wastewater injection is a major concern, as seismic events with magnitudes larger than M5.5 have been linked to this practice. Much of the research in the United States is focused on the mid-continental regions, where low rates of naturally-occurring seismicity and high-volume injection activities facilitate easier identification by statistical correlation of potentially induced seismic events . However, available industry data are often limited in these regions and therefore limits our ability to connect specific human activities to earthquakes. Specifically, many previous studies have focused primarily on injection activity in single wells, ignoring the interconnectivity of production and injection in a reservoir. The situation in California differs from the central U.S. in two ways: (1) A rich dataset of oilfield activity is publically available from state agencies, which enables a more in-depth investigation of the human forcing; and (2) the identification of potential anthropogenically-induced earthquakes is complex as a result of high tectonic activity. Here we address both differences. We utilize a public database of hydrologically connected reservoirs to assess whether there are any statistically significant correlations between the net injected volumes, reservoir pressures and injection depths, and the earthquake locations and frequencies of occurrence. We introduce a framework of physical and empirical models and statistical techniques to identify potentially induced seismic events. While the aim is to apply the methods statewide, we first apply our methods in the Southern San Joaquin Valley. Although, we find an anomalously high earthquake rate in Southern Kern County oilfields, which is consistent with previous studies, we do not find a simple straightforward correlation. To successfully study induced seismicity we need a seismic catalog that is complete and consistent down to small magnitudes. During this study, we found some important seismic coverage gaps in critical oilfields in the Central Valley that need to be addressed in order to provide societally relevant assessments.

Measurement of Radon-Induced Backgrounds in the NEXT Double Beta Decay Experiment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Novella, P.; et al.

The measurement of the internal 222Rn activity in the NEXT-White detector during the so-called Run-II period with 136Xe-depleted xenon is discussed in detail, together with its implications for double beta decay searches in NEXT. The activity is measured through the alpha production rate induced in the fiducial volume by 222Rn and its alpha-emitting progeny. The specific activity is measured to bemore » $$(37.5\\pm 2.3~\\mathrm{(stat.)}\\pm 5.9~\\mathrm{(syst.)})$$~mBq/m$^3$. Radon-induced electrons have also been characterized from the decay of the 214Bi daughter ions plating out on the cathode of the time projection chamber. From our studies, we conclude that radon-induced backgrounds are sufficiently low to enable a successful NEXT-100 physics program, as the projected rate contribution should not exceed 0.2~counts/yr in the neutrinoless double beta decay sample.« less

Droplet-based magnetically activated cell separation: analysis of separation efficiency based on the variation of flow-induced circulation in a pendent drop.

PubMed

Kim, Youngho; Lee, Sang Ho; Kim, Byungkyu

2009-12-01

Under the assumption that separation efficiencies are mainly affected by the velocity of flow-induced circulation due to buffer injection in a pendent drop, this paper describes an analysis of the separation efficiency of a droplet-based magnetically activated cell separation (DMACS) system. To investigate the velocity of the flow-induced circulation, we supposed that numerous flows in a pendent drop could be considered as a "theoretically normalized" flow (or conceptually normalized flow, CNF) based on the Cauchy-Goursat theorem. With the morphological characteristics (length and duration time) of a pendent drop depending on the initial volume, we obtained the velocities of the CNF. By measuring the separation efficiencies for different initial volumes and by analyzing the separation efficiency in terms of the velocity of the CNF, we found that the separation efficiencies (in the case of a low rate of buffer injection; 5 and 15 microl x min(-1)) are mainly affected by the velocity of the CNF. Moreover, we confirmed that the phenomenological features of a pendent drop cause a fluctuation of its separation efficiencies over a range of specific volumes (initial volumes ranging from 40 to 80 microl), because of the "sweeping-off" phenomenon, that is, positive cells gathered into the positive fraction are forced to move away from the magnetic side by flow-induced circulation due to buffer injection. In addition, from the variation of the duration time, that is, the interval between the beginning of injection of the buffer solution and the time at which a pendent drop detaches, it could also be confirmed that a shorter duration time leads to decrease of the number of positive cells in negative fraction regardless of the rate of buffer injection (5, 15, and 50 microl x min(-1)). Therefore, if a DMACS system is operated with a 15 microl x min(-1) buffer injection flow rate and an initial volume of 80 microl or more, we would have the best efficiency of separation in the negative fraction.

Exercise-induced neuroplasticity in human Parkinson's disease: What is the evidence telling us?

PubMed

Hirsch, Mark A; Iyer, Sanjay S; Sanjak, Mohammed

2016-01-01

While animal models of exercise and PD have pushed the field forward, few studies have addressed exercise-induced neuroplasticity in human PD. As a first step toward promoting greater international collaboration on exercise-induced neuroplasticity in human PD, we present data on 8 human PD studies (published between 2008 and 2015) with 144 adults with PD of varying disease severity (Hoehn and Yahr stage 1 to stage 3), using various experimental (e.g., randomized controlled trial) and quasi-experimental designs on the effects of cognitive and physical activity on brain structure or function in PD. We focus on plasticity mechanisms of intervention-induced increases in maximal corticomotor excitability, exercise-induced changes in voxel-based gray matter volume changes and increases in exercise-induced serum levels of brain derived neurotrophic factor (BDNF). Finally, we provide a future perspective for promoting international, collaborative research on exercise-induced neuroplasticity in human PD. An emerging body of evidence suggests exercise triggers several plasticity related events in the human PD brain including corticomotor excitation, increases and decreases in gray matter volume and changes in BDNF levels. Copyright © 2015 Elsevier Ltd. All rights reserved.

Volume-dependent ATP-conductive large-conductance anion channel as a pathway for swelling-induced ATP release.

PubMed

Sabirov, R Z; Dutta, A K; Okada, Y

2001-09-01

In mouse mammary C127i cells, during whole-cell clamp, osmotic cell swelling activated an anion channel current, when the phloretin-sensitive, volume-activated outwardly rectifying Cl(-) channel was eliminated. This current exhibited time-dependent inactivation at positive and negative voltages greater than around +/-25 mV. The whole-cell current was selective for anions and sensitive to Gd(3)+. In on-cell patches, single-channel events appeared with a lag period of approximately 15 min after a hypotonic challenge. Under isotonic conditions, cell-attached patches were silent, but patch excision led to activation of currents that consisted of multiple large-conductance unitary steps. The current displayed voltage- and time-dependent inactivation similar to that of whole-cell current. Voltage-dependent activation profile was bell-shaped with the maximum open probability at -20 to 0 mV. The channel in inside-out patches had the unitary conductance of approximately 400 pS, a linear current-voltage relationship, and anion selectivity. The outward (but not inward) single-channel conductance was suppressed by extracellular ATP with an IC(50) of 12.3 mM and an electric distance (delta) of 0.47, whereas the inward (but not outward) conductance was inhibited by intracellular ATP with an IC(50) of 12.9 mM and delta of 0.40. Despite the open channel block by ATP, the channel was ATP-conductive with P(ATP)/P(Cl) of 0.09. The single-channel activity was sensitive to Gd(3)+, SITS, and NPPB, but insensitive to phloretin, niflumic acid, and glibenclamide. The same pharmacological pattern was found in swelling-induced ATP release. Thus, it is concluded that the volume- and voltage-dependent ATP-conductive large-conductance anion channel serves as a conductive pathway for the swelling-induced ATP release in C127i cells.

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

PubMed Central

Catalán, Marcelo A.; Kondo, Yusuke; Peña-Munzenmayer, Gaspar; Jaramillo, Yasna; Liu, Frances; Choi, Sooji; Crandall, Edward; Borok, Zea; Flodby, Per; Shull, Gary E.; Melvin, James E.

2015-01-01

Activation of an apical Ca2+-activated Cl− channel (CaCC) triggers the secretion of saliva. It was previously demonstrated that CaCC-mediated Cl− current and Cl− efflux are absent in the acinar cells of systemic Tmem16A (Tmem16A Cl− channel) null mice, but salivation was not assessed in fully developed glands because Tmem16A null mice die within a few days after birth. To test the role of Tmem16A in adult salivary glands, we generated conditional knockout mice lacking Tmem16A in acinar cells (Tmem16A−/−). Ca2+-dependent salivation was abolished in Tmem16A−/− mice, demonstrating that Tmem16A is obligatory for Ca2+-mediated fluid secretion. However, the amount of saliva secreted by Tmem16A−/− mice in response to the β-adrenergic receptor agonist isoproterenol (IPR) was comparable to that seen in controls, indicating that Tmem16A does not significantly contribute to cAMP-induced secretion. Furthermore, IPR-stimulated secretion was unaffected in mice lacking Cftr (Cftr∆F508/∆F508) or ClC-2 (Clcn2−/−) Cl− channels. The time course for activation of IPR-stimulated fluid secretion closely correlated with that of the IPR-induced cell volume increase, suggesting that acinar swelling may activate a volume-sensitive Cl− channel. Indeed, Cl− channel blockers abolished fluid secretion, indicating that Cl− channel activity is critical for IPR-stimulated secretion. These data suggest that β-adrenergic–induced, cAMP-dependent fluid secretion involves a volume-regulated anion channel. In summary, our results using acinar-specific Tmem16A−/− mice identify Tmem16A as the Cl− channel essential for muscarinic, Ca2+-dependent fluid secretion in adult mouse salivary glands. PMID:25646474

Perioperative management of paraganglioma and catecholamine-induced cardiomyopathy in child- a case report and review of the literature.

PubMed

Jia, Xixi; Guo, Xiangyang; Zheng, Qing

2017-10-17

Paragangliomas are catecholamine-secreting tumors of the paraganglia. Perioperative mortality of children with paraganglioma is high, but preoperative therapy and anesthetic management of paraganglioma resection are controversial in children. The literatures on catecholamine-induced cardiomyopathy are limited to several case reports,with few reports of studies on children. Here we report the anesthetic management of a child with paraganglioma and catecholamine-induced cardiomyopathy, and the possible perioperative anesthesia problems of the paraganglioma resection are discussed. Preoperative and intraoperative anesthetic management of Pheochromocytomas children should follow the same principles as for adults, The most important aspects are the control of blood pressure liability and maintenance of adequate blood volume. Pheochromocytomas patient may have cardiomoyopathy due to myocardial toxicity of excessive circulating catecholamines level. The perioperative management of catecholamine-induced cardiomyopathy should include lowering sympathetic activation by means of α-and β-adrenergic receptor blocker and diuretics administration in case of volume overload.

Adjudin attenuates lipopolysaccharide (LPS)- and ischemia-induced microglial activation

PubMed Central

Shao, Jiaxiang; Liu, Tengyuan; Xie, Qian Reuben; Zhang, Tingting; Yu, Hemei; Wang, Boshi; Ying, Weihai; Mruk, Dolores D.; Silvestrini, Bruno; Cheng, C. Yan; Xia, Weiliang

2014-01-01

Neuroinflammation caused by microglial activation plays a key role in ischemia, neurodegeneration and many other CNS diseases. In this study, we found that Adjudin, a potential non-hormonal male contraceptive, exhibits additional function to reduce the production of proinflammatory mediators. Adjudin significantly inhibited LPS-induced IL-6 release and IL-6, IL-1β, TNF-α expression in BV2 microglial cells. Furthermore, Adjudin exhibited anti-inflammatory properties by suppression of NF-κB p65 nuclear translocation and DNA binding activity as well as ERK MAPK phosphorylation. To determine the in vivo effect of Adjudin, we used a permanent middle cerebral artery occlusion (pMCAO) mouse model and found that Adjudin could reduce ischemia-induced CD11b expression, a marker of microglial activation. Furthermore, Adjudin treatment attenuated brain edema and neurological deficits after ischemia but did not reduce infarct volume. Thus, our data suggest that Adjudin may be useful for mitigating neuroinflammation. PMID:23084372

Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres

PubMed Central

Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

2015-01-01

Abstract Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca2+ from intracellular pools. We observed that both hyperosmotic shock-induced Ca2+ transients and RVI were inhibited by Gd3+, ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca2+ induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca2+ from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na+–K+–Cl− cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca2+ transients were abolished by the Ca2+ chelator BAPTA, the level of P-SPAKSer373 in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca2+. We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. Key points Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock-induced CS is accompanied by a small membrane depolarization responsible for a release of Ca2+ from intracellular pools. Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK). TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca2+ response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function. We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca2+ release from the sarcoplasmic reticulum, activation of the Na+–K+–Cl− cotransporter by SPAK, and the RVI response. PMID:26108786

Ganoderma lucidum total triterpenes attenuate DLA induced ascites and EAC induced solid tumours in Swiss albino mice.

PubMed

Smina, T P; Mathew, J; Janardhanan, K K

2016-04-30

G. lucidum total triterpenes were assessed for its apoptosis-inducing and anti-tumour activities. The ability of the total triterpenes to induce apoptosis was evaluated in Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines. Total triterpenes were found to be highly cytotoxic to DLA and EAC cell lines with IC50 values 5 ± 0.32 and 7.9 ± 0.2 µg/ml respectively. Total triterpenes induced apoptosis in both cell lines which is evident from the DNA fragmentation assay. Anti-tumour activity was accessed using DLA induced solid and EAC induced ascites tumour models in Swiss albino mice. Administration of 10, 50 and 100 mg/kg b. wt. total triterpenes showed 11.86, 27.27 and 40.57% increase in life span of animals in ascites tumour model. Treatment with 10, 50 and 100 mg/kg b. wt. total triterpenes exhibited 76.86, 85.01 and 91.03% inhibition in tumour volume and 67.96, 72.38 and 77.90% inhibition in tumour weight respectively in the solid tumour model. The study reveals the significant dose-dependent anti-tumour activity of total triterpenes in both models. Total triterpenes were more active against the solid tumour than the ascites tumour. The anti-oxidant potential and ability to induce cell-specific apoptosis could be contributing to its anti-tumour activities.

Corticospinal tract integrity and lesion volume play different roles in chronic hemiparesis and its improvement through motor practice.

PubMed

Sterr, Annette; Dean, Phil J A; Szameitat, Andre J; Conforto, Adriana Bastos; Shen, Shan

2014-05-01

Initial evidence suggests that the integrity of the ipsilesional corticospinal tract (CST) after stroke is strongly related to motor function in the chronic state but not the treatment gain induced by motor rehabilitation. We examined the association of motor status and treatment benefit by testing patients with a wide range of severity of hemiparesis of the left and right upper extremity. Diffusion tensor imaging was performed in 22 patients beyond 12 months after onset of stroke with severe to moderate hemiparesis. Motor function was tested before and after 2 weeks of modified constraint-induced movement therapy. CST integrity, but not lesion volume, correlated with the motor ability measures of the Wolf Motor Function Test and the Motor Activity Log. No differences were found between left and right hemiparesis. Motor performance improved significantly with the treatment regime, and did so equally for patients with left and right arm paresis. However, treatment benefit was not associated with either CST integrity or lesion volume. CST integrity correlated best in this small trial with chronic long-term status but not treatment-induced improvements. The CST may play a different role in the mechanisms mediating long-term outcome compared to those underlying practice-induced gains after a chronic plateau in motor function.

Photon activation-15O decay studies of tumor blood flow.

PubMed

Ten Haken, R K; Nussbaum, G H; Emami, B; Hughes, W L

1981-01-01

A direct, noninvasive method for measuring absolute values of specific capillary blood flow in living tissue is described. The method is based on the photon activation, in situ, of tissue elements and the measurement of the subsequent decay of the positron activity induced, employing coincidence detection of the photon pairs produced in positron annihilation. Analysis of the time-dependent coincidence spectrum reveals the contribution to the total signal from the decay of 15O, from which the specific capillary blood flow in the imaged, activated volume is ultimately determined. By virtue of its introduction of the radioisotope of interest (15O) directly and uniformly into the tissue volume under investigation, the method described permits both the nonperfused and well perfused fractions of an activated volume to be estimated and hence, the average specific blood flow within imaged tumor volumes to be computed. The model employed to describe and analyze the data is discussed in detail. Results of application of the technique to measurement of specific blood flow in rhabdomyosarcoma tumors grown in WAG/Rij rats are presented and discussed. The method is shown to be reliable and well suited to studies designed to determined the effects of various agents, such as heat, radiation and drugs, on tumor blood flow.

Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia

PubMed Central

Button, Brian; Picher, Maryse; Boucher, Richard C

2007-01-01

In the lungs, the first line of defence against bacterial infection is the thin layer of airway surface liquid (ASL) lining the airway surface. The superficial airway epithelium exhibits complex regulatory pathways that blend ion transport to adjust ASL volume to maintain proper mucociliary clearance (MCC). We hypothesized that stresses generated by airflow and transmural pressures during breathing govern ASL volume by regulating the rate of epithelial ATP release. Luminal ATP, via interactions with apical membrane P2-purinoceptors, regulates the balance of active ion secretion versus absorption to maintain ASL volume at optimal levels for MCC. In this study we tested the hypothesis that cyclic compressive stress (CCS), mimicking normal tidal breathing, regulates ASL volume in airway epithelia. Polarized tracheobronchial epithelial cultures from normal and cystic fibrosis (CF) subjects responded to a range of CCS by increasing the rate of ATP release. In normal airway epithelia, the CCS-induced increase in ASL ATP concentration was sufficient to induce purinoceptor-mediated increases in ASL height and MCC, via inhibition of epithelial Na+-channel-mediated Na+ absorption and stimulation of Cl− secretion through CFTR and the Ca2+-activated chloride channels. In contrast, static, non-oscillatory stress did not stimulate ATP release, ion transport or MCC, emphasizing the importance of rhythmic mechanical stress for airway defence. In CF airway cultures, which exhibit basal ASL depletion, CCS was partially effective, producing less ASL volume secretion than in normal cultures, but a level sufficient to restore MCC. The present data suggest that CCS may (1) regulate ASL volume in the normal lung and (2) improve clearance in the lungs of CF patients, potentially explaining the beneficial role of exercise in lung defence. PMID:17317749

Limb venous distension evokes sympathetic activation via stimulation of the limb afferents in humans.

PubMed

Cui, Jian; McQuillan, Patrick M; Blaha, Cheryl; Kunselman, Allen R; Sinoway, Lawrence I

2012-08-15

We have recently shown that a saline infusion in the veins of an arterially occluded human forearm evokes a systemic response with increases in muscle sympathetic nerve activity (MSNA) and blood pressure. In this report, we examined whether this response was a reflex that was due to venous distension. Blood pressure (Finometer), heart rate, and MSNA (microneurography) were assessed in 14 young healthy subjects. In the saline trial (n = 14), 5% forearm volume normal saline was infused in an arterially occluded arm. To block afferents in the limb, 90 mg of lidocaine were added to the same volume of saline in six subjects during a separate visit. To examine whether interstitial perfusion of normal saline alone induced the responses, the same volume of albumin solution (5% concentration) was infused in 11 subjects in separate studies. Lidocaine abolished the MSNA and blood pressure responses seen with saline infusion. Moreover, compared with the saline infusion, an albumin infusion induced a larger (MSNA: Δ14.3 ± 2.7 vs. Δ8.5 ± 1.3 bursts/min, P < 0.01) and more sustained MSNA and blood pressure responses. These data suggest that venous distension activates afferent nerves and evokes a powerful systemic sympathoexcitatory reflex. We posit that the venous distension plays an important role in evoking the autonomic adjustments seen with postural stress in human subjects.

Supraclavicular Skin Temperature as a Measure of 18F-FDG Uptake by BAT in Human Subjects

PubMed Central

van der Linden, Rianne A. D.; Pereira Arias-Bouda, Lenka; Smit, Frits; Verberne, Hein J.; van Marken Lichtenbelt, Wouter D.

2014-01-01

Background Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current ‘gold standard’ for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans. Subjects/Methods BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations. Results Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not. Conclusions Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects. Trial Registration NTR 2473 PMID:24922545

Effect of volume-oriented versus flow-oriented incentive spirometry on chest wall volumes, inspiratory muscle activity, and thoracoabdominal synchrony in the elderly.

PubMed

Lunardi, Adriana C; Porras, Desiderio C; Barbosa, Renata Cc; Paisani, Denise M; Marques da Silva, Cibele C B; Tanaka, Clarice; Carvalho, Celso R F

2014-03-01

Aging causes physiological and functional changes that impair pulmonary function. Incentive spirometry is widely used for lung expansion, but the effects of volume-oriented incentive spirometry (VIS) versus flow-oriented incentive spirometry (FIS) on chest wall volumes, inspiratory muscle activity, and thoracoabdominal synchrony in the elderly are poorly understood. We compared VIS and FIS in elderly subjects and healthy adult subjects. Sixteen elderly subjects (9 women, mean ± SD age 70.6 ± 3.9 y, mean ± SD body mass index 23.8 ± 2.5 kg/m(2)) and 16 healthy adults (8 women, mean ± age 25.9 ± 4.3 y, mean ± body mass index 23.6 ± 2.4 kg/m(2)) performed quiet breathing, VIS, and FIS in randomized sequence. Chest wall kinematics (via optoelectronic plethysmography) and inspiratory muscle activity (via surface electromyography) were assessed simultaneously. Synchrony between the superior thorax and abdominal motion was calculated (phase angle). In the elderly subjects both types of incentive spirometry increased chest wall volumes similarly, whereas in the healthy adult subjects VIS increased the chest wall volume more than did FIS. FIS and VIS triggered similar lower thoracoabdominal synchrony in the elderly subjects, whereas in the healthy adults FIS induced lower synchrony than did VIS. FIS required more muscle activity in the elderly subjects to create an increase in chest wall volume. Incentive spirometry performance is influenced by age, and the differences between elderly and healthy adults response should be considered in clinical practice.

Effect of Chronic Athletic Activity on Brown Fat in Young Women.

PubMed

Singhal, Vibha; Maffazioli, Giovana D; Ackerman, Kate E; Lee, Hang; Elia, Elisa F; Woolley, Ryan; Kolodny, Gerald; Cypess, Aaron M; Misra, Madhusmita

2016-01-01

The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross-sectional study of 24 women (16 athletes and8 non-athletes) between 18-25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8).We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. Athletes and non-athletes did not differ for age or BMI. Compared with non-athletes, athletes had lower percent body fat (p = 0.002), higher percent lean mass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = -0.46, p = 0.02).BAT volume correlated inversely with lean mass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit.

Inhaled hydrogen sulfide: a rapidly reversible inhibitor of cardiac and metabolic function in the mouse.

PubMed

Volpato, Gian Paolo; Searles, Robert; Yu, Binglan; Scherrer-Crosbie, Marielle; Bloch, Kenneth D; Ichinose, Fumito; Zapol, Warren M

2008-04-01

Breathing hydrogen sulfide (H2S) has been reported to induce a suspended animation-like state with hypothermia and a concomitant metabolic reduction in rodents. However, the impact of H2S breathing on cardiovascular function remains incompletely understood. In this study, the authors investigated the cardiovascular and metabolic effects of inhaled H2S in a murine model. The impact of breathing H2S on cardiovascular function was examined using telemetry and echocardiography in awake mice. The effects of breathing H2S on carbon dioxide production and oxygen consumption were measured at room temperature and in a warmed environment. Breathing H2S at 80 parts per million by volume at 27 degrees C ambient temperature for 6 h markedly reduced heart rate, core body temperature, respiratory rate, and physical activity, whereas blood pressure remained unchanged. Echocardiography demonstrated that H2S exposure decreased both heart rate and cardiac output but preserved stroke volume. Breathing H2S for 6 h at 35 degrees C ambient temperature (to prevent hypothermia) decreased heart rate, physical activity, respiratory rate, and cardiac output without altering stroke volume or body temperature. H2S breathing seems to induce bradycardia by depressing sinus node activity. Breathing H2S for 30 min decreased whole body oxygen consumption and carbon dioxide production at either 27 degrees or 35 degrees C ambient temperature. Both parameters returned to baseline levels within 10 min after the cessation of H2S breathing. Inhalation of H2S at either 27 degrees or 35 degrees C reversibly depresses cardiovascular function without changing blood pressure in mice. Breathing H2S also induces a rapidly reversible reduction of metabolic rate at either body temperature.

Inhaled Hydrogen Sulfide

PubMed Central

Volpato, Gian Paolo; Searles, Robert; Yu, Binglan; Scherrer-Crosbie, Marielle; Bloch, Kenneth D.; Ichinose, Fumito; Zapol, Warren M.

2010-01-01

Background Breathing hydrogen sulfide (H2S) has been reported to induce a suspended animation–like state with hypothermia and a concomitant metabolic reduction in rodents. However, the impact of H2S breathing on cardiovascular function remains incompletely understood. In this study, the authors investigated the cardiovascular and metabolic effects of inhaled H2S in a murine model. Methods The impact of breathing H2S on cardiovascular function was examined using telemetry and echocardiography in awake mice. The effects of breathing H2S on carbon dioxide production and oxygen consumption were measured at room temperature and in a warmed environment. Results Breathing H2S at 80 parts per million by volume at 27°C ambient temperature for 6 h markedly reduced heart rate, core body temperature, respiratory rate, and physical activity, whereas blood pressure remained unchanged. Echocardiography demonstrated that H2S exposure decreased both heart rate and cardiac output but preserved stroke volume. Breathing H2S for 6 h at 35°C ambient temperature (to prevent hypothermia) decreased heart rate, physical activity, respiratory rate, and cardiac output without altering stroke volume or body temperature. H2S breathing seems to induce bradycardia by depressing sinus node activity. Breathing H2S for 30 min decreased whole body oxygen consumption and carbon dioxide production at either 27° or 35°C ambient temperature. Both parameters returned to baseline levels within 10 min after the cessation of H2S breathing. Conclusions Inhalation of H2S at either 27° or 35°C reversibly depresses cardiovascular function without changing blood pressure in mice. Breathing H2S also induces a rapidly reversible reduction of metabolic rate at either body temperature. PMID:18362598

Analgesic, antipyretic, anti-inflammatory effects of methanol, chloroform and ether extracts of Vernonia cinerea less leaf.

PubMed

Iwalewa, E O; Iwalewa, O J; Adeboye, J O

2003-06-01

The chloroform, methanolic and ether extracts of Vernonia cinerea (Asteraceae; Less) leaf (100, 200 and 400mg/kg intraperitoneally) were tested in: acetic acid-induced writhing in mice, carrageenin-induced oedema and brewer's yeast-induced pyrexia in rats to assess their analgesic, anti-inflammatory, antipyretic and behavioral activities, respectively. The changes in writhings and behavioural activities in mice, the pyrexia and paw volumes in rats were reduced significantly (P<0.05) compared to the control. There was an increase in pain threshold on the oedematous right hind limb paw of the rats. These results indicate that the extracts could possess analgesic, antipyretic and anti-inflammatory properties. All these effects and the changes in the behavioural activities could be suggested as contributory effects to the use of V. cinerea leaf in the treatment of malaria.

Curcumin affects cell survival and cell volume regulation in human renal and intestinal cells

PubMed Central

Kössler, Sonja; Nofziger, Charity; Jakab, Martin; Dossena, Silvia; Paulmichl, Markus

2012-01-01

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione or diferuloyl methane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. This substance has been used extensively in Ayurvedic medicine for centuries for its anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer properties linked to its pro-apoptotic and anti-proliferative actions. The underlying mechanisms of these diverse effects are complex, not fully elucidated and subject of intense scientific debate. Despite increasing evidence indicating that different cation channels can be a molecular target for curcumin, very little is known about the effect of curcumin on chloride channels. Since, (i) the molecular structure of curcumin indicates that the substance could potentially interact with chloride channels, (ii) chloride channels play a role during the apoptotic process and regulation of the cell volume, and (iii) apoptosis is a well known effect of curcumin, we set out to investigate whether or not curcumin could (i) exert a modulatory effect (direct or indirect) on the swelling activated chloride current IClswell in a human cell system, therefore (ii) affect cell volume regulation and (iii) ultimately modulate cell survival. The IClswell channels, which are essential for regulating the cell volume after swelling, are also known to be activated under isotonic conditions as an early event in the apoptotic process. Here we show that long-term exposure of a human kidney cell line to extracellular 0.1–10 μM curcumin modulates IClswell in a dose-dependent manner (0.1 μM curcumin is ineffective, 0.5–5.0 μM curcumin increase, while 10 μM curcumin decrease the current), and short-term exposure to micromolar concentrations of curcumin does not affect IClswell neither if applied from the extracellular nor from the intracellular side – therefore, a direct effect of curcumin on IClswell can be ruled out. Furthermore, we show that curcumin exposure induces apoptosis in human kidney cells, and at a concentration of 5.0–10 μM induces the appearance of a sub-population of cells with a dramatically increased volume. In these cells the regulation of the cell volume seems to be impaired, most likely as a consequence of the IClswell blockade. Similarly, 50 μM curcumin induced apoptosis, caused cell cycle arrest in G1-phase and increased the volume of human colorectal adenocarcinoma HT-29 cells. The cell cycle arrest in G1 phase may be the mechanism underlying the volume increase observed in this cell line after exposure to curcumin. PMID:22178266

Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.

PubMed

Camilleri, Michael; Bharucha, Adil E; Ueno, Ryuji; Burton, Duane; Thomforde, George M; Baxter, Kari; McKinzie, Sanna; Zinsmeister, Alan R

2006-05-01

Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 microg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ("satiation") test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes and simulated weightlessness in rats

NASA Technical Reports Server (NTRS)

Pamnani, M. B.; Chen, S.; Haddy, F. J.; Yuan, C.; Mo, Z.

1998-01-01

We have examined the role of plasma Na+-K+ pump inhibitor (SPI) in the hypertension of streptozotocin induced insulin dependent diabetes (IDDM) in reduced renal mass rats. The increase in blood pressure (BP) was associated with an increase in extracellular fluid volume (ECFV), and SPI and a decrease in myocardial Na+,K+ATPase (NKA) activity, suggesting that increased SPI, which inhibits cardiovascular muscle (CVM) cell NKA activity, may be involved in the mechanism of IDDM-hypertension. In a second study, using prolonged suspension resulted in a decrease in cardiac NKA activity, suggesting that cardiovascular deconditioning following space flight might in part result from insufficient SPI.

Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

PubMed Central

Pruimboom, Leo; Raison, Charles L.; Muskiet, Frits A. J.

2015-01-01

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health. PMID:26074674

Sympathetic and cardiovascular responses to venous distension in an occluded limb.

PubMed

Cui, Jian; Leuenberger, Urs A; Gao, Zhaohui; Sinoway, Lawrence I

2011-12-01

We recently showed that a fixed volume (i.e., 40 ml) of saline infused into the venous circulation of an arterially occluded vascular bed increases muscle sympathetic nerve activity (MSNA) and blood pressure. In the present report, we hypothesized that the volume and rate of infusion would influence the magnitude of the sympathetic response. Blood pressure, heart rate, and MSNA were assessed in 13 young healthy subjects during forearm saline infusions (arrested circulation). The effects of different volumes of saline (i.e., 2%, 3%, 4%, or 5% forearm volume at 30 ml/min) and different rates of infusion (i.e., 5% forearm volume at 10, 20, or 30 ml/min) were evaluated. MSNA and blood pressure responses were linked with the infusion volume. Infusion of 5% of forearm volume evoked greater MSNA responses than did infusion of 2% of forearm volume (Δ11.6 ± 1.9 vs. Δ3.1 ± 1.8 bursts/min and Δ332 ± 105 vs. Δ38 ± 32 units/min, all P < 0.05). Moreover, greater MSNA responses were evoked by saline infusion at 30 ml/min than 10 ml/min (P < 0.05). Sonographic measurements confirmed that the saline infusions induced forearm venous distension. The results suggest that volume and rate of saline infusion are important factors in evoking sympathetic activation. We postulate that venous distension contributes to cardiovascular autonomic adjustment in humans.

Fresh frozen plasma resuscitation attenuates platelet dysfunction compared with normal saline in a large animal model of multisystem trauma.

PubMed

Sillesen, Martin; Johansson, Pär I; Rasmussen, Lars S; Jin, Guang; Jepsen, Cecilie H; Imam, Ayesha; Hwabejire, John O; Deperalta, Danielle; Duggan, Michael; DeMoya, Marc; Velmahos, George C; Alam, Hasan B

2014-04-01

Platelet dysfunction following trauma has been identified as an independent predictor of mortality. We hypothesized that fresh frozen plasma (FFP) resuscitation would attenuate platelet dysfunction compared with 0.9% normal saline (NS). Twelve swine were subjected to multisystem trauma (traumatic brain injury, liver injury, rib fracture, and soft tissue injury) with hemorrhagic shock (40% of estimated blood volume). Animals were left in shock (mean arterial pressure, 30-35 mm Hg) for 2 hours followed by resuscitation with three times shed volume NS (n = 6) or one times volume FFP (n = 6) and monitored for 6 hours. Platelet function was assessed by adenosine diphosphate (ADP)-induced platelet aggregation at baseline, after 2 hours of shock following resuscitation, and 6 hours after resuscitation. Fibrinogen levels and markers of platelet activation (transforming growth factor β [TGF-β], sP-Selectin, and CD40L) as well as endothelial injury (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]) were also assayed. Thromboelastography was used to measure clotting activity. ADP-induced platelet aggregation was significantly higher in the FFP group (46.3 U vs. 25.5 U, p < 0.01) following resuscitation. This was associated with higher fibrinogen levels (202 mg/dL vs. 80 mg/dL, p < 0.01) but lower endothelial activation (VCAM-1, 1.25 ng/mL vs. 3.87 ng/mL, p = 0.05). Other markers did not differ.After 6 hours of observation, ADP-induced platelet aggregation remained higher in the FFP group (53.8 U vs. 37.0 U, p = 0.03) as was fibrinogen levels (229 mg/dL vs. 153 mg/dL, p < 0.01). Endothelial activation was lower (ICAM-1, 21.0 ng/mL vs. 24.4 ng/mL, p = 0.05), whereas TGF-β levels were higher (2,138 pg/mL vs. 1,802 pg/mL, p = 0.03) in the FFP group. Other markers did not differ. Thromboelastography revealed increased clot strength in the FFP group at both postresuscitation time points. Resuscitation with FFP resulted in an immediate and sustained improvement in platelet function and clot strength compared with high-volume NS resuscitation. This was associated with an increase in fibrinogen levels and an attenuation of endothelial activation.

In vivo anti-inflammatory activity of aqueous extract of Teucrium polium against carrageenan-induced inflammation in experimental models.

PubMed

Rahmouni, Fatma; Hamdaoui, Latifa; Rebai, Tarek

2017-12-01

The aim of this study was to evaluate the anti-inflammatory activity of Teucrium polium (TP). Rats were divided into four groups: group 1 controls received standard diet; group 2 inflamed by carrageenan (Carr) (1% Carr); group 3 as reference inflamed with Carr and treated with Indometacine (Ind) (150 mg/kg bw) and group 4 inflamed with Carr and pre0treated with TP (5 g/L). Oedema volume was measured 1 h to 5 h after injection. Administration of TP or Ind decreased the levels of hematology parameters relative to Carr and reduced the volume of rats induced by Carr. TP reduced levels of CRP, fibrinogen compared to treated, a decrease in oxidative stress (LP) and AOPP with an increase in the levels of SOD, CAT, GPx and Vit C in skin and erythrocytes. Carr increased the levels of lipid peroxidation and decreased levels of antioxidant enzymatic and Vit C. Our results were confirmed by histological sections of skin.

Phloretin differentially inhibits volume-sensitive and cyclic AMP-activated, but not Ca-activated, Cl− channels

PubMed Central

Fan, Hai-Tian; Morishima, Shigeru; Kida, Hajime; Okada, Yasunobu

2001-01-01

Some phenol derivatives are known to block volume-sensitive Cl− channels. However, effects on the channel of the bisphenol phloretin, which is a known blocker of glucose uniport and anion antiport, have not been examined. In the present study, we investigated the effects of phloretin on volume-sensitive Cl− channels in comparison with cyclic AMP-activated CFTR Cl− channels and Ca2+-activated Cl− channels using the whole-cell patch-clamp technique.Extracellular application of phloretin (over 10 μM) voltage-independently, and in a concentration-dependent manner (IC50 ∼30 μM), inhibited the Cl− current activated by a hypotonic challenge in human epithelial T84, Intestine 407 cells and mouse mammary C127/CFTR cells.In contrast, at 30 μM phloretin failed to inhibit cyclic AMP-activated Cl− currents in T84 and C127/CFTR cells. Higher concentrations (over 100 μM) of phloretin, however, partially inhibited the CFTR Cl− currents in a voltage-dependent manner.At 30 and 300 μM, phloretin showed no inhibitory effect on Ca2+-dependent Cl− currents induced by ionomycin in T84 cells.It is concluded that phloretin preferentially blocks volume-sensitive Cl− channels at low concentrations (below 100 μM) and also inhibits cyclic AMP-activated Cl− channels at higher concentrations, whereas phloretin does not inhibit Ca2+-activated Cl− channels in epithelial cells. PMID:11487521

Analysis of the Spatio-Temporal Evolution of the Rockfalls in the Crater of Piton de la Fournaise Volcano, La Réunion, and their Link with the Eruptive Activity

NASA Astrophysics Data System (ADS)

Durand, V.; Mangeney, A.; Hibert, C.; Haas, F.; Peltier, A.; Kowalski, P.; Lauret, F.; Brunet, C.; Delorme, A.; Wegner, K.; Satriano, C.; Bonilla, L. F.; Aissaoui, E. M.; Protin, A.

2017-12-01

The seismic and photogrammetric networks of the Piton de la Fournaise volcano (La Réunion Island) are very well appropriate to study seismic signals generated by rockfalls in the Dolomieu crater. In particular, seismic data make it possible to precisely locate the rockfalls and recover the volume of each rockfall. Rockfall locations and volumes are validated comparing them to the ones obtained using photogrammetric data. We thus obtain an accurate catalog of 5802 rockfalls over the 2014-2016 period. This period is especially active, with 7 eruptions, after a break of 4 years. The analysis of the catalog reveals that the recovery of the eruptive activity unsettles the crater edges, increasing the average volume of the rockfalls. It also highlights that rain and seismicity could increase the volume of individual rockfalls. However, it seems that the pre-eruptive seismicity is the main triggering factor for larger volumes, with a delay of several days. We infer that the repetitive vibrations due to the high number of seismic events induce a cyclic fatigue of the material, leading to the collapse of large volumes. To better understand and discriminate the influence of seismicity and rainfall on the rockfall volumes, we investigate in the same way the transition period, from 2010 to 2014, during which there is no eruption. Finally, we show that before an eruption, the largest rockfalls tend to migrate towards the location of the eruption.

Sb lattice diffusion in Si1-xGex/Si(001) heterostructures: Chemical and stress effects

NASA Astrophysics Data System (ADS)

Portavoce, A.; Gas, P.; Berbezier, I.; Ronda, A.; Christensen, J. S.; Kuznetsov, A. Yu.; Svensson, B. G.

2004-04-01

The Sb diffusion coefficient in Si1-xGex/Si1-yGey(001) heterostructures grown by molecular beam epitaxy (MBE) was measured for temperatures ranging from 700 to 850 °C, Ge composition from 0 to 20 % and biaxial pressure from -0.8 (tension) to 1.4 GPa (compression). A quantitative separation of composition and biaxial stress effects is made. We show that the Sb lattice diffusion coefficient: (i) increases with Ge concentration in relaxed layers or at constant biaxial pressure and (ii) increases with compressive biaxial stress and decreases with tensile biaxial stress at constant Ge composition. The enhancement of Sb lattice diffusion in Si1-xGex layers in epitaxy on Si(001) is thus due to the cooperative effect of Ge composition and induced compressive biaxial stress. However, the first effect (composition) is predominant. The activation volume of Sb diffusion in Si1-xGex layers is deduced from the variation of the Sb diffusion coefficients with biaxial pressure. This volume is negative. The sign of the activation volume, its absolute value and its variation with temperature confirm the prediction of the thermodynamic model proposed by Aziz, namely, that under a biaxial stress the activation volume is reduced to the relaxation volume.

Protective role of zinc against the neurotoxicity induced by exposure to cadmium during gestation and lactation periods on hippocampal volume of pups tested in early adulthood.

PubMed

Ben Mimouna, Safa; Chemek, Marouane; Boughammoura, Sana; Haouas, Zohra; Messaoudi, Imed

2018-05-03

The present study was conducted to assess the possible effect of cadmium (Cd) throughout gestation and lactation on the volume of the subregion of the hippocampus as well as the potential protective role of zinc (Zn) against Cd neurotoxicity. For this purpose, female rats received either tap water, Cd, Zn or Cd + Zn in their drinking water during gestation and lactation. At postnatal day 35 (PND35), the male pups were sacrificed, and their brains were taken for histologic, chemical, and biochemical analysis. Hippocampal volume was measured in histologic brain slices using Cavalieri's principle. Zn depletion was observed in the brains of pups issued from mothers exposed to Cd. Biochemical analysis further revealed that Cd exposure significantly increases the superoxide dismutase (SOD) activity, as well as the metallothionein (MT) level. During histologic investigation, our results showed that gestational and lactational exposure to Cd significantly altered and decreased the volume of CA1, CA3 pyramidal cell layer and the dentate gyrus. However, there were no marked differences shown in CA2 subfield. Compared to Cd group, co-treatment with Cd and Zn provided correction of the changes induced by the Cd exposure. These results highlight the protective role of Zn against Cd-induced alteration in the hippocampus which is a crucial structure implicated in learning and memory processes.

One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons.

PubMed

Gerbaix, Maude; Gnyubkin, Vasily; Farlay, Delphine; Olivier, Cécile; Ammann, Patrick; Courbon, Guillaume; Laroche, Norbert; Genthial, Rachel; Follet, Hélène; Peyrin, Françoise; Shenkman, Boris; Gauquelin-Koch, Guillemette; Vico, Laurence

2017-06-01

The weightless environment during spaceflight induces site-specific bone loss. The 30-day Bion-M1 mission offered a unique opportunity to characterize the skeletal changes after spaceflight and an 8-day recovery period in mature male C57/BL6 mice. In the femur metaphysis, spaceflight decreased the trabecular bone volume (-64% vs. Habitat Control), dramatically increased the bone resorption (+140% vs. Habitat Control) and induced marrow adiposity invasion. At the diaphysis, cortical thinning associated with periosteal resorption was observed. In the Flight animal group, the osteocyte lacunae displayed a reduced volume and a more spherical shape (synchrotron radiation analyses), and empty lacunae were highly increased (+344% vs. Habitat Control). Tissue-level mechanical cortical properties (i.e., hardness and modulus) were locally decreased by spaceflight, whereas the mineral characteristics and collagen maturity were unaffected. In the vertebrae, spaceflight decreased the overall bone volume and altered the modulus in the periphery of the trabecular struts. Despite normalized osteoclastic activity and an increased osteoblast number, bone recovery was not observed 8 days after landing. In conclusion, spaceflight induces osteocyte death, which may trigger bone resorption and result in bone mass and microstructural deterioration. Moreover, osteocyte cell death, lacunae mineralization and fatty marrow, which are hallmarks of ageing, may impede tissue maintenance and repair.

Gastroprotective activity of alkaloid extract and 2-phenylquinoline obtained from the bark of Galipea longiflora Krause (Rutaceae).

PubMed

Zanatta, Francielle; Gandolfi, Renan Becker; Lemos, Marivane; Ticona, Juan Carlos; Gimenez, Alberto; Clasen, Bruna Kurz; Cechinel Filho, Valdir; de Andrade, Sérgio Faloni

2009-07-15

As part of our continuing search for bioactive natural products from plants, the present study was carried out in order to evaluate the gastroprotective properties of alkaloid extract and 2-phenylquinoline obtained from the bark of Galipea longiflora (Rutaceae). Anti-ulcer assays were performed using the following protocols in mice: nonsteroidal anti-inflammatory drug (NSAID)/bethanecol-induced ulcer, ethanol/HCl-induced ulcer, and stress-induced ulcer. The effects of the extract on gastric content volume, pH and total acidity were also evaluated, using the pylorus ligated model. Treatment using doses of 50, 125 and 250 mg/kg of G. longiflora alkaloid extract and positive controls (omeprazol or cimetidine) significantly diminished the lesion index, total lesion area, and percentage of lesion, in comparison with the negative control groups in all the models evaluated. Regarding the model of gastric secretion, a reduction in volume of gastric juice and total acidity was observed, as well as an increase in gastric pH. The main alkaloid of the plant, 2-phenylquinoline, was also evaluated in the ethanol-induced ulcer model. The results showed that at a dose of 50 mg/kg, it significantly inhibited ulcerative lesions. However, this effect was less than that of the alkaloid extract. All these results taken together show that G. longiflora displays gastroprotective activity, as evidenced by its significant inhibition of the formation of ulcers induced by different models. There are indications that mechanisms involved in anti-ulcer activity are related to a decrease in gastric secretion and an increase in gastric mucus content. Also, there is evidence of involvement of NO in the gastroprotector mechanisms. These effects may be attributed, at least in part, to the presence of some alkaloids, particularly 2-phenylquinoline.

Whole-body fluid distribution in humans during dehydration and recovery, before and after humid-heat acclimation induced using controlled hyperthermia.

PubMed

Patterson, M J; Stocks, J M; Taylor, N A S

2014-04-01

This experiment was designed to test the hypothesis that the plasma volume is not selectively defended during exercise- and heat-induced dehydration following humid-heat acclimation. Eight physically active males were heat acclimated (39.8 °C, relative humidity 59.2%) using 17 days of controlled hyperthermia (core temperature: 38.5 °C). Inter-compartmental fluid losses and movements were tracked (radioisotopes and Evans blue dye) during progressive dehydration (cycling) in these same conditions and also during a resting recovery without fluid replacement (28 °C), before (day 1), during (day 8) and after heat acclimation (day 22). On days 8 and 22, there were significant increases in total body water, interstitial fluid and plasma volume (P < 0.05), but the intracellular compartments did not change (P > 0.05). The baseline plasma volume remained expanded throughout: 43.4 [±2.6 (day 1)], 49.1 [±2.4 (day 8); P < 0.05] and 48.9 mL kg(-1) [±3.0 (day 22); P < 0.05]. During progressive dehydration, plasma reductions of 9.0% (±0.9: day 1), 12.4% (±1.6: day 8) and 13.6% (±1.2: day 22) were observed, with day 8 and 22 losses significantly exceeding day 1 (P < 0.05). During recovery, plasma volume restoration commenced, with the intracellular fluid contribution becoming more pronounced as acclimation progressed. It is concluded that the plasma volume was not defended more vigorously following humid-heat acclimation. Indeed, a greater fluid loss may well underlie the mechanisms for enhancing plasma volume recovery when heat acclimation is induced using the controlled-hyperthermia technique. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Peroxisome proliferator-activated receptor-γ in induced sputum is correlated with MMP-9/TIMP-1 imbalance and formation of emphysema in COPD patients.

PubMed

Zhou, Xiao-Ming; Hou, Gang; Gu, Dong-Xue; Wang, Qiu-Yue; Zhao, Li

2017-10-01

The development of chronic obstructive pulmonary disease (COPD) is modulated by the symmetry of matrix metalloproteinases (MMPs) and the counter-acting tissue inhibitors of metalloproteinases (TIMPs). We investigated the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) expression and the imbalance of MMP-9/TIMP-1 in the induced sputum of stable COPD patients. Sixty-six stable COPD patients were enrolled and the induced sputum samples were gathered. The correlation between PPARγ and other index, including MMP-9, TIMP-1, pulmonary function and the index of emphysema-the percentage of low attenuation area (LAA%), was analyzed. PPARγ and TIMP-1 concentrations were decreased and the concentration of MMP-9 and the ratio of MMP9/TIMP1 were enhanced in the induced sputum of COPD patients, compared to the healthy controls. Among COPD patients, those with worse lung function or patients with emphysema exhibited increased MMP-9 expression with decreased TIMP-1 and PPARγ expression. Besides, the concentration of PPARγ of the induced sputum was correlated with the forced expiratory volume in one second percentage (FEV1%) positively and the expression of TIMP-1; while it was negatively correlated with the residual volume (RV), RV/total lung capacity (TLC), LAA%, and MMP-9 expression. Our findings reveal the protective role of PPARγ in the maintenance of the dynamic balance of MMP-9/TIMP-1 in COPD, thus providing evidence on which to base the potential COPD treatment.

Substance P-induced respiratory excitation is blunted by delta-receptor specific opioids in the rat medulla oblongata.

PubMed

Chen, Z; Hedner, J; Hedner, T

1996-06-01

The effects of substance P (SP) and the naturally occurring met-enkephalin and the synthetic mu-specific opioid agonist, DAGO (Tyr-D-Ala-Gly-N-Methy-Phe-Gly-ol) and the delta-specific opioid agonist DADL (Tyr-D-Ala-Gly-Phe-D-Leu) on basal ventilation were investigated in halothane-anaesthetized rats. Local injections of SP (0.75-1.5 nmol) in the ventrolateral medulla oblongata (VLM), e.g. nucleus paragigantocellularis, and nucleus reticularis lateralis increased ventilation because of an elevation of tidal volume. Met-enkephalin induced a short-lasting ventilatory depression mainly because of a depression of tidal volume. Activation of delta- and mu-opioid receptors in the VLM by local application of DADL and DAGO, respectively, induced ventilatory depression, which was later in onset and more long-lasting. Local administration of met-enkephalin into the VLM also produced a long-lasting inhibition of the SP-induced ventilatory excitation. A similar blockade of the SP-induced excitatory ventilatory response could be elicited by DADL but not by DAGO. This antagonistic effect was attenuated by local application of the delta-opioid receptor antagonist ICI 154. 129. We conclude that the naturally occurring met-enkephalin as well as synthetic mu- and delta-specific enkephalin analogues (DAGO and DADL, respectively) in VLM depress basal ventilation by an effect on inspiratory drive. There is a functional antagonism between activation of delta-opioid receptors and SP receptors into the VLM in respect to respiratory regulation.

The Sponge Pump: The Role of Current Induced Flow in the Design of the Sponge Body Plan

PubMed Central

Leys, Sally P.; Yahel, Gitai; Reidenbach, Matthew A.; Tunnicliffe, Verena; Shavit, Uri; Reiswig, Henry M.

2011-01-01

Sponges are suspension feeders that use flagellated collar-cells (choanocytes) to actively filter a volume of water equivalent to many times their body volume each hour. Flow through sponges is thought to be enhanced by ambient current, which induces a pressure gradient across the sponge wall, but the underlying mechanism is still unknown. Studies of sponge filtration have estimated the energetic cost of pumping to be <1% of its total metabolism implying there is little adaptive value to reducing the cost of pumping by using “passive” flow induced by the ambient current. We quantified the pumping activity and respiration of the glass sponge Aphrocallistes vastus at a 150 m deep reef in situ and in a flow flume; we also modeled the glass sponge filtration system from measurements of the aquiferous system. Excurrent flow from the sponge osculum measured in situ and in the flume were positively correlated (r>0.75) with the ambient current velocity. During short bursts of high ambient current the sponges filtered two-thirds of the total volume of water they processed daily. Our model indicates that the head loss across the sponge collar filter is 10 times higher than previously estimated. The difference is due to the resistance created by a fine protein mesh that lines the collar, which demosponges also have, but was so far overlooked. Applying our model to the in situ measurements indicates that even modest pumping rates require an energetic expenditure of at least 28% of the total in situ respiration. We suggest that due to the high cost of pumping, current-induced flow is highly beneficial but may occur only in thin walled sponges living in high flow environments. Our results call for a new look at the mechanisms underlying current-induced flow and for reevaluation of the cost of biological pumping and its evolutionary role, especially in sponges. PMID:22180779

Double Knockout of the Na+-Driven Cl−/HCO3− Exchanger and Na+/Cl− Cotransporter Induces Hypokalemia and Volume Depletion

PubMed Central

Sinning, Anne; Radionov, Nikita; Trepiccione, Francesco; López-Cayuqueo, Karen I.; Jayat, Maximilien; Baron, Stéphanie; Cornière, Nicolas; Alexander, R. Todd; Hadchouel, Juliette; Eladari, Dominique; Hübner, Christian A.

2017-01-01

We recently described a novel thiazide–sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl−/HCO3− exchanger pendrin and the Na+–driven Cl−/2HCO3− exchanger (NDCBE) in β-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na+ balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na+ balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na+ homeostasis and provide evidence that the Na+/Cl− cotransporter (NCC) compensated for the inactivation of NDCBE. To unmask the role of NDCBE, we generated Ndcbe/Ncc double–knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K+ concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca2+–activated K+ channel BKCa. During NaCl depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCl depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K+ concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients. PMID:27151921

Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells.

PubMed

Meléndez, Giselle C; Li, Jianping; Law, Brittany A; Janicki, Joseph S; Supowit, Scott C; Levick, Scott P

2011-12-01

Substance P and neurokinin A (NKA) are sensory nerve neuropeptides encoded by the TAC1 gene. Substance P is a mast cell secretagogue and mast cells are known to play a role in adverse myocardial remodelling. Therefore, we wondered whether substance P and/or NKA modulates myocardial remodelling via a mast cell-mediated mechanism. Volume overload was induced by aortocaval fistula in TAC1(-/-) mice and their respective wild types. Left ventricular internal diameter of wild-type (WT) fistulas increased by 31.9%; this was prevented in TAC1(-/-) mice (4.2%). Matrix metalloproteinase (MMP) activity was significantly increased in WT fistula mice and was prevented in TAC1(-/-) mice. Myocardial collagen volume fraction was decreased in WT fistula mice; this collagen degradation was not observed in the TAC1(-/-) group. There were no significant differences between any groups in tumour necrosis factor (TNF)-α or cell death. Cardiac mast cells were isolated from rat hearts and stimulated with substance P or NKA. We found that these cells degranulated only to substance P, via the neurokinin-1 receptor. To determine the effect of substance P on mast cells in vivo, volume overload was created in Sprague-Dawley rats treated with the NK-1 receptor antagonist L732138 (5 mg/kg/day) for a period of 3 days. L732138 prevented: (i) increases in cardiac mast cell density; (ii) increased myocardial TNF-α; and (iii) collagen degradation. Our studies suggest that substance P may be important in mediating adverse myocardial remodelling secondary to volume overload by activating cardiac mast cells, leading to increased TNF-α and MMP activation with subsequent degradation of the extracellular matrix.

Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells

PubMed Central

Meléndez, Giselle C.; Li, Jianping; Law, Brittany A.; Janicki, Joseph S.; Supowit, Scott C.; Levick, Scott P.

2011-01-01

Aims Substance P and neurokinin A (NKA) are sensory nerve neuropeptides encoded by the TAC1 gene. Substance P is a mast cell secretagogue and mast cells are known to play a role in adverse myocardial remodelling. Therefore, we wondered whether substance P and/or NKA modulates myocardial remodelling via a mast cell-mediated mechanism. Methods and results Volume overload was induced by aortocaval fistula in TAC1−/− mice and their respective wild types. Left ventricular internal diameter of wild-type (WT) fistulas increased by 31.9%; this was prevented in TAC1−/− mice (4.2%). Matrix metalloproteinase (MMP) activity was significantly increased in WT fistula mice and was prevented in TAC1−/− mice. Myocardial collagen volume fraction was decreased in WT fistula mice; this collagen degradation was not observed in the TAC1−/− group. There were no significant differences between any groups in tumour necrosis factor (TNF)-α or cell death. Cardiac mast cells were isolated from rat hearts and stimulated with substance P or NKA. We found that these cells degranulated only to substance P, via the neurokinin-1 receptor. To determine the effect of substance P on mast cells in vivo, volume overload was created in Sprague-Dawley rats treated with the NK-1 receptor antagonist L732138 (5 mg/kg/day) for a period of 3 days. L732138 prevented: (i) increases in cardiac mast cell density; (ii) increased myocardial TNF-α; and (iii) collagen degradation. Conclusions Our studies suggest that substance P may be important in mediating adverse myocardial remodelling secondary to volume overload by activating cardiac mast cells, leading to increased TNF-α and MMP activation with subsequent degradation of the extracellular matrix. PMID:21908647

Double Knockout of the Na+-Driven Cl-/HCO3- Exchanger and Na+/Cl- Cotransporter Induces Hypokalemia and Volume Depletion.

PubMed

Sinning, Anne; Radionov, Nikita; Trepiccione, Francesco; López-Cayuqueo, Karen I; Jayat, Maximilien; Baron, Stéphanie; Cornière, Nicolas; Alexander, R Todd; Hadchouel, Juliette; Eladari, Dominique; Hübner, Christian A; Chambrey, Régine

2017-01-01

We recently described a novel thiazide-sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl - /HCO 3 - exchanger pendrin and the Na + -driven Cl - /2HCO 3 - exchanger (NDCBE) in β-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na + balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na + balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na + homeostasis and provide evidence that the Na + /Cl - cotransporter (NCC) compensated for the inactivation of NDCBE. To unmask the role of NDCBE, we generated Ndcbe/Ncc double-knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K + concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca 2+ -activated K + channel BKCa. During NaCl depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCl depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K + concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients. Copyright © 2016 by the American Society of Nephrology.

Etanercept Promotes Bone Formation via Suppression of Dickkopf-1 Expression in Rats with Collagen-Induced Arthritis

PubMed Central

Tanida, Atsushi; Kishimoto, Yuji; Okano, Toru; Hagino, Hiroshi

2013-01-01

Background Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA). Methods Total RNA was extracted from knee joints with CIA after ETN or placebo administration. Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1, Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis, the infiltrating pannus volume and pannus surface, and the following items in contact with pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling surface. These were evaluated in the distal femur with CIA with or without ETN administration. Results TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not significantly different with or without ETN administration. ETN administration significantly increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression, the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and osteoclast number, parameters of bone destruction, were not significantly different among groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation, increased significantly with ETN administration. Conclusion Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression is promoted and osteoblastogenesis becomes more active, independent of the regulation of osteoclast activity. Marked bone formation is attributed to the fact that ETN directly promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis. PMID:24031147

Experimental prestorage filtration removes antibodies and decreases lipids in RBC supernatants mitigating TRALI in vivo

PubMed Central

Kelher, Marguerite R.; Khan, Samina Y.; LaSarre, Monica; West, F. Bernadette; Land, Kevin J.; Mish, Barbara; Ceriano, Linda; Sowemimo-Coker, Samuel

2014-01-01

Transfusion-related acute lung injury (TRALI) remains a significant cause of transfusion-related mortality with red cell transfusion. We hypothesize that prestorage filtration may reduce proinflammatory activity in the red blood cell (RBC) supernatant and prevent TRALI. Filters were manufactured for both small volumes and RBC units. Plasma containing antibodies to human lymphocyte antigen (HLA)-A2 or human neutrophil antigen (HNA)-3a was filtered, and immunoglobulins and specific HNA-3a and HLA-2a neutrophil (PMN) priming activity were measured. Antibodies to OX27 were added to plasma, and filtration was evaluated in a 2-event animal model of TRALI. RBC units from 31 donors known to have antibodies against HLA antigens and from 16 antibody-negative controls were filtered. Furthermore, 4 RBC units were drawn and underwent standard leukoreduction. Immunoglobulins, HLA antibodies, PMN priming activity, and the ability to induce TRALI in an animal model were measured. Small-volume filtration of plasma removed >96% of IgG, antibodies to HLA-A2 and HNA-3a, and their respective priming activity, as well as mitigating antibody-mediated in vivo TRALI. In RBC units, experimental filtration removed antibodies to HLA antigens and inhibited the accumulation of lipid priming activity and lipid-mediated TRALI. We conclude that filtration removes proinflammatory activity and the ability to induce TRALI from RBCs and may represent a TRALI mitigation step. PMID:24747436

Anti-Inflammatory Effects of a Stauntonia hexaphylla Fruit Extract in Lipopolysaccharide-Activated RAW-264.7 Macrophages and Rats by Carrageenan-Induced Hind Paw Swelling

PubMed Central

Kim, Jaeyong; Kim, Heesook; Choi, Hakjoon; Jo, Ara; Kang, Huwon; Yun, Hyojeong; Im, Sojeong; Choi, Chulyung

2018-01-01

The fruit of Stauntonia hexaphylla is commonly used as a traditional anthelmintic in Korea, Japan, and China. However, its anti-inflammatory activity and the underlying mechanisms have not been studied systematically. In the present study, we examined the anti-inflammatory activities of an aqueous extract of S. hexaphylla fruit (SHF) in lipopolysaccharide (LPS)-activated RAW 264.7 cells. The SHF extract contained anti-inflammatory compounds, such as neochlorogenic acid, chlorogenic acid, and cryptochlorogenic acid. The extract inhibited protein levels of inducible nitric oxide synthase and the activity of cyclooxygenase enzyme, with concomitant reductions in the production of nitric oxide and prostaglandin E2 in LPS-activated RAW 264.7 cells. Additionally, the SHF extract reduced the production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. The SHF extract attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing the phosphorylation of its inhibitor, IκBα. Furthermore, the SHF extract showed a significant anti-inflammatory effect in vivo by reducing the volume of carrageenan-induced paw edema in rats. Our results suggest that the SHF extract exerts potential anti-inflammatory properties against LPS-activated RAW 254.7 cells, and in an animal model of inflammation. PMID:29361789

Anti-Inflammatory Effects of a Stauntonia hexaphylla Fruit Extract in Lipopolysaccharide-Activated RAW-264.7 Macrophages and Rats by Carrageenan-Induced Hind Paw Swelling.

PubMed

Kim, Jaeyong; Kim, Heesook; Choi, Hakjoon; Jo, Ara; Kang, Huwon; Yun, Hyojeong; Im, Sojeong; Choi, Chulyung

2018-01-22

The fruit of Stauntonia hexaphylla is commonly used as a traditional anthelmintic in Korea, Japan, and China. However, its anti-inflammatory activity and the underlying mechanisms have not been studied systematically. In the present study, we examined the anti-inflammatory activities of an aqueous extract of S. hexaphylla fruit (SHF) in lipopolysaccharide (LPS)-activated RAW 264.7 cells. The SHF extract contained anti-inflammatory compounds, such as neochlorogenic acid, chlorogenic acid, and cryptochlorogenic acid. The extract inhibited protein levels of inducible nitric oxide synthase and the activity of cyclooxygenase enzyme, with concomitant reductions in the production of nitric oxide and prostaglandin E₂ in LPS-activated RAW 264.7 cells. Additionally, the SHF extract reduced the production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. The SHF extract attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing the phosphorylation of its inhibitor, IκBα. Furthermore, the SHF extract showed a significant anti-inflammatory effect in vivo by reducing the volume of carrageenan-induced paw edema in rats. Our results suggest that the SHF extract exerts potential anti-inflammatory properties against LPS-activated RAW 254.7 cells, and in an animal model of inflammation.

Morphologic changes of the nasal cavity induced by rapid maxillary expansion: a study on 3-dimensional computed tomography models.

PubMed

Haralambidis, Adam; Ari-Demirkaya, Arzu; Acar, Ahu; Küçükkeleş, Nazan; Ateş, Mustafa; Ozkaya, Selin

2009-12-01

The aim of this study was to evaluate the effect of rapid maxillary expansion on the volume of the nasal cavity by using computed tomography. The sample consisted of 24 patients (10 boys, 14 girls) in the permanent dentition who had maxillary constriction and bilateral posterior crossbite. Ten patients had skeletal Class I and 14 had Class II relationships. Skeletal maturity was assessed with the modified cervical vertebral maturation method. Computed tomograms were taken before expansion and at the end of the 3-month retention period, after active expansion. The tomograms were analyzed by Mimics software (version 10.11, Materialise Medical Co, Leuven, Belgium) to reconstruct 3-dimensional images and calculate the volume of the nasal cavities before and after expansion. A significant (P = 0.000) average increase of 11.3% in nasal volume was found. Sex, growth, and skeletal relationship did not influence measurements or response to treatment. A significant difference was found in the volume increase between the Class I and Class II patients, but it was attributed to the longer expansion period of the latter. Therefore, rapid maxillary expansion induces a significant average increase of the nasal volume and consequently can increase nasal permeability and establish a predominant nasal respiration pattern.

Biological Bases for Radiation Adaptive Responses in the Lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scott, Bobby R.; Lin, Yong; Wilder, Julie

2015-03-01

Our main research objective was to determine the biological bases for low-dose, radiation-induced adaptive responses in the lung, and use the knowledge gained to produce an improved risk model for radiation-induced lung cancer that accounts for activated natural protection, genetic influences, and the role of epigenetic regulation (epiregulation). Currently, low-dose radiation risk assessment is based on the linear-no-threshold hypothesis, which now is known to be unsupported by a large volume of data.

Phase transformation and sustained load crack growth in ZrO[sub 2] + 3 mol% Y[sub 2]O[sub 3]: Experiments and kinetic modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, H.; Gao, M.; Wei, R.P.

1995-01-01

To better understand environmentally assisted crack growth (SCG) in yttria stabilized zirconia, experimental studies were undertaken to characterize the kinetics of crack growth and the associated stress/moisture induced phase transformation in ZrO[sub 2] + 3 mol% Y[sub 2]O[sub 3] (3Y-TZP) in water, dry nitrogen and toluene from 3 to 70 C. The results showed that crack growth in water depended strongly on stress intensity factor (K[sub 1]) and temperature (T) and involved the transformation of a thin layer of material near the crack tip from the tetragonal (t) to the monoclinic (m) phase. These results, combined with literature data onmore » moisture-induced phase transformation, suggested that crack growth enhancement by water is controlled by the rate of this transformation and reflects the environmental cracking susceptibility of the transformed m-phase. A model was developed to link subcritical crack growth (SCG) rate to the kinetics of t [yields] m phase transformation. The SCG rate is expressed as an exponential function of stress-free activation energy, a stress-dependent contribution in terms of the mode 1 stress intensity factor K[sub I] and actuation volume, and temperature. The stress-free activation energies for water and the inert environments were determined to be 82 [+-] 3 and 169 [+-] 4 kJ/mol, respectively, at the 95% confidence level, and the corresponding activation volumes were 14 and 35 unit cells. The decreases in activation energy and activation volume may be attributed to a change in surface energy by water.« less

Regional blood flow volume in the eustachian tube.

PubMed

Minami, T; Kubo, N; Tomoda, K; Yamashita, T; Kumazawa, T

1993-01-01

Measurements of regional blood flow around the pharyngeal orifice of the Eustachian tube were carried out after topical administration of various inflammatory mediators in 14 mongrel dogs by the hydrogen clearance method. Histamine and platelet-activating factor (PAF) resulted in a significant alteration of blood flow volume. Histamine was found to induce a dose-response related increase, whereas blood flow volume tended to decrease in each concentration range in the series of PAF administration. There was no significant difference in blood flow between topical application of leukotriene C4 and leukotriene D4. It is likely that in upper respiratory tract inflammation, such as in otitis media and in nasal allergy, activated histamine and PAF affect the microcirculation of the tubal orifice. These results suggest that disturbance of the microcirculatory system in the Eustachian tube mucosa could be involved in the pathogenesis of chronic otitis media with effusion.

Antidiarrheal and antinociceptive activities of ethanol extract and its chloroform and pet ether fraction of Phrynium imbricatum (Roxb.) leaves in mice.

PubMed

Hossain, Mohammed Munawar; Kabir, Mohammad Shah Hafez; Dinar, Md Abu Monsur; Arman, Md Saiful Islam; Rahman, Md Mominur; Hosen, S M Zahid; Dash, Raju; Uddin, Mir Muhammad Nasir

2017-09-26

The objective of the study was to evaluate the antidiarrheal and antinociceptive activities of ethanol extract and its chloroform and pet ether fraction of Phrynium imbricatum (Roxb.) leaves in mice. In the present study, the dried leaves of P. imbricatum were subjected to extraction with ethanol, and then it was fractioned by chloroform and pet ether solvent. Antidiarrheal effects were tested by using castor oil-induced diarrhea, castor oil-induced enteropooling, and gastrointestinal transit test. Antinociceptive activity was evaluated by using the acetic acid-induced writhing test and formalin-induced paw licking test. The standard drug loperamide (5 mg/kg) showed significant (p<0.001) inhibitory activity against castor oil-induced diarrhea, in which all the examined treatments decreased the frequency of defecation and were found to possess an anti-castor oil-induced enteropooling effect in mice by reducing both weight and volume of intestinal content significantly, and reducing the propulsive movement in castor oil-induced gastrointestinal transit using charcoal meal in mice. The results showed that the ethanol extract of P. imbricatum leaves has significant dose-dependent antinociceptive activity, and among its two different fractions, the pet ether fraction significantly inhibited the abdominal writhing induced by acetic acid and the licking times in formalin test at both phases. These findings suggest that the plant may be a potential source for the development of a new antinociceptive drug and slightly suitable for diarrhea, as it exhibited lower activity. Our observations resemble previously published data on P. imbricatum leaves.

Role of isothiocyanate conjugate of pterostilbene on the inhibition of MCF-7 cell proliferation and tumor growth in Ehrlich ascitic cell induced tumor bearing mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta

2014-01-15

Naturally occurring pterostilbene (PTER) and isothiocyanate (ITC) attract great attention due to their wide range of biological properties, including anti-cancer, anti-leukemic, anti-bacterial and anti-inflammatory activities. A novel class of hybrid compound synthesized by introducing an ITC moiety on PTER backbone was evaluated for its anti-cancer efficacy in hormone-dependent breast cancer cell line (MCF-7) in vitro and Ehrlich ascitic tumor bearing mice model in vivo. The novel hybrid molecule showed significant in vitro anti-cancer activity (IC{sub 50}=25±0.38) when compared to reference compound PTER (IC{sub 50}=65±0.42). The conjugate molecule induced both S and G2/M phase cell cycle arrest as indicated by flowmore » cytometry analysis. In addition, the conjugate induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-9, release of cytochrome-c into cytosol and increased Bax: Bcl-2 ratio. The conjugate also suppressed the phosphorylation of Akt and ERK. The conjugate induced cell death was significantly increased in presence of A6730 (a potent Akt1/2 kinase inhibitor) and PD98059 (a specific ERK inhibitor). Moreover, the conjugated PTER inhibited tumor growth in Ehrlich ascitic cell induced tumor bearing mice as observed by reduction in tumor volume compared to untreated animals. Collectively, the pro-apoptotic effect of conjugate is mediated through the activation of caspases, and is correlated with the blockade of the Akt and ERK signaling pathways in MCF-7 cells. - Highlights: • Conjugate was prepared by appending isothiocyanate moiety on pterostilbene backbone. • Conjugate showed anticancer effects at comparatively lower dose than pterostilbene. • Conjugate caused blockage of the Akt and ERK signaling pathways in MCF-7 cells. • Conjugate significantly reduced solid tumor volume as compared to pterostilbene.« less

Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres.

PubMed

Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

2015-09-01

Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock-induced CS is accompanied by a small membrane depolarization responsible for a release of Ca(2+) from intracellular pools. Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK). TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca(2+) response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function. We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca(2+) release from the sarcoplasmic reticulum, activation of the Na(+) -K(+) -Cl(-) cotransporter by SPAK, and the RVI response. Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca(2+) from intracellular pools. We observed that both hyperosmotic shock-induced Ca(2+) transients and RVI were inhibited by Gd(3+) , ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca(2+) induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca(2+) from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na(+) -K(+) -Cl(-) cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca(2+) transients were abolished by the Ca(2+) chelator BAPTA, the level of P-SPAK(Ser373) in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca(2+) . We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Antidiarrhoeal activity of leaf methanolic extract of Rauwolfia serpentina.

PubMed

Ezeigbo, I I; Ezeja, M I; Madubuike, K G; Ifenkwe, D C; Ukweni, I A; Udeh, N E; Akomas, S C

2012-06-01

To evaluate the antidiarrhoeal property of methanol extract of the leaves of Rauwolfia serpentina (R. serpentina) in experimental diarrhoea induced by castor oil in mice. Doses of 100, 200 and 400 mg/kg R. serpentina leaf methanol extracts were administered to castor oil induced diarrhoea mice to determine its antidiarrhoeal activity. All doses of the extract and the reference drug atropine sulphate (3 mg/kg, i.p.) produced a dose-dependent reduction in intestinal weight and fluid volume. The extracts also significantly reduced the intestinal transit in charcoal meal test when compared to diphenoxylate Hcl (5 mg/kg, p.o.). The results show that the extract of R. serpentina leaves has a significant antidiarrhoeal activity and supports its traditional uses in herbal medicine.

Role of GPR30 in estrogen-induced prostate epithelial apoptosis and benign prostatic hyperplasia.

PubMed

Yang, Deng-Liang; Xu, Jia-Wen; Zhu, Jian-Guo; Zhang, Yi-Lin; Xu, Jian-Bang; Sun, Qing; Cao, Xiao-Nian; Zuo, Wu-Lin; Xu, Ruo-Shui; Huang, Jie-Hong; Jiang, Fu-Neng; Zhuo, Yang-Jia; Xiao, Bai-Quan; Liu, Yun-Zhong; Yuan, Dong-Bo; Sun, Zhao-Lin; He, Hui-Chan; Lun, Zhao-Rong; Zhong, Wei-De; Zhou, Wen-Liang

2017-06-03

Several studies have implicated estrogen and the estrogen receptor (ER) in the pathogenesis of benign prostatic hyperplasia (BPH); however, the mechanism underlying this effect remains elusive. In the present study, we demonstrated that estrogen (17β-estradiol, or E2)-induced activation of the G protein-coupled receptor 30 (GPR30) triggered Ca 2+ release from the endoplasmic reticulum, increased the mitochondrial Ca 2+ concentration, and thus induced prostate epithelial cell (PEC) apoptosis. Both E2 and the GPR30-specific agonist G1 induced a transient intracellular Ca 2+ release in PECs via the phospholipase C (PLC)-inositol 1, 4, 5-triphosphate (IP 3 ) pathway, and this was abolished by treatment with the GPR30 antagonist G15. The release of cytochrome c and activation of caspase-3 in response to GPR30 activation were observed. Data generated from the analysis of animal models and human clinical samples indicate that treatment with the GPR30 agonist relieves testosterone propionate (TP)-induced prostatic epithelial hyperplasia, and that the abundance of GPR30 is negatively associated with prostate volume. On the basis of these results, we propose a novel regulatory mechanism whereby estrogen induces the apoptosis of PECs via GPR30 activation. Inhibition of this activation is predicted to lead to abnormal PEC accumulation, and to thereby contribute to BPH pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Modulation of induced gamma band activity in the human EEG by attention and visual information processing.

PubMed

Müller, M M; Gruber, T; Keil, A

2000-12-01

Here we present a series of four studies aimed to investigate the link between induced gamma band activity in the human EEG and visual information processing. We demonstrated and validated the modulation of spectral gamma band power by spatial selective visual attention. When subjects attended to a certain stimulus, spectral power was increased as compared to when the same stimulus was ignored. In addition, we showed a shift in spectral gamma band power increase to the contralateral hemisphere when subjects shifted their attention to one visual hemifield. The following study investigated induced gamma band activity and the perception of a Gestalt. Ambiguous rotating figures were used to operationalize the law of good figure (gute Gestalt). We found increased gamma band power at posterior electrode sites when subjects perceived an object. In the last experiment we demonstrated a differential hemispheric gamma band activation when subjects were confronted with emotional pictures. Results of the present experiments in combination with other studies presented in this volume are supportive for the notion that induced gamma band activity in the human EEG is closely related to visual information processing and attentional perceptual mechanisms.

Sodium chloride-induced volume changes of freshwater cyanobacterium Synechococcus sp. PCC 7942 cells can be probed by chlorophyll a fluorescence.

PubMed

Stamatakis, K; Ladas, N P; Alygizaki-Zorba, A; Papageorgiou, G C

1999-10-15

Freshwater species of the cyanobacterial genus Synechococcus import NaCl passively, and export Na(+) actively, by means of primary and secondary extrusion mechanisms. As a result of the ion and water fluxes, cell volumes are enlarged. We show in this paper that the NaCl-induced volume enlargement of Synechococcus sp. PCC 7942 cells is attended by a rapid (k = 0.39 s(-1)) increase in chlorophyll (Chl) a fluorescence. The cell turgor threshold (measured by osmotic titration of Chl a fluorescence) was lower in the absence of NaCl (0.195 Osm kg(-1)) than in the presence of 0.4 M NaCl (0.248 Osm kg(-1)) indicating NaCl uptake by the cells. Turgor thresholds of cells suspended in NaCl-containing medium were enlarged further by protonophoric uncouplers, P-type ATPase inhibitors, and light starvation, conditions that are known to interfere with the active extrusion of Na(+) ions. Cell swelling exerts probably a regulation on the distribution of phycobilisome (PBS) excitation between photosystem II (fluorescent Chl a) and photosystem I (nonfluorescent Chl a), since it affects PBS-sensitized Chl a fluorescence, but not directly excited Chl a fluorescence. The dependence of the Chl a fluorescence of cyanobacteria on cell volumes allows probing of bioenergetic phenomena that are related to dynamic osmotic volume changes, transmembrane solute and water fluxes, plasma membrane permeabilities, and internal osmotic conditions of cyanobacterial cells. Thus, cyanobacteria may serve as quite convenient models of aquatic microorganisms in experimental studies directed toward the elucidation of perception mechanisms and defense mechanisms of water and solute stresses. Copyright 1999 Academic Press.

Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

PubMed

Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J; Stoltz, David A; Zabner, Joseph; Comellas, Alejandro P

2017-12-01

To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. Prospective laboratory animal investigation. Animal research laboratory. Newborn and 3 days to 1 week old pigs. Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload. Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor. Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema.

Gastroprotective Effect of Freeze Dried Stripped Snakehead Fish (Channa striata Bloch.) Aqueous Extract against Aspirin Induced Ulcerogenesis in Pylorus Ligated Rats.

PubMed

Ali Khan, Mohammed Safwan; Mat Jais, Abdul Manan; Hussain, Javeed; Siddiqua, Faiza; Gopala Reddy, A; Shivakumar, P; Madhuri, D

2014-01-01

Channa striata (Bloch.) is a fresh water fish belonging to the family Channidae. The stripped snakehead fish possesses wide range of medicinal properties. In view of traditional use of C. striata for wound healing, the present study was undertaken to investigate the beneficial effects of orally administered freeze dried aqueous extract of Channa striata (AECS) in experimentally induced gastric ulcers in Wistar rats. Aspirin induced ulcerogenesis in pyloric ligation model was used for the assessment of antiulcer activity and Ranitidine (50 mg/kg) was employed as the standard drug. The various gastric parameters like volume of gastric juice, pH, free and total acidities, ulcer index, and levels of antioxidant enzymes like catalase, superoxide dismutase, and lipid peroxidation marker malondialdehyde were determined. AECS at concentrations of 40% and 50% w/v significantly decreased the volume of gastric juice and increased the levels of catalase while considerable decrease in free and total acidities and increase in superoxide dismutase were observed with the treatment of standard drug and AECS (50% w/v). All the test doses of AECS markedly decreased ulcer index and malondialdehyde compared to the standard drug whereas AECS 30% w/v did not alter volume of gastric juice, pH, free and total acidities, catalase, and superoxide dismutase. From these findings, it can be concluded that AECS is devoid of acid neutralizing effects at lower doses and possesses antisecretory and antiulcer activities and this could be related to its antioxidant mechanism.

Effect of azathioprine on Na(+)/H(+) exchanger activity in dendritic cells.

PubMed

Bhandaru, Madhuri; Pasham, Venkanna; Yang, Wenting; Bobbala, Diwakar; Rotte, Anand; Lang, Florian

2012-01-01

Azathioprine is a powerful immunosuppressive drug, which is partially effective by interfering with the maturation and function of dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. DCs are stimulated by bacterial lipopolysaccharides (LPS), which trigger the formation of reactive oxygen species (ROS), paralleled by activation of the Na(+)/H(+) exchanger. The carrier is involved in the regulation of cytosolic pH, cell volume and migration. The present study explored whether azathioprine influences Na(+)/H(+) exchanger activity in DCs. DCs were isolated from murine bone marrow, cytosolic pH (pH(i)) was estimated utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF-AM) fluorescence, Na(+)/H(+) exchanger activity from the Na(+)-dependent realkalinization following an ammonium pulse, cell volume from forward scatter in FACS analysis, ROS production from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, TNFα release utilizing ELISA, and migration utilizing transwell migration assays. Exposure of DCs to lipopolysaccharide (LPS, 1 μg/ml) led to a transient increase of Na(+)/H(+) exchanger activity, an effect paralleled by ROS formation, increased cell volume, TNFα production and stimulated migration. Azathioprine (10 μM) did not significantly alter the Na(+)/H(+) exchanger activity, cell volume and ROS formation prior to LPS exposure but significantly blunted the LPS-induced stimulation of Na(+)/H(+) exchanger activity, ROS formation, cell swelling, TNFα production and cell migration. In conclusion, azathioprine interferes with the activation of dendritic cell Na(+)/H(+) exchanger by bacterial lipopolysaccharides, an effect likely participating in the anti-inflammatory action of the drug. Copyright © 2012 S. Karger AG, Basel.

Eating meals before wheel-running exercise attenuate high fat diet-driven obesity in mice under two meals per day schedule.

PubMed

Sasaki, Hiroyuki; Hattori, Yuta; Ikeda, Yuko; Kamagata, Mayo; Shibata, Shigenobu

2015-06-01

Mice that exercise after meals gain less body weight and visceral fat compared to those that exercised before meals under a one meal/exercise time per day schedule. Humans generally eat two or three meals per day, and rarely have only one meal. To extend our previous observations, we examined here whether a "two meals, two exercise sessions per day" schedule was optimal in terms of maintaining a healthy body weight. In this experiment, "morning" refers to the beginning of the active phase (the "morning" for nocturnal animals). We found that 2-h feeding before 2-h exercise in the morning and evening (F-Ex/F-Ex) resulted in greater attenuation of high fat diet (HFD)-induced weight gain compared to other combinations of feeding and exercise under two daily meals and two daily exercise periods. There were no significant differences in total food intake and total wheel counts, but feeding before exercise in the morning groups (F-Ex/F-Ex and F-Ex/Ex-F) increased the morning wheel counts. These results suggest that habitual exercise after feeding in the morning and evening is more effective for preventing HFD-induced weight gain. We also determined whether there were any correlations between food intake, wheel rotation, visceral fat volume and skeletal muscle volumes. We found positive associations between gastrocnemius muscle volumes and morning wheel counts, as well as negative associations between morning food intake volumes/body weight and morning wheel counts. These results suggest that morning exercise-induced increase of muscle volume may refer to anti-obesity. Evening exercise is negatively associated with fat volume increases, suggesting that this practice may counteract fat deposition. Our multifactorial analysis revealed that morning food intake helps to increase exercise, and that evening exercise reduced fat volumes. Thus, exercise in the morning or evening is important for preventing the onset of obesity.

Pharmacologic Suppression of Inflammation by a Diphenyldifluoroketone, EF24, in a Rat Model of Fixed-Volume Hemorrhage Improves Survival

PubMed Central

Yadav, Vivek R.; Sahoo, Kaustuv; Roberts, Pamela R.

2013-01-01

An exaggerated release of proinflammatory cytokines and accompanying inflammation contributes to the development of multiple organ failure after hemorrhagic shock. Here, we tested the nuclear factor (NF) κ-light-chain-enhancer of activated B cell (NF-κB)–mediated transcriptional control of inflammatory pathways as a target in the management of hemorrhage-induced inflammation. We performed a study in a rat model of fixed-volume hemorrhage to investigate the anti-inflammatory effects of the diphenyldifluoroketone EF24 [3,5-bis(2-fluorobenzylidene)piperidin-4-one], an NF-κB inhibitor, in lung tissue. EF24 treatment (0.4 mg/kg) significantly prevented the upregulation of inflammatory biomarkers in rats subjected to 50% hemorrhage and preserved the pulmonary histology in hemorrhaged rats. The lung tissue from treated rats showed marked suppression of the hemorrhage-mediated induction of Toll-like receptor 4, phospho-p65 NF-κB, inducible nitric-oxide synthase, heme oxygenase–1, and cyclooxygenase-2 (COX-2). The hemorrhage-induced COX-2 activity was also significantly inhibited by the EF24 treatment. At the same time, EF24 induced nuclear factor (erythroid-derived 2)-like 2–mediated protective mechanisms against oxidative stress. EF24 also reduced hemorrhage-induced lung myeloperoxidase activity. The plasma levels of proinflammatory tumor necrosis factor-α, interleukin (IL)-6, IL-1α, and IL-1β were lower in EF24-treated rats than in untreated rats. Moreover, there was a significant reduction in the pulmonary expression of high-mobility group B1 protein. These biochemical effects were accompanied by a significant improvement in the survival of rats administered with EF24 as compared with the rats receiving vehicle control (P < 0.05). Overall, the results suggest that EF24 attenuates hemorrhage-induced inflammation and could serve as a salutary anti-inflammatory agent in resuscitation strategies. PMID:23995597

Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com; Sane, Mukta Subhash; Gupta, Chanchal

2011-03-15

Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Ourmore » results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.« less

Comparison of water immersion and saline infusion as a means of inducing volume expansion in man

NASA Technical Reports Server (NTRS)

Epstein, M.; Pins, D. S.; Arrington, R.; Denunzio, A. G.; Engstrom, R.

1975-01-01

The study compares the natriuresis induced by head-out water immersion to that of a standard saline infusion and assesses the relative effectiveness of these two techniques as volume determinants of renal sodium and water handling in humans in a seated posture. The data obtained show that the volume stimulus of immersion is identical to that of standard saline-induced extracellular fluid volume expansion (ECVE) in normal seated subjects. The ability of head-out water immersion to induce a natriuresis without a concomitant increase in total blood volume and with a decrease in body weight suggests that water immersion may be preferred as an investigative tool for assessing the effects of ECVE in man.

Potassium Aspartate Attenuates Brain Injury Induced by Controlled Cortical Impact in Rats Through Increasing Adenosine Triphosphate (ATP) Levels, Na+/K+-ATPase Activity and Reducing Brain Edema.

PubMed

Gu, Yi; Zhang, Jie; Zhao, Yumei; Su, Yujin; Zhang, Yazhuo

2016-12-13

BACKGROUND Potassium aspartate (PA), as an electrolyte supplement, is widely used in clinical practice. In our previous study, we found PA had neuroprotective effects against apoptosis after cerebral ischemia/reperfusion in rats. In this study, we examine whether PA has protective effects on traumatic brain injury (TBI). MATERIAL AND METHODS TBI was induced by controlled cortical impact (CCI) in rats. Vehicle treatment (control) or PA treatment was administered intraperitoneally at 30 minutes after CCI. The modified neurological severity score (mNSS) and cortical lesion volume were examined. Brain edema and blood-brain barrier (BBB) integrity were measured, as well as brain ATP contents, lactic acid levels, and Na+/K+-ATPase activities. RESULTS We found that CCI induced cortical injury in rats. Acute PA treatment at the dose of 62.5 mg/kg and 125 mg/kg significantly improved neurological deficits (p<0.05 and p<0.001, respectively) and decreased the cortical lesion volume (p<0.05 and p<0.001, respectively) compared with vehicle-only treatment. PA treatment at the dose of 125 mg/kg attenuated brain edema and ameliorated BBB integrity. In addition, PA treatment significantly reduced the loss of ATP (p<0.01), reduced lactic acid levels (p<0.001), and increased the activity of Na+/K+-ATPase (p<0.01). CONCLUSIONS Our results indicate PA has neuroprotective effects on TBI through increasing ATP levels, Na+/K+-ATPase activity, and reducing brain edema. It provides experimental evidence for the clinical application of PA.

Resistance exercise-induced fluid shifts: change in active muscle size and plasma volume

NASA Technical Reports Server (NTRS)

Ploutz-Snyder, L. L.; Convertino, V. A.; Dudley, G. A.

1995-01-01

The purpose of this study was to test the hypothesis that the reduction in plasma volume (PV) induced by resistance exercise reflects fluid loss to the extravascular space and subsequently selective increase in cross-sectional area (CSA) of active but not inactive skeletal muscle. We compared changes in active and inactive muscle CSA and PV after barbell squat exercise. Magnetic resonance imaging (MRI) was used to quantify muscle involvement in exercise and to determine CSA of muscle groups or individual muscles [vasti (VS), adductor (Add), hamstring (Ham), and rectus femoris (RF)]. Muscle involvement in exercise was determined using exercise-induced contrast shift in spin-spin relaxation time (T2)-weighted MR images immediately postexercise. Alterations in muscle size were based on the mean CSA of individual slices. Hematocrit, hemoglobin, and Evans blue dye were used to estimate changes in PV. Muscle CSA and PV data were obtained preexercise and immediately postexercise and 15 and 45 min thereafter. A hierarchy of muscle involvement in exercise was found such that VS > Add > Ham > RF, with the Ham and RF showing essentially no involvement. CSA of the VS and Add muscle groups were increased 10 and 5%, respectively, immediately after exercise in each thigh with no changes in Ham and RF CSA. PV was decreased 22% immediately following exercise. The absolute loss of PV was correlated (r2 = 0.75) with absolute increase in muscle CSA immediately postexercise, supporting the notion that increased muscle size after resistance exercise reflects primarily fluid movement from the vascular space into active but not inactive muscle.

AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome.

PubMed

Lashinger, Erin S R; Steiginga, Matthew S; Hieble, J Paul; Leon, Lisa A; Gardner, Scott D; Nagilla, Rakesh; Davenport, Elizabeth A; Hoffman, Bryan E; Laping, Nicholas J; Su, Xin

2008-09-01

The activation of the TRPM8 channel, a member of the large class of TRP ion channels, has been reported to be involved in overactive bladder and painful bladder syndrome, although an endogenous activator has not been identified. In this study, N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB) was evaluated as a TRPM8 channel blocker and used as a tool to evaluate the effects of this class of ion channel blocker on volume-induced bladder contraction and nociceptive reflex responses to noxious bladder distension in the rat. AMTB inhibits icilin-induced TRPM8 channel activation as measured in a Ca(2+) influx assay, with a pIC(50) of 6.23. In the anesthetized rat, intravenous administration of AMTB (3 mg/kg) decreased the frequency of volume-induced bladder contractions, without reducing the amplitude of contraction. The nociceptive response was measured by analyzing both visceromotor reflex (VMR) and cardiovascular (pressor) responses to urinary bladder distension (UBD) under 1% isoflurane. AMTB (10 mg/kg) significantly attenuated reflex responses to noxious UBD to 5.42 and 56.51% of the maximal VMR response and pressor response, respectively. The ID50 value on VMR response was 2.42 +/- 0.46 mg/kg. These results demonstrate that TRPM8 channel blocker can act on the bladder afferent pathway to attenuate the bladder micturition reflex and nociceptive reflex responses in the rat. Targeting TRPM8 channel may provide a new therapeutic opportunity for overactive bladder and painful bladder syndrome.

The Ethanolic Stem-Bark Extract of Antrocaryon micraster Inhibits Carrageenan-Induced Pleurisy and Pedal Oedema in Murine Models of Inflammation

PubMed Central

Essel, Leslie B.; Duduyemi, Babatunde M.

2017-01-01

We investigated the antioxidant and anti-inflammatory effects of a 70% v/v ethanol extract of the stem bark of Antrocaryon micraster on murine models of carrageenan-induced pleurisy and paw oedema. Rat pleural fluid was analysed for volume, protein content, and leucocytes, while lung histology was assessed for damage. Lung tissue homogenates were assayed for glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and myeloperoxidase (MPO). Phytochemical analysis was carried out on the stem bark. Acute toxicity studies were conducted in rats. In the pleurisy model the extract (30–300 mg/kg) significantly reduced the volume and amount of proteins and leucocytes in the exudate and also protected against lung injury. Tissue level of GSH and SOD and CAT expression were increased while MDA level and MPO activity were reduced. The peak and total oedema responses were significantly suppressed when given both preemptively and curatively in the mice paw oedema test. Saponins, alkaloids, triterpenoids, and tannins were present in the stem bark. A. micraster extract exhibited no apparent acute toxicity. We conclude that the ethanolic stem-bark extract of A. micraster has antioxidant action and exhibits significant anti-inflammatory activity through suppression of pleurisy and paw oedema induced with carrageenan. PMID:28798953

Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters.

PubMed

Stone, P J; Lucey, E C; Virca, G D; Christensen, T G; Breuer, R; Snider, G L

1990-06-01

A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.

Emotions and stress increase respiratory resistance in asthma.

PubMed

Ritz, T; Steptoe, A; DeWilde, S; Costa, M

2000-01-01

Clinical reports suggest that various emotions and types of stress can precipitate asthmatic symptoms, but there is little experimental evidence to substantiate this claim. We studied the impact of different emotional states and stress on respiratory resistance in asthmatic and nonasthmatic individuals. Participants (24 asthmatic and 24 nonasthmatic patients) viewed short film sequences selected to induce anxiety, anger, depression, elation, happiness, contentment, or a neutral affective state and completed two stressful tasks, mental arithmetic to induce active coping efforts and viewing of medical slides to induce passive coping efforts. Oscillatory resistance, heart rate, blood pressure, baroreflex sensitivity, skin conductance level, respiration rate and volume, and self-reported affective state were measured throughout the session. Uniform increases in oscillatory resistance were found in all emotional states compared with the neutral state and during mental arithmetic in both groups. Asthmatic patients showed stronger reactions to the medical slides than healthy control subjects, with significant increases in oscillatory resistance, blood pressure, skin conductance level, and minute volume, as well as higher levels of self-reported depression, arousal, and shortness of breath. Changes in oscillatory resistance were inconsistently correlated with other physiological indices. Various emotional states and stress increase oscillatory resistance largely independently of concurrent increases in autonomic or ventilatory activity. The particular sensitivity of asthmatics to passive coping demand requires additional research.

Pharmaco-thermodynamics of deuterium-induced oedema in living rat brain via 1H2O MRI: implications for boron neutron capture therapy of malignant brain tumours

NASA Astrophysics Data System (ADS)

Medina, Daniel C.; Li, Xin; Springer, Charles S., Jr.

2005-05-01

In addition to its common usage as a tracer in metabolic and physiological studies, deuterium possesses anti-tumoural activity and confers protection against γ-irradiation. A more recent interest in deuterium emanates from the search for alternatives capable of improving neutron penetrance whilst reducing healthy tissue radiation dose deposition in boron neutron capture therapy of malignant brain tumours. Despite this potential clinical application, deuterium induces brain oedema, which is detrimental to neutron capture therapy. In this study, five adult male rats were titrated with deuterated drinking water while brain oedema was monitored via water proton magnetic resonance imaging. This report concludes that deuterium, as well as deuterium-induced brain oedema, possesses a uniform brain bio-distribution. At a steady-state blood fluid deuteration value of 16%, when the deuterium isotope fraction in drinking water was 25%, a mean oedematous volume change of 9 ± 2% (p-value <0.001) was observed in the rat brain—this may account for neurological and behavioural abnormalities found in mammals drinking highly deuterated water. In addition to characterizing the pharmaco-thermodynamics of deuterium-induced oedema, this report also estimates the impact of oedema on thermal neutron enhancement and effective dose reduction factors using simple linear transport calculations. While body fluid deuteration enhances thermal neutron flux penetrance and reduces dose deposition, oedema has the opposite effect because it increases the volume of interest, e.g., the brain volume. Thermal neutron enhancement and effective dose reduction factors could be reduced by as much as ~10% in the presence of a 9% water volume increase (oedema). All three authors have contributed equally to this work.

Effect of Chronic Athletic Activity on Brown Fat in Young Women

PubMed Central

Singhal, Vibha; Maffazioli, Giovana D.; Ackerman, Kate E.; Lee, Hang; Elia, Elisa F.; Woolley, Ryan; Kolodny, Gerald; Cypess, Aaron M.; Misra, Madhusmita

2016-01-01

Background The effect of chronic exercise activity on brown adipose tissue (BAT) is not clear, with some studies showing positive and others showing negative associations. Chronic exercise is associated with increased resting energy expenditure (REE) secondary to increased lean mass and a probable increase in BAT. Many athletes are in a state of relative energy deficit suggested by lower fat mass and hypothalamic amenorrhea. States of severe energy deficit such as anorexia nervosa are associated with reduced BAT. There are no data regarding the impact of chronic exercise activity on BAT volume or activity in young women and it is unclear whether relative energy deficiency modifies the effects of exercise on BAT. Purpose We assessed cold induced BAT volume and activity in young female athletes compared with non-athletes, and further evaluated associations of BAT with measures of REE, body composition and menstrual status. Methods The protocol was approved by our Institutional Review Board. Written informed consent was obtained from all participants prior to study initiation. This was a cross-sectional study of 24 women (16 athletes and8 non-athletes) between 18–25 years of age. Athletes were either oligo-amenorrheic (n = 8) or eumenorrheic (n = 8).We used PET/CT scans to determine cold induced BAT activity, VMAX Encore 29 metabolic cart to obtain measures of REE, and DXA for body composition. Results Athletes and non-athletes did not differ for age or BMI. Compared with non-athletes, athletes had lower percent body fat (p = 0.002), higher percent lean mass (p = 0.01) and trended higher in REE (p = 0.09). BAT volume and activity in athletes trended lower than in non-athletes (p = 0.06; p = 0.07, respectively). We found negative associations of BAT activity with duration of amenorrhea (r = -0.46, p = 0.02).BAT volume correlated inversely with lean mass (r = -0.46, p = 0.02), and positively with percent body fat, irisin and thyroid hormones. Conclusions Our study shows a trend for lower BAT in young female athletes compared with non-athletes, and shows associations of brown fat with menstrual status and body composition. Brown fat may undergo adaptive reductions with increasing energy deficit. PMID:27243823

Cell volume regulation and apoptotic volume decrease in rat distal colon superficial enterocytes.

PubMed

Antico, Stefania; Lionetto, Maria Giulia; Giordano, Maria Elena; Caricato, Roberto; Schettino, Trifone

2013-01-01

The colon epithelium is physiologically exposed to osmotic stress, and the activation of cell volume regulation mechanisms is essential in colonocyte physiology. Moreover, colon is characterized by a high apoptotic rate of mature cells balancing the high division rate of stem cells. The aim of the present work was to investigate the main cell volume regulation mechanisms in rat colon surface colonocytes and their role in apoptosis. Cell volume changes were measured by light microscopy and video imaging on colon explants; apoptosis sign appearance was monitored by confocal microscopy on annexin V/propidium iodide labeled explants. Superficial colonocytes showed a dynamic regulation of their cell volume during anisosmotic conditions with a Regulatory Volume Increase (RVI) response following hypertonic shrinkage and Regulatory Volume Decrease (RVD) response following hypotonic swelling. RVI was completely inhibited by bumetanide, while RVD was completely abolished by high K(+) or iberiotoxin treatment and by extracellular Ca(2+) removal. DIDS incubation was also able to affect the RVD response. When colon explants were exposed to H2O2 as apoptotic inducer, colonocytes underwent an isotonic volume decrease ascribable to Apoptotic Volume Decrease (AVD) within about four hours of exposure. AVD was shown to precede annexin V positivity. It was also inhibited by high K(+) or iberiotoxin treatment. Interestingly, treatment with iberiotoxin significantly inhibited apoptosis progression. In rat superficial colonocytes K(+) efflux through high conductance Ca(2+)-activated K(+) channels (BK channels) was demonstrated to be the main mechanism of RVD and to plays also a crucial role in the AVD process and in the progression of apoptosis. © 2013 S. Karger AG, Basel.

Causality between expansion of seismic cloud and maximum magnitude of induced seismicity in geothermal field

NASA Astrophysics Data System (ADS)

Mukuhira, Yusuke; Asanuma, Hiroshi; Ito, Takatoshi; Häring, Markus

2016-04-01

Occurrence of induced seismicity with large magnitude is critical environmental issues associated with fluid injection for shale gas/oil extraction, waste water disposal, carbon capture and storage, and engineered geothermal systems (EGS). Studies for prediction of the hazardous seismicity and risk assessment of induced seismicity has been activated recently. Many of these studies are based on the seismological statistics and these models use the information of the occurrence time and event magnitude. We have originally developed physics based model named "possible seismic moment model" to evaluate seismic activity and assess seismic moment which can be ready to release. This model is totally based on microseismic information of occurrence time, hypocenter location and magnitude (seismic moment). This model assumes existence of representative parameter having physical meaning that release-able seismic moment per rock volume (seismic moment density) at given field. Seismic moment density is to be estimated from microseismic distribution and their seismic moment. In addition to this, stimulated rock volume is also inferred by progress of microseismic cloud at given time and this quantity can be interpreted as the rock volume which can release seismic energy due to weakening effect of normal stress by injected fluid. Product of these two parameters (equation (1)) provide possible seismic moment which can be released from current stimulated zone as a model output. Difference between output of this model and observed cumulative seismic moment corresponds the seismic moment which will be released in future, based on current stimulation conditions. This value can be translated into possible maximum magnitude of induced seismicity in future. As this way, possible seismic moment can be used to have feedback to hydraulic stimulation operation in real time as an index which can be interpreted easily and intuitively. Possible seismic moment is defined as equation (1), where D is seismic moment density (Mo/m3) and V stim is stimulated rock volume (m3). Mopossible = D ∗ V stim(1) We applied this conceptual model to real microseismic data set from Basel EGS project where several induced seismicity with large magnitude occurred and brought constructive damage. Using the hypocenter location determined by the researcher of Tohoku Univ., Japan and moment magnitude estimated from Geothermal Explorers Ltd., operating company, we were able to estimate reasonable seismic moment density meaning that one representative parameter exists and can characterize seismic activity at Basel at each time step. With stimulated rock volume which was also inferred from microseismic information, we estimated possible seismic moment and assess the difference with observed value. Possible seismic moment significantly increased after shut-in when the seismic cloud (stimulated zone) mostly progressed, resulting that the difference with the observed cumulative seismic moment automatically became larger. This suggests that there is moderate seismic moment which will be released in near future. In next few hours, the largest event actually occurred. Therefore, our proposed model was successfully able to forecast occurrence of the large events. Furthermore, best forecast of maximum magnitude was Mw 3 level and the largest event was Mw 3.41, showing reasonable performance in terms of quantitative forecast in magnitude. Our attempt to assess the seismic activity from microseismic information was successful and it also suggested magnitude release can be correlate with the expansion of seismic cloud as the definition of possible seismic moment model indicates. This relationship has been observed in microseismic observational study and several previous study also suggested their correlation with stress released rock volume. Our model showed harmonic results with these studies and provide practical method having clear physical meaning to assess the seismic activity in real time, based on microseismic data.

An orally active motilin receptor antagonist, MA-2029, inhibits motilin-induced gastrointestinal motility, increase in fundic tone, and diarrhea in conscious dogs without affecting gastric emptying.

PubMed

Ozaki, Ken-ichi; Onoma, Mitsu; Muramatsu, Hiroyasu; Sudo, Hirokazu; Yoshida, Shoshin; Shiokawa, Rie; Yogo, Kenji; Kamei, Kenshi; Cynshi, Osamu; Kuromaru, Osamu; Peeters, Theo L; Takanashi, Hisanori

2009-08-01

The pharmacological properties of MA-2029, a selective and competitive motilin receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3-10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by motilin (3 microg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3-3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 microg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1-10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of motilin (3 microg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1-30 mg/kg, p.o.) reduced the incidence of diarrhea induced by motilin in a dose-dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating motilin.

Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload.

PubMed

El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K; Gardner, Jason D

2018-05-18

The cardiac extracellular matrix is a complex architectural network that serves many functions including providing structural and biochemical support to surrounding cells, and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of the pro-inflammatory and pro-fibrotic responses induce a vicious cycle which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix. Further, excess synthesis and activation of the enzyme lysyl oxidase (LOX) during disease increases collagen cross-linking, which significantly increases collagen resistance to degradation by matrix metalloproteinases (MMPs). In this study, the aortocaval fistula model of volume overload (VO) was used to determine whether LOX inhibition could prevent adverse changes in the ECM and subsequent cardiac dysfunction. The major findings from this study are that LOX inhibition: (a) prevented VO-induced increases in LV wall stress, (b) partially attenuated VO-induced ventricular hypertrophy, (c) completely blocked the increases in fibrotic proteins, including collagens, MMPs, and their tissue inhibitors (TIMPs), and (d) prevented the VO-induced decline in cardiac function. It remains unclear whether a direct interaction between LOX and MMPs exists; however our studies suggest a potential link between the two since LOX inhibition completely attenuated the VO-induced increases in MMPs. Overall, our studies demonstrate key cardioprotective effects of LOX inhibition against adverse cardiac remodeling due to chronic VO.

Identical activation volumes of dislocation mobility in the [100](010) and [001](010) slip systems in natural olivine

NASA Astrophysics Data System (ADS)

Wang, Lin; Blaha, Stephan; Kawazoe, Takaaki; Miyajima, Nobuyoshi; Katsura, Tomoo

2017-03-01

Dislocation recovery experiments were performed on predeformed olivine single crystals at pressures of 2, 7 and 12 GPa and a constant temperature of 1650 K to determine the pressure dependence of the annihilation rate constants for [100](010) edge dislocation (a dislocation) and [001](010) screw dislocation (c dislocation). The constants of both types of dislocations are comparable within 0.3 orders of magnitude. The activation volumes of a and c dislocations are small and identical within error: 2.7 ± 0.2 and 2.5 ± 0.9 cm3/mol, respectively. These values are slightly larger and smaller than those of Si lattice and grain-boundary diffusions in olivine, respectively. The small and identical activation volumes for the a and c dislocations suggest that the pressure-induced fabric transition is unlikely in the asthenosphere. The decrease in seismic anisotropy with depth down in the asthenosphere may be caused by the fabric transition from A type or B type to AG type with decreasing stress with depth.

Cover Image, Volume 119, Number 1, January 2018.

PubMed

Rubio-Infante, Nestor; Ilhuicatzi-Alvarado, Damaris; Torres-Martínez, Marilu; Reyes-Grajeda, Juan Pablo; Nava-Acosta, Raúl; González-González, Edith; Moreno-Fierros, Leticia

2018-01-01

Cover: The cover image, by Nestor Rubio-Infante et al., is based on the Article The Macrophage Activation Induced by Bacillus thuringiensis Cry1Ac Protoxin Involves ERK1/2 and p38 Pathways and the Interaction with Cell-Surface-HSP70, DOI: 10.1002/jcb.26216. © 2017 Wiley Periodicals, Inc.

Microseismicity cloud can be substantially larger than the associated stimulated fracture volume: the case of the Paralana Enhanced Geothermal System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Riffault, Jeremy; Dempsey, David; Karra, Satish

The goal of hydraulic stimulation is to increase formation permeability in the near vicinity of a well. However, there remain technical challenges around measuring the outcome of this operation. During two Enhanced Geothermal System (EGS) stimulations in South Australia, Paralana in 2011 and Habanero in 2003, extensive catalogs of microseismicity were recovered. It is often assumed that shear failure of existing fractures is the main mechanism behind both the induced earthquakes and any permeability enhancement. This underpins a common notion, that the seismically active volume is also the stimulated reservoir. In this paper, we compute the density of earthquake hypocentersmore » and provide evidence that, under certain conditions, this spatiotemporal quantity is a reasonable proxy for pore pressure increase. We then apply an inverse modeling approach that uses the earthquake observations and a modified reservoir simulator to estimate the parameters of a permeability evolution relation. The regime implied by the data indicates that most permeability enhancement occurred very near to the wellbore and was not coincident with the bulk of the seismicity, whose volume was about two orders of magnitude larger. Thus, we conclude that, in some cases, it is possible for permeability enhancement and induced seismicity to be decoupled, in which case the seismically active volume is a poor indicator of the stimulated reservoir. Our results raise serious questions about the effectiveness of hydroshearing as a stimulation mechanism in EGS. Finally, this study extends our understanding of the complex processes linking earthquakes, fluid pressure, and permeability in both natural and engineered settings.« less

Microseismicity cloud can be substantially larger than the associated stimulated fracture volume: the case of the Paralana Enhanced Geothermal System

DOE PAGES

Riffault, Jeremy; Dempsey, David; Karra, Satish; ...

2018-06-21

The goal of hydraulic stimulation is to increase formation permeability in the near vicinity of a well. However, there remain technical challenges around measuring the outcome of this operation. During two Enhanced Geothermal System (EGS) stimulations in South Australia, Paralana in 2011 and Habanero in 2003, extensive catalogs of microseismicity were recovered. It is often assumed that shear failure of existing fractures is the main mechanism behind both the induced earthquakes and any permeability enhancement. This underpins a common notion, that the seismically active volume is also the stimulated reservoir. In this paper, we compute the density of earthquake hypocentersmore » and provide evidence that, under certain conditions, this spatiotemporal quantity is a reasonable proxy for pore pressure increase. We then apply an inverse modeling approach that uses the earthquake observations and a modified reservoir simulator to estimate the parameters of a permeability evolution relation. The regime implied by the data indicates that most permeability enhancement occurred very near to the wellbore and was not coincident with the bulk of the seismicity, whose volume was about two orders of magnitude larger. Thus, we conclude that, in some cases, it is possible for permeability enhancement and induced seismicity to be decoupled, in which case the seismically active volume is a poor indicator of the stimulated reservoir. Our results raise serious questions about the effectiveness of hydroshearing as a stimulation mechanism in EGS. Finally, this study extends our understanding of the complex processes linking earthquakes, fluid pressure, and permeability in both natural and engineered settings.« less

ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK.

PubMed

Gao, Ge; Zhang, Tianshun; Wang, Qiushi; Reddy, Kanamata; Chen, Hanyong; Yao, Ke; Wang, Keke; Roh, Eunmiri; Zykova, Tatyana; Ma, Weiya; Ryu, Joohyun; Curiel-Lewandrowski, Clara; Alberts, David; Dickinson, Sally E; Bode, Ann M; Xing, Ying; Dong, Zigang

2017-09-01

Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843-54. ©2017 AACR . ©2017 American Association for Cancer Research.

Antidiarrhoeal activity of leaf methanolic extract of Rauwolfia serpentina

PubMed Central

Ezeigbo, II; Ezeja, MI; Madubuike, KG; Ifenkwe, DC; Ukweni, IA; Udeh, NE; Akomas, SC

2012-01-01

Objective To evaluate the antidiarrhoeal property of methanol extract of the leaves of Rauwolfia serpentina (R. serpentina) in experimental diarrhoea induced by castor oil in mice. Methods Doses of 100, 200 and 400 mg/kg R. serpentina leaf methanol extracts were administered to castor oil induced diarrhoea mice to determine its antidiarrhoeal activity. Results All doses of the extract and the reference drug atropine sulphate (3 mg/kg, i.p.) produced a dose-dependent reduction in intestinal weight and fluid volume. The extracts also significantly reduced the intestinal transit in charcoal meal test when compared to diphenoxylate Hcl (5 mg/kg, p.o.). Conclusions The results show that the extract of R. serpentina leaves has a significant antidiarrhoeal activity and supports its traditional uses in herbal medicine. PMID:23569944

Thermodynamic and kinetic characterization of polycyclic aromatic hydrocarbons in reversed-phase liquid chromatography.

PubMed

Howerton, Samuel B; McGuffin, Victoria L

2003-07-15

The retention of six polycyclic aromatic hydrocarbons (PAHs) was characterized by reversed-phase liquid chromatography. The PAHs were detected by laser-induced fluorescence at four points along an optically transparent capillary column. The profiles were characterized in space and time using an exponentially modified Gaussian equation. The resulting parameters were used to calculate the retention factors, as well as the concomitant changes in molar enthalpy and molar volume, for each PAH on monomeric (2.7 micromol/m2) and polymeric (5.4 micromol/m2) octadecylsilica. The changes in molar enthalpy become more exothermic as ring number increases and as annelation structure becomes less condensed. The changes in molar volume become more negative as ring number increases for the planar PAHs, but are positive for the nonplanar solutes. In addition, the rate constants, as well as the concomitant activation enthalpy and activation volume, are calculated for the first time. The kinetic data demonstrate that many of the PAHs exhibit very fast transitions between the mobile and stationary phases. The transition state is very high in energy, and the activation enthalpies and volumes become greater as ring number increases and as annelation structure becomes less condensed. The changes in thermodynamic and kinetic behavior are much more pronounced for the polymeric phase than for the monomeric phase.

Endogenous purinergic signaling is required for osmotic volume regulation of retinal glial cells.

PubMed

Wurm, Antje; Lipp, Stephan; Pannicke, Thomas; Linnertz, Regina; Krügel, Ute; Schulz, Angela; Färber, Katrin; Zahn, Dirk; Grosse, Johannes; Wiedemann, Peter; Chen, Ju; Schöneberg, Torsten; Illes, Peter; Reichenbach, Andreas; Bringmann, Andreas

2010-03-01

Intense neuronal activity in the sensory retina is associated with a volume increase of neuronal cells (Uckermann et al., J. Neurosci. 2004, 24:10149) and a decrease in the osmolarity of the extracellular space fluid (Dmitriev et al., Vis. Neurosci. 1999, 16:1157). Here, we show the existence of an endogenous purinergic mechanism that prevents hypoosmotic swelling of retinal glial (Müller) cells in mice. In contrast to the cells from wild-type mice, hypoosmotic stress induced rapid swelling of glial cell somata in retinal slices from mice deficient in P2Y(1), adenosine A(1) receptors, or ecto-5'-nucleotidase (CD73). Consistently, glial cell bodies in retinal slices from wild-type mice displayed osmotic swelling when P2Y(1) or A(1) receptors, or CD73, were pharmacologically blocked. Exogenous ATP, UTP, and UDP inhibited glial swelling in retinal slices, while the swelling of isolated glial cells was prevented by ATP but not by UTP or UDP, suggesting that uracil nucleotides indirectly regulate the glial cell volume via activation of neuronal P2Y(4/6) and neuron-to-glia signaling. It is suggested that autocrine/paracrine activation of purinergic receptors and enzymes is crucially involved in the regulation of the glial cell volume.

Vascular capacitance and cardiac output in pacing-induced canine models of acute and chronic heart failure.

PubMed

Ogilvie, R I; Zborowska-Sluis, D

1995-11-01

The relationship between stressed and total blood volume, total vascular capacitance, central blood volume, cardiac output (CO), and pulmonary capillary wedge pressure (Ppcw) was investigated in pacing-induced acute and chronic heart failure. Acute heart failure was induced in anesthetized splenectomized dogs by a volume load (20 mL/kg over 10 min) during rapid right ventricular pacing at 250 beats/min (RRVP) for 60 min. Chronic heart failure was induced by continuous RRVP for 2-6 weeks (average 24 +/- 2 days). Total vascular compliance and capacitance were calculated from the mean circulatory filling pressure (Pmcf) during transient circulatory arrest after acetylcholine at three different circulating volumes. Stressed blood volume was calculated as a product of compliance and Pmcf, with the total blood volume measured by a dye dilution. Central blood volume (CBV) and CO were measured by thermodilution. Central (heart and lung) vascular capacitance was estimated from the plot of Ppcw against CBV. Acute volume loading without RRVP increased capacitance and CO, whereas after volume loading with RRVP, capacitance and CO were unaltered from baseline. Chronic RRVP reduced capacitance and CO. All interventions, volume +/- RRVP or chronic RRVP, increased stressed and central blood volumes and Ppcw. Acute or chronic RRVP reduced central vascular capacitance. Cardiac output was increased when stressed and unstressed blood volumes increased proportionately as during volume loading alone. When CO was reduced and Ppcw increased, as during chronic RRVP or acute RRVP plus a volume load, stressed blood volume was increased and unstressed blood volume was decreased. Thus, interventions that reduced CO and increased Ppcw also increased stressed and reduced unstressed blood volume and total vascular capacitance.

Effects of 17 days of head-down bed rest on hydro-electrolytic regulation in men

NASA Technical Reports Server (NTRS)

Millet, C.; Custaud, M. A.; Allevard, A. M.; Zaouali-Ajina, M.; Monk, T. H.; Arnaud, S. B.; Gharib, C.; Gauquelin-Koch, G.

2001-01-01

Prolonged periods of head-down bed rest (HDBR) are commonly used to mimic the effects of microgravity. HDBR has been shown to produce, as in space, a cephalad redistribution of circulating blood volume with an increase in central blood volume which induces the early adaptations in blood volume regulating hormones. Changes in atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity and aldosterone have been observed. Many reports describe these endocrine adaptations but few investigations of rhythms are in the literature. We proposed to evaluate the circadian rhythms of the hormones and electrolytes involved in the hydro-electrolytic regulation during a HDBR study which was designed to simulate a 17-day spaceflight (Life and Microgravity Spacelab experiment, LMS, NASA).

Ethanol synthesis and aerobic respiration in the laboratory by leader segments of Douglas-fir seedlings from winter and spring.

PubMed

Joseph, Gladwin; Kelsey, Rick G

2004-05-01

Stem segments from terminal leaders of Douglas-fir, Pseudotsuga menziesii (Mirb.) Franco, seedlings were sampled in mid-December when cambial cells were dormant. The residual, debudded leaders were resampled again in early May when the cambium was metabolically active. May stems had higher constitutive ethanol concentrations than December stems. This was not the result of cambial hypoxia generated by rapid spring respiration rates, because when aerobic respiration was stimulated by incubating the stems in air at 30 degrees C ethanol production was induced in December, but not in May. Rapid respiration rates at 30 degrees C may have depleted O(2) supplies and induced ethanol production in December stems because dormant, thick-walled cambial cells may be less permeable to CO(2) and O(2), compared with metabolically active, thin-walled cambial cells in May. December stem segments incubated in a N(2) atmosphere at 30 degrees C synthesized 1.8 times more ethanol than segments from May, most likely because spring growth had reduced the soluble sugars available for fermentation. CO(2) efflux from May stems (after 5.5 h of incubation at 30 degrees C) was equal to December stems per unit volume, but greater than December stems per unit surface area. N(2)-induced ethanol concentrations were positively related with CO(2) efflux per unit volume, indicating that rapidly respiring leaders can maintain rapid fermentation rates, provided soluble sugars are readily available. N(2)-induced ethanol and CO(2) efflux per unit volume declined with increasing leader diameter in both seasons, whereas there were no relationships between CO(2) efflux per unit surface area and diameter. Cambium physiology and phenology influence the induction of fermentation and concentrations of ethanol produced in terminal leaders of Douglas-fir, and probably other conifers as well. This needs to be considered when comparing fermentation among species, or comparing individuals from different seasons, or disparate ages within a species.

Theoretical monochromatic-wave-induced currents in intermediate water with viscosity and nonzero mass transport

NASA Technical Reports Server (NTRS)

Talay, T. A.

1975-01-01

Wave-induced mass-transport current theories with both zero and nonzero net mass (or volume) transport of the water column are reviewed. A relationship based on the Longuet-Higgens theory is derived for wave-induced, nonzero mass-transport currents in intermediate water depths for a viscous fluid. The relationship is in a form useful for experimental applications; therefore, some design criteria for experimental wave-tank tests are also presented. Sample parametric cases for typical wave-tank conditions and a typical ocean swell were assessed by using the relation in conjunction with an equation developed by Unluata and Mei for the maximum wave-induced volume transport. Calculations indicate that substantial changes in the wave-induced mass-transport current profiles may exist dependent upon the assumed net volume transport. A maximum volume transport, corresponding to an infinite channel or idealized ocean condition, produces the largest wave-induced mass-transport currents. These calculations suggest that wave-induced mass-transport currents may have considerable effects on pollution and suspended-sediments transport as well as buoy drift, the surface and midlayer water-column currents caused by waves increasing with increasing net volume transports. Some of these effects are discussed.

Evaluation of the antiulcerogenic activity of Maytenus robusta (Celastraceae) in different experimental ulcer models.

PubMed

de Andrade, Sérgio Faloni; Lemos, Marivane; Comunello, Eros; Noldin, Vânia Floriani; Filho, Valdir Cechinel; Niero, Rivaldo

2007-09-05

Maytenus robusta (Celastraceae) is used in folk medicine for the treatment of stomach ulcers and is very well adapted to the South of Brazil. Maytenus ilicifolia is the main species of the Celastraceae family, and is used in the treatment of gastric ulcers. However, Maytenus ilicifolia is presently at the stage of extinction, due to indiscriminate use in Brazil. Thus, the use of Maytenus robusta in phytotherapeutic preparations, instead of Maytenus ilicifolia, is suggested. However, there have been no reports regarding the antiulcer activity of Maytenus robusta extract. Therefore, this study was carried out to evaluate the antiulcerogenic property of the hydroalcoholic extract of aerial parts of Maytenus robusta. The antiulcer assays were performed using the following protocols: nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, ethanol-induced ulcer, and stress-induced ulcer. The effects of the extract on gastric content volume, pH and total acidity, using the pylorus ligated model, were also evaluated. In the ethanol-induced ulcer model, it was observed that the treatment with Maytenus robusta extract significantly reduced the lesion index in 75.1 +/- 8.6, 85.0 +/- 9.2, 86.6 +/- 7.4 and 75.5 +/- 5.3 for the groups treated with 50, 250 and 500 mg/kg of Maytenus robusta and positive control (omeprazole 30 mg/kg), respectively. Also were observed significant inhibition in lesion index in the indomethacin-induced ulcer model, being the decrease of the 62.5 +/- 7.1, 62.5 +/- 6.1, 63.6 +/- 5.5 and 96.2 +/- 3.6 for groups treated with 50, 250 and 500 mg/kg of Maytenus robusta and positive control (cimetidine 100 mg/kg), respectively. Results similar were observed in the stress-induced ulcer model, where the inhibition of ulcer lesions were 71.3 +/- 5.5, 72.7 +/- 6.3, 76.5 +/- 7.1 and 92.3 +/- 7.5 for the groups treated with 50, 250 and 500 mg/kg of Maytenus robusta and positive control (cimetidine 100 mg/kg), respectively. Regarding the model of gastric secretion, a reduction in the volume of gastric juice volume and total acidity was observed, as well as an increase in gastric pH. The results of the present study showed that Maytenus robusta hydroalcoholic extract displays gastroprotective activity. These results were similar to those obtained in studies carried out with Maytenus ilicifolia, which indicate that this species could be used in phytotherapeutic preparations as a substitute for Maytenus ilicifolia. This work also corroborates the traditional indication of Maytenus robusta, contributing to its pharmacological validation.

Differential regulation of a CLC anion channel by SPAK kinase ortholog-mediated multisite phosphorylation

PubMed Central

Miyazaki, Hiroaki

2012-01-01

Shrinkage-induced inhibition of the Caenorhabditis elegans cell volume and cell cycle-dependent CLC anion channel CLH-3b occurs by concomitant phosphorylation of S742 and S747, which are located on a 175 amino acid linker domain between cystathionine-β-synthase 1 (CBS1) and CBS2. Phosphorylation is mediated by the SPAK kinase homolog GCK-3 and is mimicked by substituting serine residues with glutamate. Type 1 serine/threonine protein phosphatases mediate swelling-induced channel dephosphorylation. S742E/S747E double mutant channels are constitutively inactive and cannot be activated by cell swelling. S742E and S747E mutant channels were fully active in the absence of GCK-3 and were inactive when coexpressed with the kinase. Both channels responded to cell volume changes. However, the S747E mutant channel activated and inactivated in response to cell swelling and shrinkage, respectively, much more slowly than either wild-type or S742E mutant channels. Slower activation and inactivation of S747E was not due to altered rates of dephosphorylation or dephosphorylation-dependent conformational changes. GCK-3 binds to the 175 amino acid inter-CBS linker domain. Coexpression of wild-type CLH-3b and GCK-3 with either wild-type or S742E linkers gave rise to similar channel activity and regulation. In contrast, coexpression with the S747E linker greatly enhanced basal channel activity and increased the rate of shrinkage-induced channel inactivation. Our findings suggest the intriguing possibility that the phosphorylation state of S742 in S747E mutant channels modulates GCK-3/channel interaction and hence channel phosphorylation. These results provide a foundation for further detailed studies of the role of multisite phosphorylation in regulating CLH-3b and GCK-3 activity. PMID:22357738

PPARγ ligands decrease hydrostatic pressure-induced platelet aggregation and proinflammatory activity.

PubMed

Rao, Fang; Yang, Ren-Qiang; Chen, Xiao-Shu; Xu, Jin-Song; Fu, Hui-Min; Su, Hai; Wang, Ling

2014-01-01

Hypertension is known to be associated with platelet overactivity, but the direct effects of hydrostatic pressure on platelet function remain unclear. The present study sought to investigate whether elevated hydrostatic pressure is responsible for platelet activation and to address the potential role of peroxisome proliferator-activated receptor-γ (PPARγ). We observed that hypertensive patients had significantly higher platelet volume and rate of ADP-induced platelets aggregation compared to the controls. In vitro, Primary human platelets were cultured under standard (0 mmHg) or increased (120, 180, 240 mmHg) hydrostatic pressure for 18 h. Exposure to elevated pressure was associated with morphological changes in platelets. Platelet aggregation and PAC-1 (the active confirmation of GPIIb/IIIa) binding were increased, CD40L was translocated from cytoplasm to the surface of platelet and soluble CD40L (sCD40L) was released into the medium in response to elevated hydrostatic pressure (180 and 240 mmHg). The PPARγ activity was up-regulated as the pressure was increased from 120 mmHg to 180 mmHg. Pressure-induced platelet aggregation, PAC-1 binding, and translocation and release of CD40L were all attenuated by the PPARγ agonist Thiazolidinediones (TZDs). These results demonstrate that platelet activation and aggregation are increased by exposure to elevated pressure and that PPARγ may modulate platelet activation induced by high hydrostatic pressure.

PPARγ Ligands Decrease Hydrostatic Pressure-Induced Platelet Aggregation and Proinflammatory Activity

PubMed Central

Chen, Xiao-Shu; Xu, Jin-Song; Fu, Hui-Min; Su, Hai; Wang, Ling

2014-01-01

Hypertension is known to be associated with platelet overactivity, but the direct effects of hydrostatic pressure on platelet function remain unclear. The present study sought to investigate whether elevated hydrostatic pressure is responsible for platelet activation and to address the potential role of peroxisome proliferator-activated receptor-γ (PPARγ). We observed that hypertensive patients had significantly higher platelet volume and rate of ADP-induced platelets aggregation compared to the controls. In vitro, Primary human platelets were cultured under standard (0 mmHg) or increased (120, 180, 240 mmHg) hydrostatic pressure for 18 h. Exposure to elevated pressure was associated with morphological changes in platelets. Platelet aggregation and PAC-1 (the active confirmation of GPIIb/IIIa) binding were increased, CD40L was translocated from cytoplasm to the surface of platelet and soluble CD40L (sCD40L) was released into the medium in response to elevated hydrostatic pressure (180 and 240 mmHg). The PPARγ activity was up-regulated as the pressure was increased from 120 mmHg to 180 mmHg. Pressure-induced platelet aggregation, PAC-1 binding, and translocation and release of CD40L were all attenuated by the PPARγ agonist Thiazolidinediones (TZDs). These results demonstrate that platelet activation and aggregation are increased by exposure to elevated pressure and that PPARγ may modulate platelet activation induced by high hydrostatic pressure. PMID:24586940

Soccer Attenuates the Asymmetry of Rectus Abdominis Muscle Observed in Non-Athletes

PubMed Central

Idoate, Fernando; Calbet, Jose A. L.; Izquierdo, Mikel; Sanchis-Moysi, Joaquin

2011-01-01

Purpose To determine the volume and degree of asymmetry of the rectus abdominis muscle (RA) in professional soccer players. Methods The volume of the RA was determined using magnetic resonance imaging (MRI) in 15 professional male soccer players and 6 non-active male control subjects. Results Soccer players had 26% greater RA volume than controls (P<0.05), due to hypertrophy of both the dominant (28% greater volume, P<0.05) and non-dominant (25% greater volume, P<0.01) sides, after adjusting for age, length of the RA muscle and body mass index (BMI) as covariates. Total volume of the dominant side was similar to the contralateral in soccer players (P = 0.42) and in controls (P = 0.75) (Dominant/non-dominant = 0.99, in both groups). Segmental analysis showed a progressive increase in the degree of side-to-side asymmetry from the first lumbar disc to the pubic symphysis in soccer players (r = 0.80, P<0.05) and in controls (r = 0.75, P<0.05). The slope of the relationship was lower in soccer players, although this trend was not statistically significant (P = 0.14). Conclusions Professional soccer is associated with marked hypertrophy of the rectus abdominis muscle, which achieves a volume that is 26% greater than in non-active controls. Soccer induces the hypertrophy of the non-dominant side in proximal regions and the dominant side in regions closer to pubic symphysis, which attenuates the pattern of asymmetry of rectus abdominis observed in non-active population. It remains to be determined whether the hypertrophy of rectus abdominis in soccer players modifies the risk of injury. PMID:21541351

Binge ethanol effects on prefrontal cortex neurons, spatial working memory and task-induced neuronal activation in male and female rats.

PubMed

West, Rebecca K; Maynard, Mark E; Leasure, J Leigh

2018-05-01

Excessive alcohol intake is associated with a multitude of health risks, especially for women. Recent studies in animal models indicate that the female brain is more negatively affected by alcohol, compared to the male brain. Among other regions, excessive alcohol consumption damages the frontal cortex, an area important for many functions and decision making of daily life. The objective of the present study was to determine whether the medial prefrontal cortex (mPFC) in female rats is selectively vulnerable to alcohol-induced damage. In humans, loss of prefrontal grey matter resulting from heavy alcohol consumption has been documented, however this volume loss is not necessarily due to a decrease in the number of neurons. We therefore quantified both number and nuclear volume of mPFC neurons following binge alcohol, as well as performance and neuronal activation during a prefrontal-dependent behavioral task. Adult male and female Long-Evans rats were assigned to binge or control groups and exposed to ethanol using a well-established 4-day model of alcohol-induced neurodegeneration. Both males and females had significantly smaller average neuronal nuclei volumes than their respective control groups immediately following alcohol binge, but neither sex showed a decrease in neuron number. Binged rats of both sexes initially showed spatial working memory deficits. Although they eventually achieved control performance, binged rats of both sexes showed increased c-Fos labeling in the mPFC during rewarded alternation, suggesting decreased neural efficiency. Overall, our results substantiate prior evidence indicating that the frontal cortex is vulnerable to alcohol, but also indicate that sex-specific vulnerability to alcohol may be brain region-dependent. Copyright © 2018 Elsevier Inc. All rights reserved.

Rat injury model of docetaxel extravasation.

PubMed

Zhu, Jing-Jing; Fu, Jian-Fei; Yang, Jiao; Hu, Bing; Zhang, Hui; Yu, Jian-Hua

2014-09-01

Docetaxel is a novel type of chemotherapy drug that actively treats a number of malignant tumors. The aim of the present study was to explore the severity and natural course of tissue damage induced by docetaxel extravasation and to confirm the vesicant potential of docetaxel. Rats were selected for the establishment of the ulcer model. Different volumes and concentrations were explored to induce the skin ulcer and to confirm the optimum rational injection model. The natural course of tissue injury and pathological changes produced by docetaxel extravasation were observed by comparing to vinorelbine extravasation. A 0.4 ml volume and a 6 mg/ml concentration were the optimum rational injection model for the induction of the skin ulcer. The docetaxel extravasation induced local tissue necrosis, followed by granuloma formation and hyperpigmentation or scar formation. The severity of the injury depended on the concentration of the extravasation used in the rat model. The injury occurred on the first day following extravasation and lasted 4-6 weeks. The damage from docetaxel was weaker than vinorelbine in association with the depth and extension of necrosis. In conclusion, docetaxel extravasation can induce tissue necrosis. However, the severity of necrosis was weaker than that of vinorelbine. Docetaxel has superficial vesicant properties.

Rat injury model of docetaxel extravasation

PubMed Central

ZHU, JING-JING; FU, JIAN-FEI; YANG, JIAO; HU, BING; ZHANG, HUI; YU, JIAN-HUA

2014-01-01

Docetaxel is a novel type of chemotherapy drug that actively treats a number of malignant tumors. The aim of the present study was to explore the severity and natural course of tissue damage induced by docetaxel extravasation and to confirm the vesicant potential of docetaxel. Rats were selected for the establishment of the ulcer model. Different volumes and concentrations were explored to induce the skin ulcer and to confirm the optimum rational injection model. The natural course of tissue injury and pathological changes produced by docetaxel extravasation were observed by comparing to vinorelbine extravasation. A 0.4 ml volume and a 6 mg/ml concentration were the optimum rational injection model for the induction of the skin ulcer. The docetaxel extravasation induced local tissue necrosis, followed by granuloma formation and hyperpigmentation or scar formation. The severity of the injury depended on the concentration of the extravasation used in the rat model. The injury occurred on the first day following extravasation and lasted 4–6 weeks. The damage from docetaxel was weaker than vinorelbine in association with the depth and extension of necrosis. In conclusion, docetaxel extravasation can induce tissue necrosis. However, the severity of necrosis was weaker than that of vinorelbine. Docetaxel has superficial vesicant properties. PMID:25054005

Protective effect of aqueous extract of Feronia elephantum correa leaves on thioacetamide induced liver necrosis in diabetic rats

PubMed Central

Sharma, Prashant; Bodhankar, Subhash L; Thakurdesai, Prasad A

2012-01-01

Objective To evalueate hepatoprotective effects Feronia elephantum (F. elephantum) correa against thioacetamide (TA) induced liver necrosis in diabetic rats. Methods Male wistar rats were made diabetic with alloxan (160 mg/kg) on day 0 of the study. They were intoxicated with hepatotoxicant (thioacetamide, 300 mg/kg, ip) on day 9 of study to produce liver necrosis. Effects of 7 day daily once administration (day 2 to day 9) of EF (400 and 800 mg/kg, po) were evaluated on necorosis of liver in terms of mortality, liver volume, liver weight, serum aspartate aminotransferase (AST) and serum alanine transaminase (ALT), and histopathology of liver sections (for signs of necorosis and inflammation) on day-9 of the study. Separate groups of rats with treated only with alloxan (DA control), thioacetamide (TA control) and both (TA+DA control) were maintained. Results FE significantly lowered the mortality rate and showed improvement in liver function parameters in TA-induced diabetic rats without change in liver weight, volume and serum glucose levels. Conclusions FE showed promising activity against TA-induced liver necorsis in diabetic rats and so might be useful for prevention of liver complications in DM. PMID:23569996

Anatomical and functional assessment of brown adipose tissue by magnetic resonance imaging.

PubMed

Chen, Y Iris; Cypess, Aaron M; Sass, Christina A; Brownell, Anna-Liisa; Jokivarsi, Kimmo T; Kahn, C Ronald; Kwong, Kenneth K

2012-07-01

Brown adipose tissue (BAT) is the primary tissue responsible for nonshivering thermogenesis in mammals. The amount of BAT and its level of activation help regulate the utilization of excessive calories for thermogenesis as opposed to storage in white adipose tissue (WAT) which would lead to weight gain. Over the past several years, BAT activity in vivo has been primarily assessed by positron emission tomography-computed tomography (PET-CT) scan using 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) to measure glucose utilization associated with BAT mitochondrial respiration. In this study, we demonstrate the feasibility of mapping and estimating BAT volume and metabolic function in vivo in rats at a 9.4T magnetic resonance imaging (MRI) scanner using sequences available from clinical MR scanners. Based on the morphological characteristics of BAT, we measured the volume distribution of BAT with MRI sequences that have strong fat-water contrast. We also investigated BAT volume by utilizing spin-echo MRI sequences. The in vivo MRI-estimated BAT volumes were correlated with direct measurement of BAT mass from dissected samples. Using MRI, we also were able to map hemodynamic responses to changes in BAT metabolism induced pharmacologically by β3-adrenergic receptor agonist, CL-316,243 and compare this to BAT activity in response to CL-316,243 assessed by PET 18F-FDG. In conclusion, we demonstrate the feasibility of measuring BAT volume and function in vivo using routine MRI sequences. The MRI measurement of BAT volume is consistent with quantitative measurement of the tissue ex vivo.

Hemodynamics, renal function, plasma renin, and aldosterone in man after 5 to 14 days of bedrest

NASA Technical Reports Server (NTRS)

Melada, G. A.; Goldman, R. H.; Luetscher, J. A.; Zager, P. G.

1975-01-01

Continuous bedrest for 5 to 14 days had no significant effect on resting heart rate, blood pressure, or cardiac output in six normal men. Head-up tilt induced greater tachycardia in 5 of 6 patients after bed rest than in the control period. Propranolol diminished both tachycardia and the incidence of hypotension and faintness in upright posture. Plasma volume fell, extracellular fluid volume increased, and plasma renin activity was significantly elevated following bedrest. Unusually large increases in plasma renin followed head-up tilt or administration of isoproterenol during bedrest and after resuming normal activity. During bedrest, plasma aldosterone was often increased in the early morning. It is concluded that after bedrest, upright posture evokes strong beta-adrenergic activity as well as exaggerated metabolic and circulatory responses which can be reduced or abolished by the beta-adrenergic blocker, propranolol.

Blood Volume: Importance and Adaptations to Exercise Training, Environmental Stresses and Trauma/Sickness

NASA Technical Reports Server (NTRS)

Sawka, Michael N.; Convertino, Victor A.; Eichner, E. Randy; Schnieder, Suzanne M.; Young, Andrew J.

2000-01-01

This paper reviews the influence of several perturbations (physical exercise, heat stress, terrestrial altitude, microgravity, and trauma/sickness) on adaptations of blood volume (BV), erythrocyte volume (EV), and plasma volume (PV). Exercise training can induced BV expansion; PV expansion usually occurs immediately, but EV expansion takes weeks. EV and PV expansion contribute to aerobic power improvements associated with exercise training. Repeated heat exposure induces PV expansion but does not alter EV. PV expansion does not improve thermoregulation, but EV expansion improves thermoregulation during exercise in the heat. Dehydration decreases PV (and increases plasma tonicity) which elevates heat strain and reduces exercise performance. High altitude exposure causes rapid (hours) plasma loss. During initial weeks at altitude, EV is unaffected, but a gradual expansion occurs with extended acclimatization. BV adjustments contribute, but are not key, to altitude acclimatization. Microgravity decreases PV and EV which contribute to orthostatic intolerance and decreased exercise capacity in astronauts. PV decreases may result from lower set points for total body water and central venous pressure, which EV decrease bay result form increased erythrocyte destruction. Trauma, renal disease, and chronic diseases cause anemia from hemorrhage and immune activation, which suppressions erythropoiesis. The re-establishment of EV is associated with healing, improved life quality, and exercise capabilities for these injured/sick persons.

Activation of the ventral and dorsal striatum during cue reactivity in Internet gaming disorder

PubMed Central

Liu, Lu; Yip, Sarah W.; Zhang, Jin-Tao; Wang, Ling-Jiao; Shen, Zi-Jiao; Liu, Ben; Ma, Shan-Shan; Yao, Yuan-Wei; Fang, Xiao-Yi

2017-01-01

Studies conducted in drug addiction suggest a transition in processing of drug-related cues from the ventral to the dorsal component of the striatum. However, this process has not been studied in a behavioral addiction. Assessment of this process in a non-drug addiction can provide insight into the pathophysiology of both substance and behavioral addictions. Thirty-nine male IGD subjects and 23 male matched healthy controls (HCs) participated in functional magnetic resonance imaging (fMRI) during performance of a cue-reactivity task involving alternating presentation of Internet gaming-related stimuli (game cues) and general Internet surfing-related stimuli (control cues). Cue-induced neural activations in the ventral and dorsal striatum were compared between IGD and HC participants. Associations between cue-reactivity within these regions and cue-induced craving and severity and duration of IGD were also explored. IGD participants exhibited higher cue-induced activations within both the ventral and dorsal striatum (DS) when compared to HCs. Within the IGD group, activity within the left ventral striatum (VS) was correlated negatively with cue-induced craving; positive associations were found between activations within the DS (right putamen, pallidum and left caudate) and duration of IGD. Cue-induced activity within the left putamen was negatively associated with right VS volumes among IGD participants. Consistent with studies in substance addictions, our results suggest that a transition from ventral to dorsal striatal processing may occur among individuals with Internet gaming disorder, a condition without the impact of substance intake. PMID:26732520

Nicotinamide attenuates the ischemic brain injury-induced decrease of Akt activation and Bad phosphorylation.

PubMed

Koh, Phil-Ok

2011-07-08

Nicotinamide protects cortical neuronal cells against cerebral ischemic injury through activation of various cytoprotective mechanisms. Here, this study confirmed the neuroprotective effects of nicotinamide in focal cerebral ischemic injury and investigated whether nicotinamide modulates a crucial survival pathway, Akt and its downstream targets. Adult male rats were treated with vehicle or nicotinamide (500 mg/kg) 2h after the onset of middle cerebral artery occlusion (MCAO). Brains were collected 24h after MCAO and infarct volumes were analyzed. Nicotinamide significantly reduced the infarct volume in the cerebral cortex. Potential activation was measured by phosphorylation of PDK1 at Ser(241), Akt at Ser(473), and Bad at Ser(136) using Western blot analysis. Nicotinamide prevented the injury-induced decrease of pPDK1, pAkt, and pBad levels. 14-3-3 levels were not different between vehicle- and nicotinamide-treated animals. However, pBad and 14-3-3 interaction levels decreased during MCAO, but were maintained in the presence of nicotinamide, compared to levels in control animals. These findings suggest that nicotinamide attenuates cell death due to focal cerebral ischemic injury and that neuroprotective effects are mediated through the Akt signaling pathway, thus enhancing neuronal survival. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats.

PubMed

Mundhe, Nitin Arunrao; Kumar, Parveen; Ahmed, Sahabuddin; Jamdade, Vinayak; Mundhe, Sanjay; Lahkar, Mangala

2015-09-01

Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats. Copyright © 2015 Elsevier B.V. All rights reserved.

Treatment with adipose derived mesenchymal stem cells and their conditioned media reverse carrageenan induced paw oedema in db/db mice.

PubMed

Shree, Nitya; Venkategowda, Sunil; Venkatranganna, M V; Bhonde, Ramesh R

2017-06-01

Mesenchymal stem cells are known for anti inflammatory and immunomodulatory activities. The aim of our study was to evaluate the effect of human adipose derived mesenchymal stem cells (hADMSCs) and its conditioned media (CM) on carrageenan induced acute inflammation in db/db mice. We injected 5×10 5 ADMSCs or the CM in the inflamed paw. We assessed the paw volume, serum IL6 levels and histopathology of the paw to reveal the anti inflammatory effect. We observed a single injection of hADMSCs or CM could reverse the inflammation within 24h as evidenced by reduction in paw volume, IL6 levels and histological examination. Our result equivocally demonstrates the role of CM in normalising the inflammation better than hADMSCs. This study will pave way for an alternative to anti inflammatory drugs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Transient flows in active porous media

NASA Astrophysics Data System (ADS)

Kosmidis, Lefteris I.; Jensen, Kaare H.

2017-06-01

Stimuli-responsive materials that modify their shape in response to changes in environmental conditions—such as solute concentration, temperature, pH, and stress—are widespread in nature and technology. Applications include micro- and nanoporous materials used in filtration and flow control. The physiochemical mechanisms that induce internal volume modifications have been widely studied. The coupling between induced volume changes and solute transport through porous materials, however, is not well understood. Here, we consider advective and diffusive transport through a small channel linking two large reservoirs. A section of stimulus-responsive material regulates the channel permeability, which is a function of the local solute concentration. We derive an exact solution to the coupled transport problem and demonstrate the existence of a flow regime in which the steady state is reached via a damped oscillation around the equilibrium concentration value. Finally, the feasibility of an experimental observation of the phenomena is discussed.

[Effect of epsilon-aminocaproic acid, cyclophosphamide and their combination on the growth of autochthonous sarcomas of mice induced by benzo(a)pyrene].

PubMed

Anikin, I V; Tyndyk, M L; Zabezhinskiĭ, M A; Popovich, I G; Anisimov, V N; Pliss, G B

2014-01-01

Antifibrinolytic drug epsilon-aminocaproic acid as a therapeutic form (5% solution in saline) was tested for antitumor activity in the autochthonous subcutaneous tumors of mice, induced by benzo (a) pyrene, in monotherapy mode (instead animals received drinking water) and in combination with cyclophosphamide, which was administered once intraperitoneally in the dose of 200 mg/kg. In the control groups, treated with drinking water and saline solution instead of water, there was no stabilization and reduction in tumor volume, while in the groups receiving epsilon-aminocaproic acid, cyclophosphamide and their combination statistically significantly in comparison with the control groups there was increased the proportion of tumors with not changed or reduced volume; epsilon-aminocaproic acid enhanced the antitumor effect of cyclophosphamide. The data obtained are for further study of the antitumor effect of epsilon-aminocaproic acid.

Chloride channels in stroke

PubMed Central

Zhang, Ya-ping; Zhang, Hao; Duan, Dayue Darrel

2013-01-01

Vascular remodeling of cerebral arterioles, including proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMCs), is the major cause of changes in the cross-sectional area and diameter of the arteries and sudden interruption of blood flow or hemorrhage in the brain, ie, stroke. Accumulating evidence strongly supports an important role for chloride (Cl−) channels in vascular remodeling and stroke. At least three Cl− channel genes are expressed in VSMCs: 1) the TMEM16A (or Ano1), which may encode the calcium-activated Cl− channels (CACCs); 2) the CLC-3 Cl− channel and Cl−/H+ antiporter, which is closely related to the volume-regulated Cl− channels (VRCCs); and 3) the cystic fibrosis transmembrane conductance regulator (CFTR), which encodes the PKA- and PKC-activated Cl− channels. Activation of the CACCs by agonist-induced increase in intracellular Ca2+ causes membrane depolarization, vasoconstriction, and inhibition of VSMC proliferation. Activation of VRCCs by cell volume increase or membrane stretch promotes the production of reactive oxygen species, induces proliferation and inhibits apoptosis of VSMCs. Activation of CFTR inhibits oxidative stress and may prevent the development of hypertension. In addition, Cl− current mediated by gamma-aminobutyric acid (GABA) receptor has also been implicated a role in ischemic neuron death. This review focuses on the functional roles of Cl− channels in the development of stroke and provides a perspective on the future directions for research and the potential to develop Cl− channels as new targets for the prevention and treatment of stroke. PMID:23103617

Finite volume analysis of temperature effects induced by active MRI implants with cylindrical symmetry: 1. Properly working devices.

PubMed

Busch, Martin H J; Vollmann, Wolfgang; Schnorr, Jörg; Grönemeyer, Dietrich H W

2005-04-08

Active Magnetic Resonance Imaging implants are constructed as resonators tuned to the Larmor frequency of a magnetic resonance system with a specific field strength. The resonating circuit may be embedded into or added to the normal metallic implant structure. The resonators build inductively coupled wireless transmit and receive coils and can amplify the signal, normally decreased by eddy currents, inside metallic structures without affecting the rest of the spin ensemble. During magnetic resonance imaging the resonators generate heat, which is additional to the usual one described by the specific absorption rate. This induces temperature increases of the tissue around the circuit paths and inside the lumen of an active implant and may negatively influence patient safety. This investigation provides an overview of the supplementary power absorbed by active implants with a cylindrical geometry, corresponding to vessel implants such as stents, stent grafts or vena cava filters. The knowledge of the overall absorbed power is used in a finite volume analysis to estimate temperature maps around different implant structures inside homogeneous tissue under worst-case assumptions. The "worst-case scenario" assumes thermal heat conduction without blood perfusion inside the tissue around the implant and mostly without any cooling due to blood flow inside vessels. The additional power loss of a resonator is proportional to the volume and the quality factor, as well as the field strength of the MRI system and the specific absorption rate of the applied sequence. For properly working devices the finite volume analysis showed only tolerable heating during MRI investigations in most cases. Only resonators transforming a few hundred mW into heat may reach temperature increases over 5 K. This requires resonators with volumes of several ten cubic centimeters, short inductor circuit paths with only a few 10 cm and a quality factor above ten. Using MR sequences, for which the MRI system manufacturer declares the highest specific absorption rate of 4 W/kg, vascular implants with a realistic construction, size and quality factor do not show temperature increases over a critical value of 5 K. The results show dangerous heating for the assumed "worst-case scenario" only for constructions not acceptable for vascular implants. Realistic devices are safe with respect to temperature increases. However, this investigation discusses only properly working devices. Ruptures or partial ruptures of the wires carrying the electric current of the resonance circuits or other defects can set up a power source inside an extremely small volume. The temperature maps around such possible "hot spots" should be analyzed in an additional investigation.

Betanin attenuates carbon tetrachloride (CCl4)-induced liver injury in common carp (Cyprinus carpio L.).

PubMed

Han, Junyan; Gao, Cheng; Yang, Shaobin; Wang, Jun; Tan, Dehong

2014-06-01

This study investigates the protective effect of betanin against liver injury induced by carbon tetrachloride (CCl4) in common carp (Cyprinus carpio L.). The fish were treated with 1, 2, and 4 % betanin in fodder throughout the experiment. After 20 days of treatment, the fish were intraperitoneally injected with 20 % (v/v in peanut oil) CCl4 at a volume of 0.5 mL/kg body weight. The fish were killed 3 days after CCl4 intoxication, and then, histological and biochemical assays were performed. Results showed that CCl4-induced liver CYP2E1 activity, oxidative stress, and injury, as indicated by the depleted glycogen storage, increased serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) activities and liver histological damage. Compared with the CCl4 control group, the betanin-treated groups exhibited reduced CYP2E1 activity, decreased malondialdehyde level, increased liver antioxidative capacity (increased glutathione level and superoxide dismutase and catalase activities), increased liver glycogen storage, and reduced serum AST/ALT activities, with significant differences in the 2 and 4 % groups (p < 0.05). Histological assay further confirmed the protective effect of betanin. In conclusion, betanin attenuates CCl4-induced liver damage in common carp. Moreover, the inhibition of CYP2E1 activity and oxidative stress may have significant roles in the protective effect of betanin.

Cooperative mechanisms involved in chronic antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus.

PubMed

Moosavi, S M S; Karimi, Z

2014-03-01

Previous studies of central diabetes insipidus suggested that thiazides acutely exerted a paradoxical antidiuresis by either indirectly activating volume-homeostatic reflexes to decrease distal fluid-delivery, or directly stimulating distal water-reabsorption. This study investigated whether the direct and indirect actions of bendroflumethiazide (BFTZ) simultaneously cooperated and also whether the renal nerves were involved in inducing long-term antidiuresis in nephrogenic diabetes insipidus (NDI). BFTZ or vehicle was gavaged into bilateral renal denervated and innervated rats with lithium-induced NDI for 10 days, constituting four groups. At one day before (D0) and one, five and ten days after starting administration of BFTZ or vehicle, rats were placed in metabolic cages to collect urine for 6 hours. BFTZ-treatment in both renal innervated and denervated rats caused equivalent reductions in urine-flow, creatinine clearance, lithium clearance and free-water clearance, but rises in urine-osmolality, fractional proximal reabsorption and fractional distal reabsorption at all days compared to D0, as well as to those of their relevant vehicle-received group. Therefore, the chronic antidiuretic response to BFTZ in conscious NDI rats was exerted through a concomitant cooperation of its direct distal effect of stimulating water-reabsorption and its indirect effect of reducing distal fluid-delivery by activating volume-homeostatic mechanisms, which appeared independent of the renal nerves.

Effect of micro-stirring on enzymatic reaction kinetics inside a biomimetic container

NASA Astrophysics Data System (ADS)

Gozen, Irep; Horowitz, Viva; Chambers, Zachary; Manoharan, Vinothan

The intracellular environment is dynamic, influenced by the motion of active machinery such as cytoskeleton filaments and molecular motors. To understand whether and how such activity affects the rates of diffusion-limited reactions, we construct a model system consisting of a phospholipid vesicle encapsulating a small number of micro- or nanoparticles, the active motion of which can be induced by chemical or magnetic cues. We aim to determine a relation between active motion of particles and rates of enzymatic reactions in the confined volume. Our findings might illuminate how active motion influences cytoplasmic reaction dynamics, or may have played a role in protocell genetics.

Hemodynamic and ADH responses to central blood volume shifts in cardiac-denervated humans

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Thompson, C. A.; Benjamin, B. A.; Keil, L. C.; Savin, W. M.; Gordon, E. P.; Haskell, W. L.; Schroeder, J. S.; Sandler, H.

1990-01-01

Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes designed to induce blood volume shifts in ten cardiac transplant recipients to assess the contribution of cardiac and vascular volume receptors in the control of ADH secretion. Each subject underwent 15 min of a control period in the seated posture, then assumed a lying posture for 30 min at 6 deg head down tilt (HDT) followed by 20 min of seated recovery. Venous blood samples and cardiac dimensions (echocardiography) were taken at 0 and 15 min before HDT, 5, 15, and 30 min of HDT, and 5, 15, and 30 min of seated recovery. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Resting plasma volume (PV) was measured by Evans blue dye and percent changes in PV during posture changes were calculated from changes in hematocrit. Heart rate (HR) and blood pressure (BP) were recorded every 2 min. Results indicate that cardiac volume receptors are not the only mechanism for the control of ADH release during acute blood volume shifts in man.

Functional photoacoustic imaging to observe regional brain activation induced by cocaine hydrochloride

NASA Astrophysics Data System (ADS)

Jo, Janggun; Yang, Xinmai

2011-09-01

Photoacoustic microscopy (PAM) was used to detect small animal brain activation in response to drug abuse. Cocaine hydrochloride in saline solution was injected into the blood stream of Sprague Dawley rats through tail veins. The rat brain functional change in response to the injection of drug was then monitored by the PAM technique. Images in the coronal view of the rat brain at the locations of 1.2 and 3.4 mm posterior to bregma were obtained. The resulted photoacoustic (PA) images showed the regional changes in the blood volume. Additionally, the regional changes in blood oxygenation were also presented. The results demonstrated that PA imaging is capable of monitoring regional hemodynamic changes induced by drug abuse.

Plasminogen Activator Inhibitor-1 Deficiency Augments Visceral Mesothelial Organization, Intrapleural Coagulation, and Lung Restriction in Mice with Carbon Black/Bleomycin–Induced Pleural Injury

PubMed Central

Jeffers, Ann; Alvarez, Alexia; Owens, Shuzi; Koenig, Kathleen; Quaid, Brandon; Komissarov, Andrey A.; Florova, Galina; Kothari, Hema; Pendurthi, Usha; Mohan Rao, L. Vijaya; Idell, Steven

2014-01-01

Local derangements of fibrin turnover and plasminogen activator inhibitor (PAI)-1 have been implicated in the pathogenesis of pleural injury. However, their role in the control of pleural organization has been unclear. We found that a C57Bl/6j mouse model of carbon black/bleomycin (CBB) injury demonstrates pleural organization resulting in pleural rind formation (14 d). In transgenic mice overexpressing human PAI-1, intrapleural fibrin deposition was increased, but visceral pleural thickness, lung volumes, and compliance were comparable to wild type. CBB injury in PAI-1−/− mice significantly increased visceral pleural thickness (P < 0.001), elastance (P < 0.05), and total lung resistance (P < 0.05), while decreasing lung compliance (P < 0.01) and lung volumes (P < 0.05). Collagen, α-smooth muscle actin, and tissue factor were increased in the thickened visceral pleura of PAI-1−/− mice. Colocalization of α-smooth muscle actin and calretinin within pleural mesothelial cells was increased in CBB-injured PAI-1−/− mice. Thrombin, factor Xa, plasmin, and urokinase induced mesothelial–mesenchymal transition, tissue factor expression, and activity in primary human pleural mesothelial cells. In PAI-1−/− mice, D-dimer and thrombin–antithrombin complex concentrations were increased in pleural lavage fluids. The results demonstrate that PAI-1 regulates CBB-induced pleural injury severity via unrestricted fibrinolysis and cross-talk with coagulation proteases. Whereas overexpression of PAI-1 augments intrapleural fibrin deposition, PAI-1 deficiency promotes profibrogenic alterations of the mesothelium that exacerbate pleural organization and lung restriction. PMID:24024554

The effect of stinging nettle (Urtica dioica) seed oil on experimental colitis in rats.

PubMed

Genc, Zeynep; Yarat, Aysen; Tunali-Akbay, Tugba; Sener, Goksel; Cetinel, Sule; Pisiriciler, Rabia; Caliskan-Ak, Esin; Altıntas, Ayhan; Demirci, Betul

2011-12-01

This study investigated the effect of Urtica dioica, known as stinging nettle, seed oil (UDO) treatment on colonic tissue and blood parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Experimental colitis was induced with 1 mL of TNBS in 40% ethanol by intracolonic administration with a 8-cm-long cannula with rats under ether anesthesia, assigned to a colitis group and a colitis+UDO group. Rats in the control group were given saline at the same volume by intracolonic administration. UDO (2.5 mL/kg) was given to the colitis+UDO group by oral administration throughout a 3-day interval, 5 minutes later than colitis induction. Saline (2.5 mL/kg) was given to the control and colitis groups at the same volume by oral administration. At the end of the experiment macroscopic lesions were scored, and the degree of oxidant damage was evaluated by colonic total protein, sialic acid, malondialdehyde (MDA), and glutathione levels, collagen content, tissue factor activity, and superoxide dismutase and myeloperoxidase activities. Colonic tissues were also examined by histological and cytological analysis. Pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), lactate dehydrogenase activity, and triglyceride and cholesterol levels were analyzed in blood samples. We found that UDO decreased levels of pro-inflammatory cytokines, lactate dehydrogenase, triglyceride, and cholesterol, which were increased in colitis. UDO administration ameliorated the TNBS-induced disturbances in colonic tissue except for MDA. In conclusion, UDO, through its anti-inflammatory and antioxidant actions, merits consideration as a potential agent in ameliorating colonic inflammation.

Relationships between Induced Seismicity and Fluid Injection: Development of Strategies to Manage Injection

NASA Astrophysics Data System (ADS)

Eichhubl, Peter; Frohlich, Cliff; Gale, Julia; Olson, Jon; Fan, Zhiqiang; Gono, Valerie

2014-05-01

Induced seismicity during or following the subsurface injection of waste fluids such as well stimulation flow back and production fluids has recently received heightened public and industry attention. It is understood that induced seismicity occurs by reactivation of existing faults that are generally present in the injection intervals. We seek to address the question why fluid injection triggers earthquakes in some areas and not in others, with the aim toward improved injection methods that optimize injection volume and cost while avoiding induced seismicity. A GIS database has been built of natural and induced earthquakes in four hydrocarbon-producing basins: the Fort Worth Basin, South Texas, East Texas/Louisiana, and the Williston Basin. These areas are associated with disposal from the Barnett, Eagle Ford, Bakken, and Haynesville Shales respectively. In each region we analyzed data that were been collected using temporary seismographs of the National Science Foundation's USArray Transportable Array. Injection well locations, formations, histories, and volumes are also mapped using public and licensed datasets. Faults are mapped at a range of scales for selected areas that show different levels of seismic activity, and scaling relationships used to extrapolate between the seismic and wellbore scale. Reactivation potential of these faults is assessed using fault occurrence, and in-situ stress conditions, identifying areas of high and low fault reactivation potential. A correlation analysis between fault reactivation potential, induced seismicity, and fluid injection will use spatial statistics to quantify the probability of seismic fault reactivation for a given injection pressure in the studied reservoirs. The limiting conditions inducing fault reactivation will be compared to actual injection parameters (volume, rate, injection duration and frequency) where available. The objective of this project is a statistical reservoir- to basin-scale assessment of fault reactivation and seismicity induced by fluid injection. By assessing the occurrence of earthquakes (M>2) evenly across large geographic regions, this project differs from previous studies of injection-induced seismicity that focused on earthquakes large enough to cause public concern in well-populated areas. The understanding of triggered seismicity gained through this project is expected to allow for improved design strategies for waste fluid injection to industry and public decision makers.

Combination of Extracorporeal Life Support and Mesenchymal Stem Cell Therapy for Treatment of ARDS in Combat Casualties and Evacuation of Service Members with ARDS

DTIC Science & Technology

2017-10-01

invasiveness of mechanical ventilation and inflammatory mediators as well as improvement in oxygenation and functional outcome. 4 Keywords Acute...The Clark system is allowing us to measure the mitochondrial activity by the oxygen consumption during activation. Because the LPS-induced injury we... Ventilation • Tidal Volume • Respiratory Rate • Peak inspiratory Pressure • Positive End Expiratory Pressure (PEEP) • Fraction of inspired oxygen

Activity-induced clustering in model dumbbell swimmers: the role of hydrodynamic interactions.

PubMed

Furukawa, Akira; Marenduzzo, Davide; Cates, Michael E

2014-08-01

Using a fluid-particle dynamics approach, we numerically study the effects of hydrodynamic interactions on the collective dynamics of active suspensions within a simple model for bacterial motility: each microorganism is modeled as a stroke-averaged dumbbell swimmer with prescribed dipolar force pairs. Using both simulations and qualitative arguments, we show that, when the separation between swimmers is comparable to their size, the swimmers' motions are strongly affected by activity-induced hydrodynamic forces. To further understand these effects, we investigate semidilute suspensions of swimmers in the presence of thermal fluctuations. A direct comparison between simulations with and without hydrodynamic interactions shows these to enhance the dynamic clustering at a relatively small volume fraction; with our chosen model the key ingredient for this clustering behavior is hydrodynamic trapping of one swimmer by another, induced by the active forces. Furthermore, the density dependence of the motility (of both the translational and rotational motions) exhibits distinctly different behaviors with and without hydrodynamic interactions; we argue that this is linked to the clustering tendency. Our study illustrates the fact that hydrodynamic interactions not only affect kinetic pathways in active suspensions, but also cause major changes in their steady state properties.

Activity-induced clustering in model dumbbell swimmers: The role of hydrodynamic interactions

NASA Astrophysics Data System (ADS)

Furukawa, Akira; Marenduzzo, Davide; Cates, Michael E.

2014-08-01

Using a fluid-particle dynamics approach, we numerically study the effects of hydrodynamic interactions on the collective dynamics of active suspensions within a simple model for bacterial motility: each microorganism is modeled as a stroke-averaged dumbbell swimmer with prescribed dipolar force pairs. Using both simulations and qualitative arguments, we show that, when the separation between swimmers is comparable to their size, the swimmers' motions are strongly affected by activity-induced hydrodynamic forces. To further understand these effects, we investigate semidilute suspensions of swimmers in the presence of thermal fluctuations. A direct comparison between simulations with and without hydrodynamic interactions shows these to enhance the dynamic clustering at a relatively small volume fraction; with our chosen model the key ingredient for this clustering behavior is hydrodynamic trapping of one swimmer by another, induced by the active forces. Furthermore, the density dependence of the motility (of both the translational and rotational motions) exhibits distinctly different behaviors with and without hydrodynamic interactions; we argue that this is linked to the clustering tendency. Our study illustrates the fact that hydrodynamic interactions not only affect kinetic pathways in active suspensions, but also cause major changes in their steady state properties.

Hypervolemia and plasma vasopressin response during water immersion in men

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.; Morse, J. T.; Barnes, P. R.; Silver, J.; Keil, L. C.

1983-01-01

Immersion studies were performed on seven mildly dehydrated male subjects to examine the effect of suppression of plasma vasopressin (PVP) on diuresis in water immersion. The water was kept at close to 34.5 C and the subjects remained in the water for 4 hr after sitting for 2 hr. Na and K levels in the serum and urine were analyzed, as were osmolality, red blood cell count, renin activity, total protein, albumin amounts, hematocrit, and hemoglobin. Plasma volume was monitored from samples drawn at specified intervals during immersion. The plasma volume increased significantly 30 min after immersion, but no PVP was observed. The dehydration induced elevated serum osmotic concentrations. It is concluded that the hydration condition before immersion and the volume of fluid intake during immersion affects the hemodilution during immersion.

Oxygen-sensitive regulatory volume increase and Na transport in red blood cells from the cane toad, Bufo marinus.

PubMed

Kristensen, Karina; Koldkjaer, Pia; Berenbrink, Michael; Wang, Tobias

2007-07-01

The red blood cells (RBCs) of cane toad, Bufo marinus, are only partially saturated with oxygen in most of the circulation due to cardiac shunts that cause desaturation of arterial blood. The present study examines the oxygen dependency of RBC ouabain-insensitive unidirectional Na transport, using 22Na, in control cells and in cells exposed to hyperosmotic shrinkage or the beta-adrenergic agonist isoproterenol. Deoxygenation per se induced a slow, but significant Na influx, which was paralleled by a slow increase in RBC volume. Hyperosmotic shrinkage by a calculated 25% activated a robust Na influx that in the first 30 min had a strong PO2 dependency with maximal activation at low PO2 values and a P50 of approximately 5.5 kPa. This activation was completely abolished by the Na/H exchanger (NHE) inhibitor EIPA (10(-4) mol l(-1)). Hyperosmotic shrinkage is particularly interesting in B. marinus as it withstands considerable elevation in extracellular osmolarity following dehydration. Parallel studies showed that deoxygenated B. marinus RBCs had a much faster regulatory volume increase (RVI) response than air-equilibrated RBCs, reflecting the difference in magnitude of Na influxes at the two PO2 values. The extent of RVI ( approximately 60%) after 90 min, however, was similar under the two conditions, reflecting a more prolonged elevation of the shrinkage-induced Na influx in air-equilibrated RBCs. There were no significant differences in the ability to perform RVI between whole blood cells at a PCO2 of 1 and 3 kPa or washed RBCs, and 10(-4) mol l(-1) amiloride reduced the RVI under all conditions, whereas 10(-5) mol l(-1) bumetanide had no effect. Isoproterenol (10(-5) mol l(-1)) induced a significant and prolonged increase in an EIPA-sensitive and bumetanide-insensitive Na influx at low PO2 under iso-osmotic conditions, whilst there was no stimulation by isoproterenol for up to 45 min in air-equilibrated RBCs. The prolonged beta-adrenergic activation of the Na influx at low PO2 is distinctly different from the rapid and transient stimulation in teleost RBCs, suggesting significant differences in the signal transduction pathways leading to transporter activation between vertebrate groups.

The free-radical scavenger edaravone accelerates thrombolysis with alteplase in an experimental thrombosis model.

PubMed

Yamashita, Tsutomu; Sato, Takumi; Sakamoto, Kumi; Ishii, Hiromitsu; Yamamoto, Junichiro

2015-06-01

Reperfusion injury after thrombolytic therapy can have adverse neurologic effects. The free-radical scavenger edaravone is used in combination with the recombinant tissue plasminogen activator alteplase to treat acute ischemic stroke. However, basic investigations of this combination use remain inadequate. Here, we used an in vivo model to investigate the effects of edaravone on alteplase-induced thrombolysis. Thrombolysis was evaluated by using a He-Ne-laser-induced thrombosis model in rat mesenteric microvessels. Changes in thrombus volume were analyzed with the image analysis software Image-Pro Plus (Media Cybernetics, USA). There were three experimental groups (placebo, alteplase 0.6 mg/kg, alteplase 0.6 mg/kg + edaravone 10.5 mg/kg). Sequential changes (0 to 60 min) in thrombus volume were compared by using a relative optical density method that we had used previously. In the placebo group, the thrombus volume at 60 min, reflecting the extent of thrombolysis, was 97.2% ± 5.7% of the initial value. In the alteplase group, thrombus volume decreased to 70.7% ± 4.1% (P<0.01) after 20 min and 14.2% ± 6.6% after 60 min. In the alteplase+edaravone group, thrombus volume decreased to 66.9% ± 7.2% (P<0.001) after 10 min and 10.9% ± 2.3% after 60 min. These results support the hypothesis that edaravone accelerates thrombolysis by alteplase. Copyright © 2015 Elsevier Ltd. All rights reserved.

Great heterogeneity of commercial fruit juices to induce endothelium-dependent relaxations in isolated porcine coronary arteries: role of the phenolic content and composition.

PubMed

Auger, Cyril; Pollet, Brigitte; Arnold, Cécile; Marx, Céline; Schini-Kerth, Valérie B

2015-01-01

Since polyphenol-rich products such as red wine, grape juice, and grape extracts have been shown to induce potent endothelium-dependent relaxations, we have evaluated whether commercial fruit juices such as those from berries are also able to induce endothelium-dependent relaxations of isolated coronary arteries and, if so, to determine whether this effect is related to their phenolic content. Among the 51 fruit juices tested, 2/12 grape juices, 3/7 blackcurrant juices, 4/5 cranberry juices, 1/6 apple juices, 0/5 orange juices, 2/6 red fruit and berry juices, 3/6 blends of red fruit juices, and 0/4 non-red fruit juices were able to induce relaxations achieving more than 50% at a volume of 1%. The active fruit juices had phenolic contents ranging from 0.31 to 1.86 g GAE/L, which were similar to those of most of the less active juices with the exception of one active grape juice (2.14 g GAE/L) and one active blend of red fruit juices (3.48 g GAE/L). Altogether, these findings indicate that very few commercial fruit juices have the ability to induce potent endothelium-dependent relaxations, and that this effect is not related to their quantitative phenolic content, but rather to their qualitative phenolic composition.

DCPIB, a potent volume-regulated anion channel antagonist, attenuates microglia-mediated inflammatory response and neuronal injury following focal cerebral ischemia.

PubMed

Han, Qingdong; Liu, Shengwen; Li, Zhengwei; Hu, Feng; Zhang, Qiang; Zhou, Min; Chen, Jingcao; Lei, Ting; Zhang, Huaqiu

2014-01-13

Accumulating evidence indicates that extensive microglia activation-mediated local inflammation contributes to neuronal injury in cerebral ischemia. We have previously shown that 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), a potent volume-regulated anion channel (VRAC) inhibitor, suppresses pathological glutamate release and excitatory neurotoxicity in reversible middle cerebral artery occlusion (rMCAO) model in vivo. In the present study, we sought to determine whether DCPIB also attenuates microglia activation that could contribute to neuronal injury in the cerebral ischemia/reperfusion pathology. We show that oxygen-glucose deprivation (OGD) induced microglia proliferation, migration, and secretion of cytokines and all these pathological changes were effectively inhibited by DCPIB in vitro. In the microglia/neuron co-cultures, OGD induced neuronal damage was reduced markedly in the presence of DCPIB. In rat rMCAO animal model, DCPIB significantly attenuated microglia activation and neuronal death. Activation of mitogen-activated protein kinase (MAPK) signaling pathway is known to be a critical signaling pathway for microglia activation. We further explored a potential involvement of DCPIB in this pathway by western blot analysis. Under the conditions that MAPK pathway was activated either by lipopolysaccharides (LPS) or OGD, the levels of phosphorylated ERK1/2, JNK and p38 were reduced significantly in the presence of DCPIB. Altogether, our study demonstrated that DCPIB inhibits microglia activation potently under ischemic conditions both in vitro and in vivo. The DCPIB effect is likely attributable to both direct inhibition VRAC and indirect inhibition of MAPK pathway in microglia that are beneficial for the survival of neurons in cerebral ischemic conditions. © 2013 Elsevier B.V. All rights reserved.

Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation

PubMed Central

Sørensen, Belinda Halling; Nielsen, Dorthe; Thorsteinsdottir, Unnur Arna; Hoffmann, Else Kay

2016-01-01

The leucine-rich repeat containing 8A (LRRC8A) protein is an essential component of the volume-sensitive organic anion channel (VSOAC), and using pharmacological anion channel inhibitors (NS3728, DIDS) and LRRC8A siRNA we have investigated its role in development of Cisplatin resistance in human ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21Waf1/Cip1, Bax, Noxa, MDM2, and activation of Caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter apoptosis, i.e., their p53 and downstream signaling are reduced and caspase activity unaltered following Cisplatin exposure. Reduced LRRC8A expression and VSOAC activity are previously shown to correlate with Cisplatin resistance, and here we demonstrate that pharmacological inhibition and transient knockdown of LRRC8A reduce the protein level of p53, MDM2, and p21Waf1/Cip1 as well as Caspase-9/-3 activation in Cisplatin-sensitive cells. Cisplatin resistance is accompanied by reduction in total LRRC8A expression (A2780) or LRRC8A expression in the plasma membrane (A549). Activation of Caspase-3 dependent apoptosis by TNFα-exposure or hyperosmotic cell shrinkage is almost unaffected by pharmacological anion channel inhibition. Our data indicate 1) that expression/activity of LRRC8A is essential for Cisplatin-induced increase in p53 protein level and its downstream signaling, i.e., Caspase-9/-3 activation, expression of p21Waf1/Cip1 and MDM2; and 2) that downregulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A-containing channels is upstream to apoptotic volume decrease as hypertonic cell shrinkage induces apoptosis independent of the presence of LRRC8A. PMID:26984736

Respiratory Sinus Arrhythmia as an Index of Vagal Activity during Stress in Infants: Respiratory Influences and Their Control

PubMed Central

Ritz, Thomas; Bosquet Enlow, Michelle; Schulz, Stefan M.; Kitts, Robert; Staudenmayer, John; Wright, Rosalind J.

2012-01-01

Respiratory sinus arrhythmia (RSA) is related to cardiac vagal outflow and the respiratory pattern. Prior infant studies have not systematically examined respiration rate and tidal volume influences on infant RSA or the extent to which infants' breathing is too fast to extract a valid RSA. We therefore monitored cardiac activity, respiration, and physical activity in 23 six-month old infants during a standardized laboratory stressor protocol. On average, 12.6% (range 0–58.2%) of analyzed breaths were too short for RSA extraction. Higher respiration rate was associated with lower RSA amplitude in most infants, and lower tidal volume was associated with lower RSA amplitude in some infants. RSA amplitude corrected for respiration rate and tidal volume influences showed theoretically expected strong reductions during stress, whereas performance of uncorrected RSA was less consistent. We conclude that stress-induced changes of peak-valley RSA and effects of variations in breathing patterns on RSA can be determined for a representative percentage of infant breaths. As expected, breathing substantially affects infant RSA and needs to be considered in studies of infant psychophysiology. PMID:23300753

Neuroprotection by the Traditional Chinese Medicine, Tao-Hong-Si-Wu-Tang, against Middle Cerebral Artery Occlusion-Induced Cerebral Ischemia in Rats

PubMed Central

Wu, Chih-Jen; Chen, Jui-Tai; Yen, Ting-Lin; Jayakumar, Thanasekaran; Chou, Duen-Suey; Hsiao, George; Sheu, Joen-Rong

2011-01-01

Tao-Hong-Si-Wu-Tang (THSWT) is a famous traditional Chinese medicine (TMC). In the present study, oral administration of THSWT (0.7 and 1.4 g kg−1day−1) for 14 days before MCAO dose-dependently attenuated focal cerebral ischemia in rats. MCAO-induced focal cerebral ischemia was associated with increases in hypoxia-inducible factor (HIF)-1α, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and active caspase-3 expressions in ischemic regions. These expressions were obviously inhibited by 0.7 g kg−1day−1 THSWT treatment. In addition, THSWT inhibited platelet aggregation stimulated by collagen in washed platelets. In an in vivo study, THSWT (16 g kg−1) significantly prolonged platelet plug formation in mice. However, THSWT (20 and 40 μg mL−1) did not significantly reduce the electron spin resonance (ESR) signal intensity of hydroxyl radical (OH•) formation. In conclusion, the most important findings of this study demonstrate for the first time that THSWT possesses potent neuroprotective activity against MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both HIF-1α and TNF-α activation, followed by the inhibition of inflammatory responses (i.e., iNOS expression), apoptosis formation (active caspase-3), and platelet activation, resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. PMID:21076527

Hydraulic fracturing volume is associated with induced earthquake productivity in the Duvernay play

NASA Astrophysics Data System (ADS)

Schultz, R.; Atkinson, G.; Eaton, D. W.; Gu, Y. J.; Kao, H.

2018-01-01

A sharp increase in the frequency of earthquakes near Fox Creek, Alberta, began in December 2013 in response to hydraulic fracturing. Using a hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We show that induced earthquakes are associated with completions that used larger injection volumes (104 to 105 cubic meters) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have an insignificant association with seismic response. Further findings suggest that geological factors play a prominent role in seismic productivity, as evidenced by spatial correlations. Together, volume and geological factors account for ~96% of the variability in the induced earthquake rate near Fox Creek. This result is quantified by a seismogenic index–modified frequency-magnitude distribution, providing a framework to forecast induced seismicity.

Learnings from the Monitoring of Induced Seismicity in Western Canada over the Past Three Years

NASA Astrophysics Data System (ADS)

Yenier, E.; Moores, A. O.; Baturan, D.; Spriggs, N.

2017-12-01

In response to induced seismicity observed in western Canada, existing public networks have been densified and a number of private networks have been deployed to closely monitor the earthquakes induced by hydraulic fracturing operations in the region. These networks have produced an unprecedented volume of seismic data, which can be used to map pre-existing geological structures and understand their activation mechanisms. Here, we present insights gained over the past three years from induced seismicity monitoring (ISM) for some of the most active operators in Canada. First, we discuss the benefits of high-quality ISM data sets for making operational decisions and how their value largely depends on choice of instrumentation, seismic network design and data processing techniques. Using examples from recent research studies, we illustrate the key role of robust modeling of regional source, attenuation and site attributes on the accuracy of event magnitudes, ground motion estimates and induced seismicity hazard assessment. Finally, acknowledging that the ultimate goal of ISM networks is assisting operators to manage induced seismic risk, we share some examples of how ISM data products can be integrated into existing protocols for developing effective risk management strategies.

Inertial cavitation dose produced ex vivo in rabbit ear arteries with optison

NASA Astrophysics Data System (ADS)

Tu, Juan; Brayman, Andrew; Matula, Thomas

2004-05-01

Ultrasound-induced inertial cavitation (IC) effects were studied ex vivo in rabbit ear arteries with the addition of ultrasound contrast agents (UCAs). Ears were removed from New Zealand white rabbits immediately after being euthanized under a protocol approved by the University of Washington IACUC. The auricular arteries were perfused with varying concentration of UCA (Optison) in saline and exposed to 1.155-MHz pulsed high-intensity focused ultrasound (HIFU) with constant PRF (10 Hz), pulse length (20 cycles), and total treatment time (20 s). Experiments were performed for variable peak negative acoustic pressure (P-) (from 0.19 to 3.31 Mpa) and Optison volume concentration (0% [saline only], 0.1%, 0.2%, 0.5%, and 1%). Cavitation activity was quantified by IC Dose (cumulated root-mean-squared [rms] broadband noise amplitude in a particular band in the frequency domain). The results showed that (1) IC activity was induced much more easily with the addition of Optison, even at low volume concentration, such as 0.1%. (2) IC dose increased significantly with the increasing acoustic pressure and Optison concentration. (3) Higher concentrations of Optison decreased the IC threshold. [Work supported by NIH 8RO1 EB00350-2.

High-pressure protein crystallography of hen egg-white lysozyme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamada, Hiroyuki; Nagae, Takayuki; Watanabe, Nobuhisa, E-mail: nobuhisa@nagoya-u.jp

The crystal structure of hen egg-white lysozyme (HEWL) was analyzed under pressures of up to 950 MPa. The high pressure modified the conformation of the molecule and induced a novel phase transition in the tetragonal crystal of HEWL. Crystal structures of hen egg-white lysozyme (HEWL) determined under pressures ranging from ambient pressure to 950 MPa are presented. From 0.1 to 710 MPa, the molecular and internal cavity volumes are monotonically compressed. However, from 710 to 890 MPa the internal cavity volume remains almost constant. Moreover, as the pressure increases to 950 MPa, the tetragonal crystal of HEWL undergoes a phasemore » transition from P4{sub 3}2{sub 1}2 to P4{sub 3}. Under high pressure, the crystal structure of the enzyme undergoes several local and global changes accompanied by changes in hydration structure. For example, water molecules penetrate into an internal cavity neighbouring the active site and induce an alternate conformation of one of the catalytic residues, Glu35. These phenomena have not been detected by conventional X-ray crystal structure analysis and might play an important role in the catalytic activity of HEWL.« less

Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula

PubMed Central

Červenka, Luděk; Melenovský, Vojtěch; Husková, Zuzana; Sporková, Alexandra; Bürgelová, Marcela; Škaroupková, Petra; Hwang, Sung Hee; Hammock, Bruce D.; Imig, John D.; Sadowski, Janusz

2016-01-01

The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/L in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue. PMID:26047375

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis.

PubMed

Dong, Mei-Xue; Hu, Qing-Chuan; Shen, Peng; Pan, Jun-Xi; Wei, You-Dong; Liu, Yi-Yun; Ren, Yi-Fei; Liang, Zi-Hong; Wang, Hai-Yang; Zhao, Li-Bo; Xie, Peng

2016-01-01

Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger's test were obtained to detect publication bias. We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis

PubMed Central

Wei, You-Dong; Liu, Yi-Yun; Ren, Yi-Fei; Liang, Zi-Hong; Wang, Hai-Yang; Zhao, Li-Bo; Xie, Peng

2016-01-01

Background and Purpose Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Methods Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias. Results We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. Conclusions This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA. PMID:27387385

Combined passive detection and ultrafast active imaging of cavitation events induced by short pulses of high-intensity ultrasound.

PubMed

Gateau, Jérôme; Aubry, Jean-François; Pernot, Mathieu; Fink, Mathias; Tanter, Mickaël

2011-03-01

The activation of natural gas nuclei to induce larger bubbles is possible using short ultrasonic excitations of high amplitude, and is required for ultrasound cavitation therapies. However, little is known about the distribution of nuclei in tissues. Therefore, the acoustic pressure level necessary to generate bubbles in a targeted zone and their exact location are currently difficult to predict. To monitor the initiation of cavitation activity, a novel all-ultrasound technique sensitive to single nucleation events is presented here. It is based on combined passive detection and ultrafast active imaging over a large volume using the same multi-element probe. Bubble nucleation was induced using a focused transducer (660 kHz, f-number = 1) driven by a high-power electric burst (up to 300 W) of one to two cycles. Detection was performed with a linear array (4 to 7 MHz) aligned with the single-element focal point. In vitro experiments in gelatin gel and muscular tissue are presented. The synchronized passive detection enabled radio-frequency data to be recorded, comprising high-frequency coherent wave fronts as signatures of the acoustic emissions linked to the activation of the nuclei. Active change detection images were obtained by subtracting echoes collected in the unnucleated medium. These indicated the appearance of stable cavitating regions. Because of the ultrafast frame rate, active detection occurred as quickly as 330 μs after the high-amplitude excitation and the dynamics of the induced regions were studied individually.

Combined passive detection and ultrafast active imaging of cavitation events induced by short pulses of high-intensity ultrasound

PubMed Central

Gateau, Jérôme; Aubry, Jean-François; Pernot, Mathieu; Fink, Mathias; Tanter, Mickaël

2011-01-01

The activation of natural gas nuclei to induce larger bubbles is possible using short ultrasonic excitations of high amplitude, and is required for ultrasound cavitation therapies. However, little is known about the distribution of nuclei in tissues. Therefore, the acoustic pressure level necessary to generate bubbles in a targeted zone and their exact location are currently difficult to predict. In order to monitor the initiation of cavitation activity, a novel all-ultrasound technique sensitive to single nucleation events is presented here. It is based on combined passive detection and ultrafast active imaging over a large volume and with the same multi-element probe. Bubble nucleation was induced with a focused transducer (660kHz, f#=1) driven by a high power (up to 300 W) electric burst of one to two cycles. Detection was performed with a linear array (4–7MHz) aligned with the single-element focal point. In vitro experiments in gelatin gel and muscular tissue are presented. The synchronized passive detection enabled radio-frequency data to be recorded, comprising high-frequency coherent wave fronts as signatures of the acoustic emissions linked to the activation of the nuclei. Active change detection images were obtained by subtracting echoes collected in the unucleated medium. These indicated the appearance of stable cavitating regions. Thanks to the ultrafast frame rate, active detection occurred as soon as 330 μs after the high amplitude excitation and the dynamics of the induced regions were studied individually. PMID:21429844

Diuretic Activity of Ethanolic Root Extract of Mimosa Pudica in Albino Rats

PubMed Central

SL, Shruthi; PS, Vaibhavi; VH, Pushpa; AM, Satish; Sibgatullah, Mohammad

2015-01-01

Introducation Diuretics are the drugs which increase the urine output. This property is useful in various pathological conditions of fluid overload. The presently available diuretics have lot of adverse effects. Our study has evaluated the diuretic activity of ethanolic root extract of Mimosa pudica as an alternative/new drug which may induce diuresis. Aim To evaluate the diuretic activity of ethanolic root extract of Mimosa pudicaa in albino rats. Materials and Methods Ethanolic root extract of Mimosa pudica (EEMP) was prepared using soxhlet’s apparatus. Albino rats were divided into 5 groups of 6 rats each. Group-I (Control) received distilled water 25ml/kg orally. Group-II (Standard) received Furosemide 20mg/kg orally. Group-III received EEMP 100 mg/kg, Group-IV received EEMP 200 mg/kg and Group-V received EEMP 400 mg/kg. The urine samples were collected for all the groups upto 5 hours after dosing and urine volume was measured. Urine was analysed for electrolytes (Na+, K+ and Cl-). ANOVA, Dunnet’s test and p-values were measured and data was analysed. Results EEMP exhibited significant diuretic activity by increasing urine volume and also by enhancing elimination of Sodium (Na+), Potassium (K+) and Chloride (Cl-) at doses of 100 and 200mg/kg. Conclusion EEMP possesses significant diuretic activity and has a beneficial role in volume overload conditions. PMID:26870704

Study of cavitating inducer instabilities

NASA Technical Reports Server (NTRS)

Young, W. E.; Murphy, R.; Reddecliff, J. M.

1972-01-01

An analytic and experimental investigation into the causes and mechanisms of cavitating inducer instabilities was conducted. Hydrofoil cascade tests were performed, during which cavity sizes were measured. The measured data were used, along with inducer data and potential flow predictions, to refine an analysis for the prediction of inducer blade suction surface cavitation cavity volume. Cavity volume predictions were incorporated into a linearized system model, and instability predictions for an inducer water test loop were generated. Inducer tests were conducted and instability predictions correlated favorably with measured instability data.

Fluid responsiveness predicted by transcutaneous partial pressure of oxygen in patients with circulatory failure: a prospective study.

PubMed

Xu, Jingyuan; Peng, Xiao; Pan, Chun; Cai, Shixia; Zhang, Xiwen; Xue, Ming; Yang, Yi; Qiu, Haibo

2017-12-01

Significant effort has been devoted to defining parameters for predicting fluid responsiveness. Our goal was to study the feasibility of predicting fluid responsiveness by transcutaneous partial pressure of oxygen (PtcO 2 ) in the critically ill patients. This was a single-center prospective study conducted in the intensive care unit of a tertiary care teaching hospital. Shock patients who presented with at least one clinical sign of inadequate tissue perfusion, defined as systolic blood pressure <90 mmHg or a decrease >40 mmHg in previously hypertensive patients or the need for vasopressive drugs; urine output <0.5 ml/kg/h for 2 h; tachycardia; lactate >4 mmol/l, for less than 24 h in the absence of a contraindication for fluids were eligible to participate in the study. PtcO 2 was continuously recorded before and during a passive leg raising (PLR) test, and then before and after a 250 ml rapid saline infusion in 10 min. Fluid responsiveness is defined as a change in the stroke volume ≥10% after 250 ml of volume infusion. Thirty-four patients were included, and 14 responded to volume expansion. In the responders, the mean arterial pressure, central venous pressure, cardiac output, stroke volume and PtcO 2 increased significantly, while the heart rate decreased significantly by both PLR and volume expansion. Changes in the stroke volume induced either by PLR or volume expansion were significantly greater in responders than in non-responders. The correlation between the changes in PtcO 2 and stroke volume induced by volume expansion was significant. Volume expansion induced an increase in the PtcO 2 of 14% and PLR induced an increase in PtcO 2 of 13% predicted fluid responsiveness. This study suggested the changes in PtcO 2 induced by volume expansion and a PLR test predicted fluid responsiveness in critically ill patients. Trial registration NCT02083757.

Activation of the ventral and dorsal striatum during cue reactivity in Internet gaming disorder.

PubMed

Liu, Lu; Yip, Sarah W; Zhang, Jin-Tao; Wang, Ling-Jiao; Shen, Zi-Jiao; Liu, Ben; Ma, Shan-Shan; Yao, Yuan-Wei; Fang, Xiao-Yi

2017-05-01

Studies conducted in drug addiction suggest a transition in processing of drug-related cues from the ventral to the dorsal component of the striatum. However, this process has not been studied in a behavioral addiction. Assessment of this process in a non-drug addiction can provide insight into the pathophysiology of both substance and behavioral addictions. Thirty-nine male Internet gaming disorder (IGD) subjects and 23 male matched healthy controls (HCs) participated in functional magnetic resonance imaging during performance of a cue-reactivity task involving alternating presentation of Internet gaming-related stimuli (game cues) and general Internet surfing-related stimuli (control cues). Cue-induced neural activations in the ventral and dorsal striatum (DS) were compared between IGD and HC participants. Associations between cue-reactivity within these regions and cue-induced craving and severity and duration of IGD were also explored. IGD participants exhibited higher cue-induced activations within both the ventral and DS when compared with HCs. Within the IGD group, activity within the left ventral striatum (VS) was correlated negatively with cue-induced craving; positive associations were found between activations within the DS (right putamen, pallidum and left caudate) and duration of IGD. Cue-induced activity within the left putamen was negatively associated with right VS volumes among IGD participants. Consistent with studies in substance addictions, our results suggest that a transition from ventral to dorsal striatal processing may occur among individuals with IGD, a condition without the impact of substance intake. © 2016 Society for the Study of Addiction.

Earthquakes induced by fluid injection: Implications for secure CO2 storage

NASA Astrophysics Data System (ADS)

Verdon, J.; Kendall, J. M.

2013-12-01

It is well understood that the injection of fluids into the subsurface can trigger seismic activity. Recently, the US unconventional gas boom has lead to an increase in the volumes of produced water being disposed in geological formations and a concomitant increase in triggered seismic events. This issue is especially pertinent for geologic carbon sequestration, where the injection volumes necessary to store the CO2 emissions from a typical coal-fired power station far exceed the volumes known to have triggered seismic activity. Moreover, unlike water disposal operations, where there is no strong buoyancy drive to return injected fluids to the surface, CO2 sequestration requires a sealing caprock to prevent upward CO2 migration. Induced seismic events may create or reactivate faults and fracture networks, compromising the hydraulic integrity of the caprock. Therefore, induced seismic activity at future CCS sites is of doubly significant, given both the direct seismic hazard and the risk to secure CO2 storage. With this in mind, we re-examine case histories of seismic activity induced by waste water disposal into sedimentary formations with the intention of learning lessons that can be applied to future CCS sites. In particular, we examine the spatial and temporal distributions of events to determine whether there are any rules-of-thumb that might be usefully applied when appraising and monitoring operations. We find that in all cases, at least some seismicity occurs at the depth of the injection interval, but the majority (~80% of events) occur at least 500m below the injection depth. Less than 2% of events occur more than 500m above the shallowest injection interval. This observation must be considered encouraging from a CCS perspective, where seismicity in sealing caprocks will be of greatest concern. However, without a phenomenological explanation for the relative lack of seismicity above injection depths, it cannot be guaranteed that such observations would be repeated at CCS sites. We also examine the lateral distance between induced events and injection wells. The maximum distance between wells and events will define a minimum radius of influence, a distance over which geomechanical appraisal and fault characterization studies must be carried out at future CCS sites. We find that 62% of events occur within 5km, and that 99% of events occur within 19km of injection wells. These case examples highlight the importance of seismic monitoring at future CCS sites. Of the two large-scale CCS sites to deploy microseismic arrays, both have detected induced seismic events. During 6 years of monitoring at Weyburn, ~100 events with magnitudes between -3.0 and -1.0 have been detected, while at In Salah more than 1000 events, with magnitudes as large as 1.0, have been detected during 6 months of monitoring. Combined the case examples from water disposal operations, these operations demonstrate the need for dedicated local seismic monitoring networks to be installed at future CO2 injection sites.

Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis.

PubMed

Rink, Cameron; Christoforidis, Greg; Khanna, Savita; Peterson, Laura; Patel, Yojan; Khanna, Suchin; Abduljalil, Amir; Irfanoglu, Okan; Machiraju, Raghu; Bergdall, Valerie K; Sen, Chandan K

2011-11-01

Vitamin E consists of tocopherols and tocotrienols, in which α-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.

Neuroprotective effect of p-coumaric acid in mice with cerebral ischemia reperfusion injuries.

PubMed

Sakamula, Romgase; Thong-Asa, Wachiryah

2018-06-01

Cerebral ischemia reperfusion (IR) is associated with neuronal death, which leads to disability and cognitive decline. The pathomechanism occurs because ischemia is exacerbated during the reperfusion period. Neuronal damage susceptibility depends on the affected brain areas and the duration of ischemia. Prevention and supplementation to neurons may help them endure during IR and further benefit them in rehabilitation. We investigated the protective effect of p-coumaric acid (PC) on cerebral IR injuries in mice. We randomly divided 30 male ICR mice into 3 groups of Sham (received vehicle and not induced IR), Control-IR (received vehicle and induced IR) and PC-IR (received 100 mg/kg PC and induced IR). We orally administered vehicle or 100 mg/kg of p-coumaric acid for 2 weeks before inducing the cerebral IR injuries by using 30 min of a bilateral common carotid artery occlusion followed by a 45-min reperfusion. We induced the IR condition in the Control-IR and PC-IR groups but not the Sham group, and only the PC-IR group received p-coumaric acid. After IR induction, we sacrificed all the mice and collected their brain tissues to evaluate their oxidative statuses, whole brain infarctions and vulnerable neuronal deaths. We studied the whole-brain infarction volume by 2, 3, 5-triethyltetrazoliumchloride staining of sections. We performed a histological investigation of the vulnerable neuronal population in the dorsal hippocampus by staining brain sections with 0.1% cresyl violet. The results indicated that IR caused significant increases in calcium and malondialdehyde (MDA) levels, whole brain infarction volume and hippocampal neuronal death. Pretreatment with p-coumaric acid significantly reduced MDA levels, whole-brain infarction volume and hippocampal neuronal death together and increased catalase and superoxide dismutase activities. We conclude here that pretreating animals with p-coumaric acid can prevent IR-induced brain oxidative stress, infarction size and neuronal vulnerability to death in cerebral IR injuries.

The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor

PubMed Central

Chojnacka, Kinga; Horenstein, Nicole A.

2014-01-01

The minimum pharmacophore for activation of the human α7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were α7-selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor’s preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist’s cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed “silent agonists,” which are able to induce allosteric modulator-dependent activation but not the normal activated state. PMID:24990939

Mechanosensing in hypothalamic osmosensory neurons.

PubMed

Prager-Khoutorsky, Masha

2017-11-01

Osmosensory neurons are specialized cells activated by increases in blood osmolality to trigger thirst, secretion of the antidiuretic hormone vasopressin, and elevated sympathetic tone during dehydration. In addition to multiple extrinsic factors modulating their activity, osmosensory neurons are intrinsically osmosensitive, as they are activated by increased osmolality in the absence of neighboring cells or synaptic contacts. This intrinsic osmosensitivity is a mechanical process associated with osmolality-induced changes in cell volume. This review summarises recent findings revealing molecular mechanisms underlying the mechanical activation of osmosensory neurons and highlighting important roles of microtubules, actin, and mechanosensitive ion channels in this process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease.

PubMed

Höllmer, M; Willesen, J L; Tolver, A; Koch, J

2017-02-01

Myxomatous mitral valve disease (MMVD) induces progressive left atrial (LA) enlargement. The LA modulates left ventricular filling and performance through its reservoir, conduit, and contractile function. Assessment of LA size and function may provide valuable information on the level of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD. This prospective study included 205 client-owned dogs of different breeds, 114 healthy dogs, and 91 dogs with MMVD of different disease severities. Using two-dimensional echocardiography, the biplane area-length method was applied to assess LA volume and calculate volumetric indices of LA reservoir, conduit, and contractile function. Left atrial volume and LA stroke volume increased, whereas LA reservoir and contractile function decreased with increasing disease severity. A maximal LA volume <2.25mL/kg was the optimal cut off identified for excluding congestive heart failure in dogs with chronic MMVD with a sensitivity of 96% and a specificity of 100%. An active LA emptying fraction <24% and/or a LA expansion index <126% were suggestive of congestive heart failure in dogs with chronic MMVD with a sensitivity of 77% and a specificity of 89% and a sensitivity of 82% and a specificity of 82%, respectively. Dogs with MMVD appear to have larger LA volumes with poorer LA function. Deteriorating LA function, characterized by a decreasing reservoir and active contractile function, was evident in dogs with MMVD with increasing disease severity. Copyright © 2016 Elsevier B.V. All rights reserved.

The non-diuretic hypotensive effects of thiazides are enhanced during volume depletion states

PubMed Central

Alshahrani, Saeed; Rapoport, Robert M.; Zahedi, Kamyar; Jiang, Min; Nieman, Michelle; Barone, Sharon; Meredith, Andrea L.; Lorenz, John N.; Rubinstein, Jack

2017-01-01

Thiazide derivatives including Hydrochlorothiazide (HCTZ) represent the most common treatment of mild to moderate hypertension. Thiazides initially enhance diuresis via inhibition of the kidney Na+-Cl- Cotransporter (NCC). However, chronic volume depletion and diuresis are minimal while lowered blood pressure (BP) is maintained on thiazides. Thus, a vasodilator action of thiazides is proposed, likely via Ca2+-activated K+ (BK) channels in vascular smooth muscles. This study ascertains the role of volume depletion induced by salt restriction or salt wasting in NCC KO mice on the non-diuretic hypotensive action of HCTZ. HCTZ (20mg/kg s.c.) lowered BP in 1) NCC KO on a salt restricted diet but not with normal diet; 2) in volume depleted but not in volume resuscitated pendrin/NCC dKO mice; the BP reduction occurs without any enhancement in salt excretion or reduction in cardiac output. HCTZ still lowered BP following treatment of NCC KO on salt restricted diet with paxilline (8 mg/kg, i.p.), a BK channel blocker, and in BK KO and BK/NCC dKO mice on salt restricted diet. In aortic rings from NCC KO mice on normal and low salt diet, HCTZ did not alter and minimally decreased maximal phenylephrine contraction, respectively, while contractile sensitivity remained unchanged. These results demonstrate 1) the non-diuretic hypotensive effects of thiazides are augmented with volume depletion and 2) that the BP reduction is likely the result of HCTZ inhibition of vasoconstriction through a pathway dependent on factors present in vivo, is unrelated to BK channel activation, and involves processes associated with intravascular volume depletion. PMID:28719636

Root induced changes of effective 1D hydraulic properties in a soil column.

PubMed

Scholl, P; Leitner, D; Kammerer, G; Loiskandl, W; Kaul, H-P; Bodner, G

Roots are essential drivers of soil structure and pore formation. This study aimed at quantifying root induced changes of the pore size distribution (PSD). The focus was on the extent of clogging vs. formation of pores during active root growth. Parameters of Kosugi's lognormal PSD model were determined by inverse estimation in a column experiment with two cover crops (mustard, rye) and an unplanted control. Pore dynamics were described using a convection-dispersion like pore evolution model. Rooted treatments showed a wider range of pore radii with increasing volumes of large macropores >500 μm and micropores <2.5 μm, while fine macropores, mesopores and larger micropores decreased. The non-rooted control showed narrowing of the PSD and reduced porosity over all radius classes. The pore evolution model accurately described root induced changes, while structure degradation in the non-rooted control was not captured properly. Our study demonstrated significant short term root effects with heterogenization of the pore system as dominant process of root induced structure formation. Pore clogging is suggested as a partial cause for reduced pore volume. The important change in micro- and large macropores however indicates that multiple mechanic and biochemical processes are involved in root-pore interactions.

The VCS parameters: Potential hematological indicators for predicting antituberculosis drug-induced neutropenia.

PubMed

Shen, Tian; Gu, Delin; Zhu, Yihua; Shi, Junwei; Xu, Dongsheng; Cao, Xingjian

2016-08-01

The morphological changes in activated neutrophils associated with antituberculosis drugs can be measured by volume, conductivity, and scatter (VCS) technology on the Coulter LH750 hematology analyzer. We conducted the current study to further validate the clinical usefulness of the neutrophil VCS parameters in predicting drug-induced neutropenia. Peripheral blood samples were collected from 52 patients with drug-induced neutropenia, 309 patients without any abnormal CBC, and 237 healthy controls. The mean neutrophil volume (MNV) with its distribution width (NDW) and the mean neutrophil scatter (MNS) were studied. We observed a significant increase in the MNV and NDW as well as a significant decrease in the MNS in neutropenia patients approximately one week prior to development of neutropenia compared to healthy controls as well as to case controls. In addition, the delta MNV and delta MNS were respectively correlated well with delta absolute neutrophil counts when neutropenia occurred. The ROC curve analyses showed that the MNV、NDW and MNS had larger areas under curves compared to conventional parameters. With a cutoff of 150.15 for the MNV, a sensitivity of 84.4% and specificity of 75.7% were achieved prior to neutropenia. The neutrophil VCS parameters may be clinically useful as potential hematological indicators for predicting antituberculosis drug-induced neutropenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Cavitation enhances coagulated size during pulsed high-intensity focussed ultrasound ablation in an isolated liver perfusion system.

PubMed

Zhao, Lu-Yan; Liu, Shan; Chen, Zong-Gui; Zou, Jian-Zhong; Wu, Feng

2016-11-24

To investigate whether cavitation enhances the degree of coagulation during pulsed high-intensity focussed ultrasound (HIFU) in an isolated liver perfusion system. Isolated liver was treated by pulsed HIFU or continuous-wave HIFU with different portal vein flow rates. The cavitation emission during exposure was recorded, and real-time ultrasound images were used to observe changes in the grey scale. The coagulation size was measured and calculated. HIFU treatment led to complete coagulation necrosis and total cell destruction in the target regions. Compared to exposure at a duty cycle (DC) of 100%, the mean volumes of lesions induced by 6 s exposure at DCs of 50% and 10% were significantly larger (P < .01) but were smaller at a DC of 5%. The necrosis volume was negatively related to the perfusion rate in the pulsed HIFU at a DC of 50% for exposure durations of 4 and 6 s, while the perfusion flow rate did not affect the necrosis volume for exposure durations of 1, 2 and 3 s. For increased perfusion flow rates, there was no significant decrease in the cavitation activity for the pulsed-HIFU (P > .05). For continuous-wave HIFU exposure, there was a significant decrease in the necrosis volume and cavitation activity for exposure times of 1, 2, 3, 4, and 6 s with increasing portal perfusion rates. Perfusion flow rates negatively influence cavitation activity and coagulation volume. Ablation is significantly enhanced during pulsed HIFU exposure compared with continuous-wave HIFU.

Gated CT imaging using a free-breathing respiration signal from flow-volume spirometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Souza, Warren D.; Kwok, Young; Deyoung, Chad

2005-12-15

Respiration-induced tumor motion is known to cause artifacts on free-breathing spiral CT images used in treatment planning. This leads to inaccurate delineation of target volumes on planning CT images. Flow-volume spirometry has been used previously for breath-holds during CT scans and radiation treatments using the active breathing control (ABC) system. We have developed a prototype by extending the flow-volume spirometer device to obtain gated CT scans using a PQ 5000 single-slice CT scanner. To test our prototype, we designed motion phantoms to compare image quality obtained with and without gated CT scan acquisition. Spiral and axial (nongated and gated) CTmore » scans were obtained of phantoms with motion periods of 3-5 s and amplitudes of 0.5-2 cm. Errors observed in the volume estimate of these structures were as much as 30% with moving phantoms during CT simulation. Application of motion-gated CT with active breathing control reduced these errors to within 5%. Motion-gated CT was then implemented in patients and the results are presented for two clinical cases: lung and abdomen. In each case, gated scans were acquired at end-inhalation, end-exhalation in addition to a conventional free-breathing (nongated) scan. The gated CT scans revealed reduced artifacts compared with the conventional free-breathing scan. Differences of up to 20% in the volume of the structures were observed between gated and free-breathing scans. A comparison of the overlap of structures between the gated and free-breathing scans revealed misalignment of the structures. These results demonstrate the ability of flow-volume spirometry to reduce errors in target volumes via gating during CT imaging.« less

Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in a genetic model of differential anxiety: Behavioral-volumetric associations in the Roman rat strains.

PubMed

Río-Álamos, Cristóbal; Oliveras, Ignasi; Piludu, Maria Antonietta; Gerbolés, Cristina; Cañete, Toni; Blázquez, Gloria; Lope-Piedrafita, Silvia; Martínez-Membrives, Esther; Torrubia, Rafael; Tobeña, Adolf; Fernández-Teruel, Alberto

2017-02-01

The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat lines/strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, we hypothesized a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures, in particular in the RLA strain. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image. As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

IMPACT OF OBESITY SEVERITY AND DURATION ON PANCREATIC β-AND α-CELLS DYNAMICS IN NORMOGLYCEMIC NON-HUMAN PRIMATES

PubMed Central

Guardado-Mendoza, Rodolfo; Jimenez-Ceja, Lilia; Majluf-Cruz, Abraham; Kamath, Subhash; Fiorentino, Teresa Vanessa; Casiraghi, Francesca; Velazquez, Alberto Omar Chavez; DeFronzo, Ralph Anthony; Dick, Edward; Davalli, Alberto; Folli, Franco

2012-01-01

Objective Obesity is associated to high insulin and glucagon plasma levels. Enhanced β–cell function and β–cell expansion are responsible for insulin hypersecretion. It is unknown whether hyperglucagonemia is due to α-cell hypersecretion or to an increase in α-cell mass. In this study, we investigated the dynamics of the β-cell and α-cell function and mass in pancreas of obese normoglycemic baboons. Methods Pancreatic β- and α-cell volumes were measured in 51 normoglycemic baboons divided into 6 groups according to overweight severity or duration. Islets morphometric parameters were correlated to overweight and to diverse metabolic and laboratory parameters. Results Relative α-cell volume (RαV) and relative islet α-cell volume (RIαV) increased significantly with both overweight duration and severity. Conversely, in spite of the induction of insulin resistance, overweight produced only modest effects on relative β-cell volume (RβV) and relative islet β-cell volume (RIβV). Of note, RIβV did not increase neither with overweight duration nor with overweight severity, supposedly because of the concomitant, greater, increase in RIαV. Baboons' body weights correlated with serum levels of Interleukin-6 and Tumour Necrosis Factor-α soluble Receptors (IL-6sR and sTNF-R1), demonstrating that overweight induces abnormal activation of the signaling of two cytokines known to impact differently β- and α-cell viability and replication. Conclusion In conclusion, overweight and insulin resistance induce in baboons a significant increase in α-cell volumes (RαV, RIαV) while have minimal effects on the β-cells. This study suggests that an increase in the α-cell mass may precede the loss of β-cells and the transition to overt hyperglycemia and diabetes. PMID:23229736

Proteomic analysis of cPKCβII-interacting proteins involved in HPC-induced neuroprotection against cerebral ischemia of mice.

PubMed

Bu, Xiangning; Zhang, Nan; Yang, Xuan; Liu, Yanyan; Du, Jianli; Liang, Jing; Xu, Qunyuan; Li, Junfa

2011-04-01

Hypoxic preconditioning (HPC) initiates intracellular signaling pathway to provide protection against subsequent cerebral ischemic injuries, and its mechanism may provide molecular targets for therapy in stroke. According to our study of conventional protein kinase C βII (cPKCβII) activation in HPC, the role of cPKCβII in HPC-induced neuroprotection and its interacting proteins were determined in this study. The autohypoxia-induced HPC and middle cerebral artery occlusion (MCAO)-induced cerebral ischemia mouse models were prepared as reported. We found that HPC reduced 6 h MCAO-induced neurological deficits, infarct volume, edema ratio and cell apoptosis in peri-infarct region (penumbra), but cPKCβII inhibitors Go6983 and LY333531 blocked HPC-induced neuroprotection. Proteomic analysis revealed that the expression of four proteins in cytosol and eight proteins in particulate fraction changed significantly among 49 identified cPKCβII-interacting proteins in cortex of HPC mice. In addition, HPC could inhibit the decrease of phosphorylated collapsin response mediator protein-2 (CRMP-2) level and increase of CRMP-2 breakdown product. TAT-CRMP-2 peptide, which prevents the cleavage of endogenous CRMP-2, could inhibit CRMP-2 dephosphorylation and proteolysis as well as the infarct volume of 6 h MCAO mice. This study is the first to report multiple cPKCβII-interacting proteins in HPC mouse brain and the role of cPKCβII-CRMP-2 in HPC-induced neuroprotection against early stages of ischemic injuries in mice. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Antisecretory and antiulcer activity of Asparagus racemosus Willd. against indomethacin plus phyloric ligation-induced gastric ulcer in rats.

PubMed

Bhatnagar, Maheep; Sisodia, S S

2006-01-01

To study the antisecretory and antiulcer activity of Asparagus racemosus Willd. (methanolic extract) and its action against indomethacin (a non-steroidal anti-inflammatory drug) plus pyloric ligation (PL)-induced gastric ulcers in rats. Indomethacin plus PL-induced gastric ulceration model was used in the study. Treatment with Asparagus racemosus (Shatavari) crude extract (100 mg/kg/day orally) for fifteen days significantly reduced ulcer index when compared with control group. The reduction in gastric lesions was comparable to a standard antiulcer drug Ranitidine (30 mg/kg/ day orally). Crude extract also significantly reduced volume of gastric secretion, free acidity and total acidity. A significant increase in total carbohydrate (TC) and TC/total protein (TP) ratio of gastric juice was also observed. No significant change in the total protein was noted. Asparagus racemosus was found to be an effective antiulcerogenic agent, whose activity can well be compared with that of ranitidine hydrochloride. The results of this study suggest that Asparagus racemosus causes an inhibitory effect on release of gastric hydrochloric acid and protects gastric mucosal damage.

Analgesic, diuretic, and anti-inflammatory principle from Scoparia dulcis.

PubMed

Ahmed, M; Shikha, H A; Sadhu, S K; Rahman, M T; Datta, B K

2001-08-01

Scoparinol, a diterpene, isolated from Scoparia dulcis showed significant analgesic (p < 0.001) and anti-inflammatory activity (p < 0.01) in animals. A sedative action of scoparinol was demonstrated by a marked potentiation of pentobarbital-induced sedation with a significant effect on both onset and duration of sleep (p < 0.05). Measurement of urine volume after administration of scoparinol indicated its significant diuretic action.

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis

PubMed Central

Matyas, Csaba; Varga, Zoltan V.; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T.; Nan, Mintong; Hasko, Gyorgy; Gao, Bin

2016-01-01

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. PMID:27106042

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis.

PubMed

Matyas, Csaba; Varga, Zoltan V; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T; Nan, Mintong; Hasko, Gyorgy; Gao, Bin; Pacher, Pal

2016-06-01

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. Copyright © 2016 the American Physiological Society.

Serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) improves voiding efficiency in the diabetic rat.

PubMed

Tu, Hongjian; Cao, Nailong; Gu, Baojun; Si, Jiemin; Chen, Zhong; Andersson, Karl-Erik

2015-07-01

To examine the effects of the serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) on micturition in rats with diabetes mellitus (DM). Female Sprague-Dawley rats (n = 16) were divided into two groups: rats with Type 1 DM and age-matched control rats. DM was induced by i.p. injection of streptozotocin (65 mg/kg) and detailed cystometrogram (CMG) studies were performed 8 weeks post-injection in all rats under urethane anaesthesia. The selective 5-HT2A antagonist ketanserin was administered after each DOI dose-response curve was plotted. All drugs were administered i.v. Compared with controls, comprehensive urodynamic studies showed that DM rats had a higher bladder capacity and post-void residual urine volume (PVR), and a markedly lower voiding efficiency. In DM rats, DOI (0.01-0.3 mg/kg) induced significant dose-dependent increases in micturition volume and reductions in PVR, resulting in greater voiding efficiency. CMG measurements showed a dose-dependent increase in high-frequency oscillation (HFO) activity, evidenced by an increased duration of HFOs per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI-induced changes. The HFOs observed in the present study seem to correlate with external urethral sphincter bursting activity during voiding. Bladder voiding efficiency was reduced in DM rats. The 5-HT2A receptor agonist can enhance HFO activity and improves voiding efficiency, and so may represent a new strategy to improve voiding efficiency after DM in experimental studies. © 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.

Novel phenanthridine (PHE-4i) derivative inhibits carrageenan-induced rat hind paw oedema through suppression of hydrogen sulfide.

PubMed

George, Leema; Ramasamy, Tamizhselvi; Manickam, Venkatraman; Iyer, Sathiyanarayanan Kulathu; Radhakrishnan, Vidya

2016-08-01

This study was conducted to assess the anti-inflammatory effect of a novel synthesized phenanthridine alkaloid (PHE-4i) and to examine the possible involvement of hydrogen sulfide (H2S) in anti-inflammatory mechanism. The synthesized phenanthridine derivative PHE-4i (2, 5, and 10 mg/kg) was administered intraperitoneally to rats. One hour following treatment, inflammation was induced by intraplantar injection of carrageenan (1 %), in the hind paw. Paw volume as the index of inflammation was measured before and after carrageenan injection. Neutrophil sequestration into the hind paw was quantified by measuring tissue myeloperoxidase (MPO) activity and was compared for the inhibition of H2S production. Pretreatment with PHE-4i significantly reduced carrageenan-induced hind paw weight, MPO activity, leukocyte infiltration, and H2S production in a dose-dependent manner (p < 0.001). These results indicate that the anti-inflammatory effect of PHE-4i on carrageenan-induced rat paw oedema could be via the inhibition of the gaseous mediator H2S.

Hydraulic Fracturing Completion Volume is Associated with Induced Earthquake Productivity in the Duvernay Play

NASA Astrophysics Data System (ADS)

Schultz, R.; Atkinson, G. M.; Eaton, D. W. S.; Gu, Y. J.; Kao, H.

2017-12-01

A sharp increase in the frequency of earthquakes near Fox Creek, Alberta began in December 2013 as a result of hydraulic fracturing completions in the Duvernay Formation. Using a newly compiled hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We find that induced earthquakes are associated with pad completions that used larger injection volumes (104-5 m3) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have limited or insignificant correlation with the seismic response. Further findings suggest that geological susceptibilities play a prominent role in seismic productivity, as evidenced by spatial correlations in the seismicity patterns. Together, volume and geological susceptibilities account for 96% of the variability in the induced earthquake rate near Fox Creek. We suggest this result is fit by a modified Gutenberg-Richter earthquake frequency-magnitude distribution which provides a conceptual framework with which to forecast induced seismicity hazard.

Methylmercury-induced inhibition of regulatory volume decrease in astrocytes: characterization of osmoregulator efflux and its reversal by amiloride.

PubMed

Aschner, M; Vitarella, D; Allen, J W; Conklin, D R; Cowan, K S

1998-11-16

Swelling of neonatal rat primary astrocyte cultures by hypotonic media leads to regulatory volume decrease (RVD) and the resumption of resting cell volume. RVD is associated with activation of conductive K+ and Cl- channels, allowing for the escape of KCl, as well as the release of osmoregulators, such as taurine and myoinositol. As we have previously shown [D. Vitarella, H.K. Kimelberg, M. Aschner, Inhibition of RVD in swollen rat primary astrocyte cultures by methylmercury (MeHg) is due to increase amiloride-sensitive Na+ uptake, Brain Res. 732 (1996) 169-178.], MeHg, when added to hypotonic buffer inhibits RVD, primarily due to increased cellular permeability to Na+ via the Na+/H+ antiporter. The present study was, therefore, undertaken to assess the ability of cation-anion cotransport blockers to reverse the inhibitory effect of MeHg on RVD in swollen astrocytes, and to further characterize MeHg-induced changes in astrocytic osmoregulatory release processes. The studies demonstrate the following: (1) MeHg-induced inhibition of RVD is partially inhibited by the Na+/H+ antiporter blocker, amiloride, but not SITS (4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid), DIDS (4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid), furosemide or bumetanide; (2) exposure of swollen astrocytes to MeHg is associated with specific effects on osmoregulatory release, leading to significant inhibition of taurine release and a significant increase in potassium and myoinositol release compared with release in hypotonic conditions. Copyright 1998 Elsevier Science B.V.

Human Cardiovascular Adaptation to Weightlessness

NASA Technical Reports Server (NTRS)

Norsk, Peter

2011-01-01

Entering weightlessness (0 G) induces immediately a shift of blood and fluid from the lower to the upper parts of the body inducing expansion of the cardiac chambers (Bungo et al. 1986; Charles & Lathers 1991; Videbaek & Norsk 1997). For many years the effects of sudden 0 G on central venous pressure (CVP) was discussed, and it puzzled researchers that CVP compared to the 1-G supine position decreased during the initial hours of spaceflight, when at the same time left atrial diameter increased (Buckey et al. 1996). By measuring esophageal pressure as an estimate of inter-pleural pressure, it was later shown that this pressure decreases more than CVP does during 0 G induced by parabolic flights (Videbaek & Norsk 1997). Thus, transmural CVP is increased, which distends the cardiac chambers. This unique lung-heart interaction whereby 1) inter-pleural pressure decreases and 2) central blood volume is expanded is unique for 0 G. Because transmural CVP is increased, stroke volume increases according to the law of Frank-Starling leading to an increase in cardiac output, which is maintained increased during months of 0 G in space to levels of some 25% above that of the 1-G seated position (Norsk unpublished). Simultaneously, sympathetic nervous activity is at the level of the upright 1-G posture, which is difficult to explain based on the high stroke volume and decreased blood pressure and systemic vascular resistance. This paradox should be explored and the mechanisms revealed, because it might have implications for estimating the cardiovascular risk of travelling in space.

Increased renal tubular sodium reabsorption during exercise-induced hypervolemia in humans

NASA Technical Reports Server (NTRS)

Nagashima, K.; Wu, J.; Kavouras, S. A.; Mack, G. W.

2001-01-01

We tested the hypothesis that renal tubular Na(+) reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O(2) uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P < 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na(+) in the proximal tubules was higher in Ex than in C (P < 0.05). Saline loading decreased fractional tubular reabsorption of Na(+) from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P < 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P < 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na(+) reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na(+) reabsorption during saline infusion 24 h after exercise.

Gastroprotective activity of ethanolic root extract of Potentilla fulgens Wall. ex Hook.

PubMed

Laloo, Damiki; Prasad, Satyendra K; Krishnamurthy, Sairam; Hemalatha, Siva

2013-03-27

Potentilla fulgens (Wall.) ex Hook. (Rosaceae) is a potent medicinal plant of the Western Himalayas, known under the name "Himalayan Cinquefoil or Bajradanti", and has been used traditionally to treat ailments including peptic ulcers, mouth ulcers, diarrhea, diabetes and cancer. The aim of the present study was to scientifically evaluate the gastric-ulcer protective effect of P. fulgens ethanolic root extract (EPF) on experimental rats. The gastroprotective activity of EPF was evaluated on four gastric-ulcer models such as pyloric ligation (PL), ethanol (EtOH), cold restrain stress (CRS) and aspirin (ASP)-induced gastric ulcers. The gastric acid obtained from 4h PL-induced gastric ulcer rats was determined for total volume content, pH and total acid-pepsin output. Total carbohydrates and protein ratio, expressed as index of mucin activity, and DNA content were estimated in the gastric juice and gastric mucosal tissue. The microvascular permeability, H(+)K(+)-ATPase activity, gastric mucus and histamine content were also determined. The levels of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) and malondialdehyde in the stomach tissue (mucosal scrapings) were quantified. A histopathological study of the stomach was evaluated using eosin-haematoxylin stain. EPF (200-400mg/kg, p.o.) showed significant protection against acute gastric-ulcer induced by EtOH, PL and CRS (400mg/kg, p.o.), but was found to be ineffective against ASP-induced ulcerogens. The effect of EPF on gastric juice studies in 4h PL rats significantly produced an increased level in gastric pH, whereas the effect on gastric volume and acid-pepsin output was observed to decrease significantly. However, EPF was found to have no significant effect on the defensive factors, thus revealing its antisecretory property by inhibiting the aggressive factors. EPF, significantly decreased the histamine level, inhibited the H(+)K(+)-ATPase activity and prevented the microvascular injury caused by ethanol in the rat stomach. Moreover, it was also observed to have antioxidant effects by producing a significant increase in the levels of SOD, CAT, and GSH and decreased the LPO activity. Histopathological studies showed that EPF significantly prevented gastric lesions caused by ethanol. The present study showed that EPF has potent gastroprotective and antisecretory effects, thus justifying the traditional usage of this herb to treat gastric ulcers. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Rapamycin protects against neuronal death and improves neurological function with modulation of microglia after experimental intracerebral hemorrhage in rats.

PubMed

Li, D; Liu, F; Yang, T; Jin, T; Zhang, H; Luo, X; Wang, M

2016-09-30

Intracerebral hemorrhage (ICH) results in a devastating brain disorder with high mortality and poor prognosis and effective therapeutic intervention for the disease remains a challenge at present. The present study investigated the neuroprotective effects of rapamycin on ICH-induced brain damage and the possible involvement of activated microglia. ICH was induced in rats by injection of type IV collagenase into striatum. Different dose of rapamycin was systemically administrated by intraperitoneal injection beginning at 1 h after ICH induction. Western blot analysis showed that ICH led to a long-lasting increase of phosphorylated mTOR and this hyperactivation of mTOR was reduced by systemic administration of rapamycin. Rapamycin treatment significantly improved the sensorimotor deficits induced by ICH, and attenuated ICH-induced brain edema formation as well as lesion volume. Nissl and Fluoro-Jade C staining demonstrated that administration with rapamycin remarkably decreased neuronal death surrounding the hematoma at 7 d after ICH insult. ELISA and real-time quantitative PCR demonstrated that rapamycin inhibited ICH-induced excessive expression of TNF-α and IL-1β in ipsilateral hemisphere. Furthermore, activation of microglia induced by ICH was significantly suppressed by rapamycin administration. These data indicated that treatment of rapamycin following ICH decreased the brain injuries and neuronal death at the peri-hematoma striatum, and increased neurological function, which associated with reduced the levels of proinflammatory cytokines and activated microglia. The results provide novel insight into the neuroprotective therapeutic strategy of rapamycin for ICH insult, which possibly involving the regulation of microglial activation.

Study of inducer load and stress, volume 2

NASA Technical Reports Server (NTRS)

1972-01-01

A program of analysis, design, fabrication and testing has been conducted to develop computer programs for predicting rocket engine turbopump inducer hydrodynamic loading, stress magnitude and distribution, and vibration characteristics. Methods of predicting blade loading, stress, and vibration characteristics were selected from a literature search and used as a basis for the computer programs. An inducer, representative of typical rocket engine inducers, was designed, fabricated, and tested with special instrumentation selected to provide measurements of blade surface pressures and stresses. Data from the tests were compared with predicted values and the computer programs were revised as required to improve correlation. For Volume 1 see N71-20403. For Volume 2 see N71-20404.

Payload/orbiter contamination control requirement study, volume 1, exhibit A

NASA Technical Reports Server (NTRS)

Bareiss, L. E.; Hooper, V. W.; Rantanen, R. O.; Ress, E. B.

1974-01-01

This study is to identify and quantify the expected molecular and particulate on orbit contaminant environment for selected shuttle payloads as a result of major spacelab and shuttle orbiter contaminant sources. This investigation reviews individual payload susceptibilities to contamination, identifies the combined induced environment, identifies the risk of spacelab/payload critical surface(s) degradation, and provides preliminary contamination recommendations. It also establishes limiting factors which may depend upon operational activities associated with the payloads, spacelab, and the shuttle orbiter interface or upon independent payload functional activities.

An in vivo and in vitro potential of Indian ayurvedic herbal formulation Triphala on experimental gouty arthritis in mice.

PubMed

Sabina, E P; Rasool, M

2008-01-01

In the present study, we have investigated the efficacy of Indian ayurvedic herbal formulation Triphala on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, Indomethacin. The anti-arthritic effect of Triphala was evaluated by measuring changes in the paw volume, lysosomal enzyme activities, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-alpha in control and monosodium urate crystal-induced mice. The levels of beta-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL). Triphala treatment (1 gm/kg/b.w. orally) significantly inhibited the paw volume and the levels of lysosomal enzymes, lipid peroxidation and inflammatory mediator tumour necrosis factor-alpha; however the anti-oxidant status was found to be increased in plasma, liver and spleen of monosodium urate crystal-induced mice when compared to control mice. In addition, beta-glucuronidase and lactate dehydrogenase level were reduced in Triphala (100 microg/ml) treated monosodium urate crystal-incubated polymorphonuclear leucocytes. In conclusion, the results obtained clearly indicated that Triphala exerted a strong anti-inflammatory effect against gouty arthritis.

Finite volume analysis of temperature effects induced by active MRI implants with cylindrical symmetry: 1. Properly working devices

PubMed Central

Busch, Martin HJ; Vollmann, Wolfgang; Schnorr, Jörg; Grönemeyer, Dietrich HW

2005-01-01

Background Active Magnetic Resonance Imaging implants are constructed as resonators tuned to the Larmor frequency of a magnetic resonance system with a specific field strength. The resonating circuit may be embedded into or added to the normal metallic implant structure. The resonators build inductively coupled wireless transmit and receive coils and can amplify the signal, normally decreased by eddy currents, inside metallic structures without affecting the rest of the spin ensemble. During magnetic resonance imaging the resonators generate heat, which is additional to the usual one described by the specific absorption rate. This induces temperature increases of the tissue around the circuit paths and inside the lumen of an active implant and may negatively influence patient safety. Methods This investigation provides an overview of the supplementary power absorbed by active implants with a cylindrical geometry, corresponding to vessel implants such as stents, stent grafts or vena cava filters. The knowledge of the overall absorbed power is used in a finite volume analysis to estimate temperature maps around different implant structures inside homogeneous tissue under worst-case assumptions. The "worst-case scenario" assumes thermal heat conduction without blood perfusion inside the tissue around the implant and mostly without any cooling due to blood flow inside vessels. Results The additional power loss of a resonator is proportional to the volume and the quality factor, as well as the field strength of the MRI system and the specific absorption rate of the applied sequence. For properly working devices the finite volume analysis showed only tolerable heating during MRI investigations in most cases. Only resonators transforming a few hundred mW into heat may reach temperature increases over 5 K. This requires resonators with volumes of several ten cubic centimeters, short inductor circuit paths with only a few 10 cm and a quality factor above ten. Using MR sequences, for which the MRI system manufacturer declares the highest specific absorption rate of 4 W/kg, vascular implants with a realistic construction, size and quality factor do not show temperature increases over a critical value of 5 K. Conclusion The results show dangerous heating for the assumed "worst-case scenario" only for constructions not acceptable for vascular implants. Realistic devices are safe with respect to temperature increases. However, this investigation discusses only properly working devices. Ruptures or partial ruptures of the wires carrying the electric current of the resonance circuits or other defects can set up a power source inside an extremely small volume. The temperature maps around such possible "hot spots" should be analyzed in an additional investigation. PMID:15819973

Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats.

PubMed

Horiguchi, Takashi; Kis, Bela; Rajapakse, Nishadi; Shimizu, Katsuyoshi; Busija, David W

2003-04-01

The role of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoK(ATP) activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK(ATP) blocker, on neurotoxin 3-nitropropionic acid (3-NPA)-induced ischemic tolerance to transient focal cerebral ischemia in rats. Male Wistar rats were administrated 3-NPA (20 mg/kg IP; n=16) or vehicle (saline; n=16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; n=16) was injected 20 minutes before 3-NPA administration. Infarct volumes were measured 4 days after reperfusion. To directly investigate whether chemical preconditioning activates mitoK(ATP), we tested the effect of prior incubation with 1 mmol/L 5-HD on 300 micromol/L 3-NPA-induced alterations of mitochondrial membrane potential (Delta(Psi)m) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester. Treatment with 3-NPA exhibited a 16% reduction (P<0.05) and 23% reduction in infarct volume (P<0.01) for total brain and cortex, respectively. Pretreatment with 5-HD completely abolished the neuroprotective effect of chemical preconditioning. In cultured cells, 3-NPA resulted in mitochondrial depolarization. This change of Delta(Psi)m was completely blocked by 5-HD pretreatment. These results strongly suggest that opening of mitoK(ATP) plays a key role as the trigger in the development of 3-NPA-induced ischemic tolerance in brain.

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis.

PubMed

Rigby, Cynthia M; Roy, Srirupa; Deep, Gagan; Guillermo-Lagae, Ruth; Jain, Anil K; Dhar, Deepanshi; Orlicky, David J; Agarwal, Chapla; Agarwal, Rajesh

2017-01-01

Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53 +/- ) and p53 knockout (p53 -/- ) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53 +/+ mice, p53 +/- mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53 +/+ mice but silibinin' protective efficacy was significantly compromised in p53 +/- mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53 -/- mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53 +/+ mice while its efficacy was partially compromised in p53 -/- mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

PubMed Central

Rigby, Cynthia M.; Roy, Srirupa; Deep, Gagan; Guillermo-Lagae, Ruth; Jain, Anil K.; Dhar, Deepanshi; Orlicky, David J.; Agarwal, Chapla; Agarwal, Rajesh

2017-01-01

Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53+/−) and p53 knockout (p53−/−) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53+/+ mice, p53+/− mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53+/+ mice but silibinin’ protective efficacy was significantly compromised in p53+/− mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53−/− mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53+/+ mice while its efficacy was partially compromised in p53−/− mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation. PMID:27729375

Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice†

PubMed Central

Deng, Jiao; Zhang, Junfeng; Feng, Chenzhuo; Xiong, Lize; Zuo, Zhiyi

2014-01-01

Aims About one-third of American adults and 20% of teenagers are obese. Obesity and its associated metabolic disturbances including hyperlipidaemia are risk factors for cardiovascular diseases including stroke. They can worsen neurological outcome after stroke. We determined whether obesity and hyperlipidaemia could induce cerebral vascular remodelling via matrix metalloproteases (MMP) and whether this remodelling affected neurological outcome after brain ischaemia. Methods and results Six-week-old male CD1, C57BL/6J, and MMP-9−/− mice were fed regular diet (RD) or high-fat diet (HFD) for 10 weeks. They were subjected to vascular casting or a 90 min middle cerebral arterial occlusion (MCAO). Mice on HFD were heavier and had higher blood glucose and lipid levels than those on RD. HFD-fed CD1 and C57BL/6J mice had an increased cerebral vascular tortuosity index and decreased inner diameters of the middle cerebral arterial root. HFD increased microvessel density in CD1 mouse cerebral cortex. After MCAO, CD1 and C57BL/6J mice on HFD had a bigger infarct volume, more severe brain oedema and blood–brain barrier damage, higher haemorrhagic transformation rate, greater haemorrhagic volume, and worse neurological function. HFD increased MMP-9 activity in the ischaemic and non-ischaemic brain tissues. Although HFD increased the body weights, blood glucose, and lipid levels in the MMP-9−/− mice on a C57BL/6J genetic background, the HFD-induced cerebral vascular remodelling and worsening of neurological outcome did not occur in these mice. Conclusion HFD induces cerebral vascular remodelling and worsens neurological outcome after transient focal brain ischaemia. MMP-9 activation plays a critical role in these HFD effects. PMID:24935427

Protective Effect of Crocodile Hemoglobin and Whole Blood Against Hydrogen Peroxide-Induced Oxidative Damage in Human Lung Fibroblasts (MRC-5) and Inflammation in Mice.

PubMed

Phosri, Santi; Jangpromma, Nisachon; Patramanon, Rina; Kongyingyoes, Bunkerd; Mahakunakorn, Pramote; Klaynongsruang, Sompong

2017-02-01

A putative protective effect of cHb and cWb against H 2 O 2 -induced oxidative damage was evaluated in detail using MRC-5 cells. In addition, the carrageenan (Carr)-induced mouse paw edema model and the cotton pellet-induced granuloma model were employed to examine the in vivo anti-inflammatory activity of cHb and cWb in mice. It was demonstrated that both cHb and cWb treatments significantly increased cell viability and inhibited morphology alterations in MRC-5 cells exposed to H 2 O 2 . Orally administered cHb and cWb significantly reduced Carr-induced paw edema volume and cotton pellet-induced granuloma formation. Moreover, cHb and cWb decreased the expression levels of important pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), while only cWb was found to increase the expression of the anti-inflammatory cytokine IL-10 significantly. Finally, the activity of antioxidant enzymes (SOD, CAT, and GPx) in the liver improved after cHb and cWb treatment under acute and chronic inflammation. Taken collectively, the results of this study suggest that both cHb and cWb protect against hydrogen peroxide-induced damage in fibroblast cells. Moreover, cHb and cWb were found to exhibit anti-inflammatory activity in both the acute and chronic stages of inflammation and appear to enhance antioxidant enzyme activity and decrease lipid peroxidation in the livers of mice. Therefore, this study indicates that cHb and cWb have great potential to be used in the development of dietary supplements for the prevention of oxidative stress related to inflammatory disorders.

Mechanical stretch induces MMP-2 release and activation in lung endothelium: role of EMMPRIN.

PubMed

Haseneen, Nadia A; Vaday, Gayle G; Zucker, Stanley; Foda, Hussein D

2003-03-01

High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.

Respiratory uncoupling by increased H(+) or K(+) flux is beneficial for heart mitochondrial turnover of reactive oxygen species but not for permeability transition.

PubMed

Morota, Saori; Piel, Sarah; Hansson, Magnus J

2013-09-22

Ischemic preconditioning has been proposed to involve changes in mitochondrial H(+) and K(+) fluxes, in particular through activation of uncoupling proteins and ATP-sensitive K(+) channels (MitoKATP). The objectives of the present study were to explore how increased H(+) and K(+) fluxes influence heart mitochondrial physiology with regard to production and scavenging of reactive oxygen species (ROS), volume changes and resistance to calcium-induced mitochondrial permeability transition (mPT). Isolated rat heart mitochondria were exposed to a wide concentration range of the protonophore CCCP or the potassium ionophore valinomycin to induce increased H(+) and K(+) conductance, respectively. Simultaneous monitoring of mitochondrial respiration and calcium retention capacity (CRC) demonstrated that the relative increase in respiration caused by valinomycin or CCCP correlated with a decrease in CRC, and that no level of respiratory uncoupling was associated with enhanced resistance to mPT. Mitochondria suspended in hyperosmolar buffer demonstrated a dose-dependent reduction in CRC with increasing osmolarity. However, mitochondria in hypoosmolar buffer to increase matrix volume did not display increased CRC. ROS generation was reduced by both K(+)- and H(+)-mediated respiratory uncoupling. The ability of heart mitochondria to detoxify H2O2 was substantially greater than the production rate. The H2O2 detoxification was dependent on respiratory substrates and was dramatically decreased following calcium-induced mPT, but was unaffected by uncoupling via increased K(+) and H(+) conductance. It is concluded that respiratory uncoupling is not directly beneficial to rat heart mitochondrial resistance to calcium overload irrespective of whether H(+) or K(+) conductance is increased. The negative effects of respiratory uncoupling thus probably outweigh the reduction in ROS generation and a potential positive effect by increased matrix volume, resulting in a net sensitization of heart mitochondria to mPT activation.

Theoretical study of the partial molar volume change associated with the pressure-induced structural transition of ubiquitin

PubMed Central

Imai, Takashi; Ohyama, Shusaku; Kovalenko, Andriy; Hirata, Fumio

2007-01-01

The partial molar volume (PMV) change associated with the pressure-induced structural transition of ubiquitin is analyzed by the three-dimensional reference interaction site model (3D-RISM) theory of molecular solvation. The theory predicts that the PMV decreases upon the structural transition, which is consistent with the experimental observation. The volume decomposition analysis demonstrates that the PMV reduction is primarily caused by the decrease in the volume of structural voids in the protein, which is partially canceled by the volume expansion due to the hydration effects. It is found from further analysis that the PMV reduction is ascribed substantially to the penetration of water molecules into a specific part of the protein. Based on the thermodynamic relation, this result implies that the water penetration causes the pressure-induced structural transition. It supports the water penetration model of pressure denaturation of proteins proposed earlier. PMID:17660257

Theoretical study of the partial molar volume change associated with the pressure-induced structural transition of ubiquitin.

PubMed

Imai, Takashi; Ohyama, Shusaku; Kovalenko, Andriy; Hirata, Fumio

2007-09-01

The partial molar volume (PMV) change associated with the pressure-induced structural transition of ubiquitin is analyzed by the three-dimensional reference interaction site model (3D-RISM) theory of molecular solvation. The theory predicts that the PMV decreases upon the structural transition, which is consistent with the experimental observation. The volume decomposition analysis demonstrates that the PMV reduction is primarily caused by the decrease in the volume of structural voids in the protein, which is partially canceled by the volume expansion due to the hydration effects. It is found from further analysis that the PMV reduction is ascribed substantially to the penetration of water molecules into a specific part of the protein. Based on the thermodynamic relation, this result implies that the water penetration causes the pressure-induced structural transition. It supports the water penetration model of pressure denaturation of proteins proposed earlier.

Exercise-induced myocardial ischemia in patients with coronary artery disease: lack of evidence for platelet activation or fibrin formation in peripheral venous blood.

PubMed

Marcella, J J; Nichols, A B; Johnson, L L; Owen, J; Reison, D S; Kaplan, K L; Cannon, P J

1983-05-01

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.

Physical Activity, Health Benefits, and Mortality Risk

PubMed Central

Kokkinos, Peter

2012-01-01

A plethora of epidemiologic evidence from large studies supports unequivocally an inverse, independent, and graded association between volume of physical activity, health, and cardiovascular and overall mortality. This association is evident in apparently healthy individuals, patients with hypertension, type 2 diabetes mellitus, and cardiovascular disease, regardless of body weight. Moreover, the degree of risk associated with physical inactivity is similar to, and in some cases even stronger than, the more traditional cardiovascular risk factors. The exercise-induced health benefits are in part related to favorable modulations of cardiovascular risk factors observed by increased physical activity or structured exercise programs. Although the independent contribution of the exercise components, intensity, duration, and frequency to the reduction of mortality risk is not clear, it is well accepted that an exercise volume threshold defined at caloric expenditure of approximately 1,000 Kcal per week appears to be necessary for significant reduction in mortality risk. Further reductions in risk are observed with higher volumes of energy expenditure. Physical exertion is also associated with a relatively low and transient increase in risk for cardiac events. This risk is significantly higher for older and sedentary individuals. Therefore, such individuals should consult their physician prior to engaging in exercise. “Walking is man’s best medicine”Hippocrates PMID:23198160

Structural but not functional neuroplasticity one year after effective cognitive behaviour therapy for social anxiety disorder.

PubMed

Månsson, Kristoffer N T; Salami, Alireza; Carlbring, Per; Boraxbekk, C-J; Andersson, Gerhard; Furmark, Tomas

2017-02-01

Effective psychiatric treatments ameliorate excessive anxiety and induce neuroplasticity immediately after the intervention, indicating that emotional components in the human brain are rapidly adaptable. Still, the interplay between structural and functional neuroplasticity is poorly understood, and studies of treatment-induced long-term neuroplasticity are rare. Functional and structural magnetic resonance imaging (using 3T MRI) was performed in 13 subjects with social anxiety disorder on 3 occasions over 1year. All subjects underwent 9 weeks of Internet-delivered cognitive behaviour therapy in a randomized cross-over design and independent assessors used the Clinically Global Impression-Improvement (CGI-I) scale to determine treatment response. Gray matter (GM) volume, assessed with voxel-based morphometry, and functional blood-oxygen level-dependent (BOLD) responsivity to self-referential criticism were compared between treatment responders and non-responders using 2×2 (group×time; pretreatment to follow-up) ANOVA. At 1-year follow-up, 7 (54%) subjects were classified as CGI-I responders. Left amygdala GM volume was more reduced in responders relative to non-responders from pretreatment to 1-year follow-up (Z=3.67, Family-Wise Error corrected p=0.02). In contrast to previous short-term effects, altered BOLD activations to self-referential criticism did not separate responder groups at follow-up. The structure and function of the amygdala changes immediately after effective psychological treatment of social anxiety disorder, but only reduced amygdala GM volume, and not functional activity, is associated with a clinical response 1year after CBT. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity.

PubMed

Guo, Hong; Hu, Li-Min; Wang, Shao-Xia; Wang, Yu-Lin; Shi, Fang; Li, Hui; Liu, Yang; Kang, Li-Yuan; Gao, Xiu-Mei

2011-12-31

An increasing number of studies has indicated that hypoxic-ischemic-induced cerebral injury is partly mediated via oxidative stress. Recent researches have focused on searching for drug and herbal manipulations to protect against hypoxic-ischemic-induced oxidative cell damage. Scutellarin is a flavonoid derived from the Erigeron breviscapus (vant.) and has been reported to exhibit neuroprotective properties. However, its precise mechanism, particularly its antioxidation mechanism, remains elusive. In the present study, we investigated the neuroprotective effects of scutellarin on middle cerebral artery occlusion (MCAO)-induced brain damage in rats, and oxygen-glucose deprivation (OGD)-induced toxicity in primary culture of rat cortical neurons. In vivo, intraperitoneal injections of scutellarin (20 and 60 mg/kg) improved the neurological score and diminished the percentage of brain infarct volume. At the same time, scutellarin significantly increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) level in ischemic brain tissues, enhancing endogenous antioxidant activity. Moreover, pretreatment of scutellarin (25, 50 and 100 μM) protected neurons against lethal stimuli, decreased the percentage of apoptotic cells and inhibited reactive oxygen species (ROS) generation in OGD-induced primary cortical neurons in vitro. These results suggest that the preventive and therapeutic potential of scutellarin in cerebral injury patients is, at least in part, ascribed to augmentation of cellular antioxidant defense capacity.

All-optical photochromic spatial light modulators based on photoinduced electron transfer in rigid matrices

NASA Technical Reports Server (NTRS)

Beratan, David N. (Inventor); Perry, Joseph W. (Inventor)

1991-01-01

A single material (not a multi-element structure) spatial light modulator may be written to, as well as read out from, using light. The device has tailorable rise and hold times dependent on the composition and concentration of the molecular species used as the active components. The spatial resolution of this device is limited only by light diffraction as in volume holograms. The device may function as a two-dimensional mask (transmission or reflection) or as a three-dimensional volume holographic medium. This device, based on optically-induced electron transfer, is able to perform incoherent to coherent image conversion or wavelength conversion over a wide spectral range (ultraviolet, visible, or near-infrared regions).

The effect of reservoir geometry, injection and production parameters and permeability structure on induced seismicity

NASA Astrophysics Data System (ADS)

Hosseini, S. M.; Goebel, T.; Aminzadeh, F.

2015-12-01

The recent increase in injection induced seismicity (IIS) in previously less seismically active regions highlighted a need for better mitigation strategies and physics-based models of induced seismicity. Previous models of pressure diffusion and fluid flow investigated the change in Coulomb stress as a result of induced pore-pressure perturbations (e.g. Zhang et al., 2013; Keranen et al., 2014; Hornbach et al., 2015; Segall and Lu, 2015). Here, we consider the additional effects of permeability structure, operational parameters and reservoir geometry. We numerically investigate the influence of net fluid injection volumes; linear, radial, and spherical reservoir geometry; as well as reservoir size. The latter can have a substantial effect on changes in Coulomb stress and subsequent induced seismicity. We report on results from two series of model runs, which explored pressure changes caused by wastewater disposal and water flooding. We observed that a typical water flooding operation that includes production wells and injectors has a lower probability of inducing seismicity. Our observations are in agreement with assessment by National Research Council report on induced seismicity (2012). We developed a third suite of models that investigate the effect of permeability structure on injection-induced seismicity. We examine two cases of wastewater disposal in proximity to active faults: 1) in Central Illinois Basin and 2) in central California. In both cases, we observed that the size of the reservoir, presence of faults, and permeability contrast relative to the host rock, strongly influences the pressure changes with distance and time. These pressure changes vary widely but can easily lead to fault instability and seismic activity at up to 10 km distance from the injection well. The results of this study may help to select safe injection sites and operational conditions in order to minimize injection induced seismicity hazard.

A novel osteogenic oxysterol compound for therapeutic development to promote bone growth: activation of hedgehog signaling and osteogenesis through smoothened binding.

PubMed

Montgomery, Scott R; Nargizyan, Taya; Meliton, Vicente; Nachtergaele, Sigrid; Rohatgi, Rajat; Stappenbeck, Frank; Jung, Michael E; Johnson, Jared S; Aghdasi, Bayan; Tian, Haijun; Weintraub, Gil; Inoue, Hirokazu; Atti, Elisa; Tetradis, Sotirios; Pereira, Renata C; Hokugo, Akishige; Alobaidaan, Raed; Tan, Yanlin; Hahn, Theodor J; Wang, Jeffrey C; Parhami, Farhad

2014-08-01

Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8X-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN, and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on X-ray after 4 weeks and confirmed with manual assessment, micro-CT (µCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater bone volume/tissue volume (BV/TV) ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development. © 2014 American Society for Bone and Mineral Research.

Increased Brown Adipose Tissue Oxidative Capacity in Cold-Acclimated Humans

PubMed Central

Blondin, Denis P.; Labbé, Sébastien M.; Tingelstad, Hans C.; Noll, Christophe; Kunach, Margaret; Phoenix, Serge; Guérin, Brigitte; Turcotte, Éric E.; Carpentier, André C.

2014-01-01

Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes, which may have important pathological and therapeutic implications. Although many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: Our objective was to determine whether 4 weeks of daily cold exposure could increase both the volume of metabolically active BAT and its oxidative capacity. Design: Six nonacclimated men were exposed to 10°C for 2 hours daily for 4 weeks (5 d/wk), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with [11C]acetate and [18F]fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake, and volume before and after 4 weeks of cold acclimation were examined under controlled acute cold-exposure conditions. Results: The 4-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66 ± 30 to 95 ± 28 mL, P < .05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725 ± 0.300 to 1.591 ± 0.326 mL·s−1, P < .05). Shivering intensity was not significantly different before compared with after acclimation (2.1% ± 0.7% vs 2.0% ± 0.5% maximal voluntary contraction, respectively). Fractional glucose uptake in BAT increased after acclimation (from 0.035 ± 0.014 to 0.048 ± 0.012 min−1), and net glucose uptake also trended toward an increase (from 163 ± 60 to 209 ± 50 nmol·g−1·min−1). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis. PMID:24423363

Cofilin Knockdown Attenuates Hemorrhagic Brain Injury-induced Oxidative Stress and Microglial Activation in Mice.

PubMed

Alhadidi, Qasim; Nash, Kevin M; Alaqel, Saleh; Sayeed, Muhammad Shahdaat Bin; Shah, Zahoor A

2018-05-08

Intracerebral hemorrhage (ICH) resulting from the rupture of the blood vessels in the brain is associated with significantly higher mortality and morbidity. Clinical studies focused on alleviating the primary injury, hematoma formation and expansion, were largely ineffective, suggesting that secondary injury-induced inflammation and the formation of reactive species also contribute to the overall injury process. In this study, we explored the effects of cofilin knockdown in a mouse model of ICH. Animals given stereotaxic injections of cofilin siRNA, 72-h prior to induction of ICH by collagenase injection within the area of siRNA administration showed significantly decreased cofilin expression levels and lower hemorrhage volume and edema, and the animals performed significantly better in neurobehavioral tasks i.e., rotarod, grip strength and neurologic deficit scores. Cofilin siRNA knocked-down mice had reduced ICH-induced DNA fragmentation, blood-brain barrier disruption and microglial activation, with a concomitant increase in astrocyte activation. Increased expression of pro-survival proteins and decreased markers of oxidative stress were also observed in cofilin siRNA-treated mice possibly due to the reduced levels of cofilin. Our results suggest that cofilin plays a major role in ICH-induced secondary injury, and could become a potential therapeutic target. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis

PubMed Central

Rink, Cameron; Christoforidis, Greg; Khanna, Savita; Peterson, Laura; Patel, Yojan; Khanna, Suchin; Abduljalil, Amir; Irfanoglu, Okan; Machiraju, Raghu; Bergdall, Valerie K; Sen, Chandan K

2011-01-01

Vitamin E consists of tocopherols and tocotrienols, in which α-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke. PMID:21673716

Diet-Induced Ketosis Protects Against Focal Cerebral Ischemia in Mouse.

PubMed

Xu, Kui; Ye, Lena; Sharma, Katyayini; Jin, Yongming; Harrison, Matthew M; Caldwell, Tylor; Berthiaume, Jessica M; Luo, Yu; LaManna, Joseph C; Puchowicz, Michelle A

2017-01-01

Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective. We investigated the effects of diet-induced ketosis following transient focal cerebral ischemia in mice. The correlation between levels of ketosis and hypoxic inducible factor-1alpha (HIF-1α), AKT (also known as protein kinase B or PKB) and 5' AMP-activated protein kinase (AMPK) were determined. Mice were fed with KG diet or standard lab-chow (STD) diet for 4 weeks. For the MCAO group, mice underwent 60 min of MCAO and total brain infarct volumes were evaluated 48 h after reperfusion. In a separate group of mice, brain tissue metabolites, levels of HIF-1α, phosphorylated AKT (pAKT), and AMPK were measured. After feeding a KG diet, levels of blood ketone bodies (beta-hydroxyburyrate, BHB) were increased. There was a proportional decrease in infarct volumes with increased blood BHB levels (KG vs STD; 4.2 ± 0.6 vs 7.8 ± 2.2 mm 3 , mean ± SEM). A positive correlation was also observed with HIF-1α and pAKT relative to blood BHB levels. Our results showed that chronic ketosis can be induced in mice by KG diet and was neuroprotective against focal cerebral ischemia in a concentration dependent manner. Potential mechanisms include upregulation of cytoprotective pathways such as those associated with HIF-1α, pAKT and AMPK.

Muscle Sympathetic Nerve Activity During Intense Lower Body Negative Pressure to Presyncope in Humans

DTIC Science & Technology

2009-08-24

frequency rhythms. Arterial pressure oscillations increase with reductions in central blood volume induced by haemorrhage (Guyton & Harris, 1951), head...a finger cuff to record beat-by-beat finger arterial pressure (Finometer Blood Pressure Monitor, TNO-TPD Biomedical Instrumentation, Amsterdam, The...experienced reductions in arterial pressure at presyncope. The lowest blood pressures recorded for each subject are shown in the upper right of each

Distribution of dehydration rates generated by maximal Gardos-channel activation in normal and sickle red blood cells.

PubMed

Lew, Virgilio L; Tiffert, Teresa; Etzion, Zipora; Perdomo, Deisy; Daw, Nuala; Macdonald, Lynn; Bookchin, Robert M

2005-01-01

The Ca(2+)-activated K+ channels of human red blood cells (RBCs) (Gardos channels, hIK1, hSK4) can mediate rapid cell dehydration, of particular relevance to the pathophysiology of sickle cell disease. Previous investigations gave widely discrepant estimates of the number of Gardos channels per RBC, from as few as 1 to 3 to as many as 300, with large cell-to-cell differences, suggesting that RBCs could differ extensively in their susceptibility to dehydration by elevated Ca2+. Here we investigated the distribution of dehydration rates induced by maximal and uniform Ca2+ loads in normal (AA) and sickle (SS) RBCs by measuring the time-dependent changes in osmotic fragility and RBC volume distributions. We found a remarkable conservation of osmotic lysis and volume distribution profiles during Ca(2+)-induced dehydration, indicating overall uniformity of dehydration rates among AA and SS RBCs. In light of these results, alternative interpretations were suggested for the previously proposed low estimates and heterogeneity of channel numbers per cell. The results support the view that stochastic Ca2+ permeabilization rather than Gardos-channel variation is the main determinant selecting which SS cells dehydrate through Gardos channels in each sickling episode.

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

PubMed Central

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Furuya, Takefumi; Kobashigawa, Tsuyoshi; Kamatani, Naoyuki; Kotake, Shigeru

2007-01-01

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis. PMID:17888176

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats.

PubMed

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Furuya, Takefumi; Kobashigawa, Tsuyoshi; Kamatani, Naoyuki; Kotake, Shigeru

2007-01-01

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.

High-intensity high-volume swimming induces more robust signaling through PGC-1α and AMPK activation than sprint interval swimming in m. triceps brachii

PubMed Central

Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco J.; Aragón-Vela, Jerónimo; Robles-Sanchez, Cándido; Nordsborg, Nikolai B.; Hebberecht, Marina; Salmeron, Luis M.; Huertas, Jesus R.

2017-01-01

We aimed to test whether high-intensity high-volume training (HIHVT) swimming would induce more robust signaling than sprint interval training (SIT) swimming within the m. triceps brachii due to lower metabolic and oxidation. Nine well-trained swimmers performed the two training procedures on separate randomized days. Muscle biopsies from m. triceps brachii and blood samples were collected at three different time points: a) before the intervention (pre), b) immediately after the swimming procedures (post) and c) after 3 h of rest (3 h). Hydroperoxides, creatine kinase (CK), and lactate dehydrogenase (LDH) were quantified from blood samples, and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and the AMPKpTHR172/AMPK ratio were quantified by Western blot analysis. PGC-1α, sirtuin 3 (SIRT3), superoxide-dismutase 2 (SOD2), and vascular endothelial growth factor (VEGF) mRNA levels were also quantified. SIT induced a higher release of LDH (p < 0.01 at all time points) and CK (p < 0.01 at post) than HIHVT, but neither SIT nor HIHVT altered systemic hydroperoxides. Additionally, neither SIRT3 nor SOD2 mRNA levels increased, while PGC-1α transcription increased at 3 h after SIT (p < 0.01) and after HIHVT (p < 0.001). However, PGC-1α protein was higher after HIHVT than after SIT (p < 0.05). Moreover, the AMPKpTHR172/AMPK ratio increased at post after SIT (p < 0.05), whereas this effect was delayed after HIHVT as it increased after 3 h (p < 0.05). In addition, VEGF transcription was higher in response to HIHVT (p < 0.05). In conclusion, SIT induces higher muscular stress than HIHVT without increasing systemic oxidation. In addition, HIHVT may induce more robust oxidative adaptations through PGC-1α and AMPK. PMID:28973039

High-intensity high-volume swimming induces more robust signaling through PGC-1α and AMPK activation than sprint interval swimming in m. triceps brachii.

PubMed

Casuso, Rafael A; Plaza-Díaz, Julio; Ruiz-Ojeda, Francisco J; Aragón-Vela, Jerónimo; Robles-Sanchez, Cándido; Nordsborg, Nikolai B; Hebberecht, Marina; Salmeron, Luis M; Huertas, Jesus R

2017-01-01

We aimed to test whether high-intensity high-volume training (HIHVT) swimming would induce more robust signaling than sprint interval training (SIT) swimming within the m. triceps brachii due to lower metabolic and oxidation. Nine well-trained swimmers performed the two training procedures on separate randomized days. Muscle biopsies from m. triceps brachii and blood samples were collected at three different time points: a) before the intervention (pre), b) immediately after the swimming procedures (post) and c) after 3 h of rest (3 h). Hydroperoxides, creatine kinase (CK), and lactate dehydrogenase (LDH) were quantified from blood samples, and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and the AMPKpTHR172/AMPK ratio were quantified by Western blot analysis. PGC-1α, sirtuin 3 (SIRT3), superoxide-dismutase 2 (SOD2), and vascular endothelial growth factor (VEGF) mRNA levels were also quantified. SIT induced a higher release of LDH (p < 0.01 at all time points) and CK (p < 0.01 at post) than HIHVT, but neither SIT nor HIHVT altered systemic hydroperoxides. Additionally, neither SIRT3 nor SOD2 mRNA levels increased, while PGC-1α transcription increased at 3 h after SIT (p < 0.01) and after HIHVT (p < 0.001). However, PGC-1α protein was higher after HIHVT than after SIT (p < 0.05). Moreover, the AMPKpTHR172/AMPK ratio increased at post after SIT (p < 0.05), whereas this effect was delayed after HIHVT as it increased after 3 h (p < 0.05). In addition, VEGF transcription was higher in response to HIHVT (p < 0.05). In conclusion, SIT induces higher muscular stress than HIHVT without increasing systemic oxidation. In addition, HIHVT may induce more robust oxidative adaptations through PGC-1α and AMPK.

Surface deformation induced by magmatic processes at Pacaya Volcano, Guatemala revealed by InSAR

NASA Astrophysics Data System (ADS)

Wnuk, K.; Wauthier, C.

2017-09-01

Pacaya Volcano, Guatemala is a continuously active, basaltic volcano with an unstable western flank. Despite continuous activity since 1961, a lack of high temporal resolution geodetic surveying has prevented detailed modeling of Pacaya's underlying magmatic plumbing system. A new, temporally dense dataset of Interferometric Synthetic Aperture Radar (InSAR) RADARSAT-2 images, spanning December 2012 to March 2014, show magmatic deformation before and during major eruptions in January and March 2014. Inversion of InSAR surface displacements using simple analytical forward models suggest that three magma bodies are responsible for the observed deformation: (1) a 4 km deep spherical reservoir located northwest of the summit, (2) a 0.4 km deep spherical source located directly west of the summit, and (3) a shallow dike below the summit. Periods of heightened volcanic activity are instigated by magma pulses at depth, resulting in rapid inflation of the edifice. We observe an intrusion cycle at Pacaya that consists of deflation of one or both magma reservoirs followed by dike intrusion. Intrusion volumes are proportional to reservoir volume loss and do not always result in an eruption. Periods of increased activity culminate with larger dike-fed eruptions. Large eruptions are followed by inter-eruptive periods marked by a decrease in crater explosions and a lack of detected deformation. Co-eruptive flank motion appears to have initiated a new stage of volcanic rifting at Pacaya defined by repeated NW-SE oriented dike intrusions. This creates a positive feedback relationship whereby magmatic forcing from eruptive dike intrusions induce flank motion.

Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats.

PubMed

Tarasiuk, Ariel; Levi, Avishag; Berdugo-Boura, Nilly; Yahalom, Ari; Segev, Yael

2014-05-01

Chronic upper airway obstruction (UAO) elicits a cascade of complex endocrine derangements that affect growth, sleep, and energy metabolism. We hypothesized that elevated hypothalamic orexin has a role in maintaining ventilation during UAO, while at the same time altering sleep-wake activity and energy metabolism. Here, we sought to explore the UAO-induced changes in hypothalamic orexin and their role in sleep-wake balance, respiratory activity, and energy metabolism. The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed; UAO and sham-operated control animals were monitored for 7 weeks. We measured food intake, body weight, temperature, locomotion, and sleep-wake activity. Magnetic resonance imaging was used to quantify subcutaneous and visceral fat tissue volumes. In week 7, the rats were sacrificed and levels of hypothalamic orexin, serum leptin, and corticosterone were determined. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and respiration was also explored. UAO increased hypothalamic orexin mRNA and protein content by 64% and 65%, respectively. UAO led to 30% chronic sleep loss, excessive active phase sleepiness, decreased body temperature, increased food intake, reduction of abdominal and subcutaneous fat tissue volume, and growth retardation. Administration of almorexant normalized sleep but induced severe breathing difficulties in UAO rats, while it had no effect on sleep or on breathing of control animals. In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth.

The effects of osmotic stress on the structure and function of the cell nucleus.

PubMed

Finan, John D; Guilak, Farshid

2010-02-15

Osmotic stress is a potent regulator of the normal function of cells that are exposed to osmotically active environments under physiologic or pathologic conditions. The ability of cells to alter gene expression and metabolic activity in response to changes in the osmotic environment provides an additional regulatory mechanism for a diverse array of tissues and organs in the human body. In addition to the activation of various osmotically- or volume-activated ion channels, osmotic stress may also act on the genome via a direct biophysical pathway. Changes in extracellular osmolality alter cell volume, and therefore, the concentration of intracellular macromolecules. In turn, intracellular macromolecule concentration is a key physical parameter affecting the spatial organization and pressurization of the nucleus. Hyper-osmotic stress shrinks the nucleus and causes it to assume a convoluted shape, whereas hypo-osmotic stress swells the nucleus to a size that is limited by stretch of the nuclear lamina and induces a smooth, round shape of the nucleus. These behaviors are consistent with a model of the nucleus as a charged core/shell structure pressurized by uneven partition of macromolecules between the nucleoplasm and the cytoplasm. These osmotically-induced alterations in the internal structure and arrangement of chromatin, as well as potential changes in the nuclear membrane and pores are hypothesized to influence gene transcription and/or nucleocytoplasmic transport. A further understanding of the biophysical and biochemical mechanisms involved in these processes would have important ramifications for a range of fields including differentiation, migration, mechanotransduction, DNA repair, and tumorigenesis. (c) 2009 Wiley-Liss, Inc.

Effect of hypovolemia, infusion, and oral rehydration on plasma electrolytes, ADH, renin activity, and +G/z/ tolerance

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.; Brock, P. J.; Haines, R. F.; Rositano, S. A.; Montgomery, L. D.; Keil, L. C.

1977-01-01

Effects on plasma volume, electrolyte shifts, and +G(z) tolerance induced by: (1) blood withdrawal; (2) blood infusion; and (3) oral fluid intake, were determined at 0.5 G/min in centrifugation tests of six ambulatory male patients, aged 21 to 27 yrs. Hypovolemia induced by withdrawal of 400 ml blood, blood infusion followed by repeated centrifugation, effects of consuming an isotonic drink (0.9% NaCl) to achieve oral rehydration, and donning of red adaptation goggles were studied for effects on acceleration tolerance, pre-acceleration and post-acceleration plasma renin activity (PRA) and plasma vasopressin levels. No significant changes in post-acceleration PRA compared to pre-acceleration PRA were found, and administration of oral rehydration is found as effective as blood replacement in counteracting hypovolemic effects.

Direct and continuous strain control of catalysts with tunable battery electrode materials

DOE PAGES

Wang, Haotian; Xu, Shicheng; Tsai, Charlie; ...

2016-11-24

We report a method for using battery electrode materials to directly and continuously control the lattice strain of platinum (Pt) catalyst and thus tune its catalytic activity for the oxygen reduction reaction (ORR). Whereas the common approach of using metal overlayers introduces ligand effects in addition to strain, by electrochemically switching between the charging and discharging status of battery electrodes the change in volume can be precisely controlled to induce either compressive or tensile strain on supported catalysts. Lattice compression and tension induced by the lithium cobalt oxide substrate of ~5% were directly observed in individual Pt nanoparticles with aberration-correctedmore » transmission electron microscopy. As a result, we observed 90% enhancement or 40% suppression in Pt ORR activity under compression or tension, respectively, which is consistent with theoretical predictions.« less

Role of the superior pharyngeal constrictor muscle in forced breathing in dogs.

PubMed

Yaman, Z; Kogo, M; Senoo, H; Iida, S; Ishii, S; Matsuya, T

2000-03-01

Respiratory-related electromyographic (EMG) activity of the superior pharyngeal constrictor (SPC) muscle was analyzed during the early stage of forced breathing. Four adult dogs anesthetized with sodium pentobarbital were used. In the first part of the study, oral and nasal breathing tubes were placed into the respective cavities, and a tracheotomy tube was placed in the second part of the study. Two conditions, the presence (oral-nasal tube breathing) and absence (tracheotomy breathing) of airflow in the upper airway, were achieved in each dog. Following quiet breathing, animals were connected to a closed breathing system, first by an oral-nasal tube and then by a tracheotomy tube. We proposed to induce a forced breathing condition mechanically by using this system for 1 minute. We increased resistance to airflow during forced breathing by means of connecting tubes and a bag. Our aim was not to produce chemical drive but to produce a forced respiration by increasing the resistance to airflow. Tidal volume, breathing frequency, minute volume, chest wall movement, and EMG activity of the SPC muscle were measured and analyzed. During quiet breathing through an oral-nasal or tracheotomy tube, low-amplitude EMG activity of the SPC muscle corresponding to the expiratory cycle of the respiration was observed. In both study conditions, phasic expiratory EMG activity increased immediately after the advent of the breathing from the closed system. Tidal volumes and frequencies also increased rapidly during forced breathing. An increase in the resistance to airflow increased the activity of the SPC muscle. This augmented respiratory activity probably assists the patency of the upper airway. The augmented respiratory activity was independent of the local reflex pathways. Respiratory-related activity of the SPC muscle may help dilate and stiffen the pharyngeal airway, promoting airway patency.

Slow Breathing and Hypoxic Challenge: Cardiorespiratory Consequences and Their Central Neural Substrates

PubMed Central

Critchley, Hugo D.; Nicotra, Alessia; Chiesa, Patrizia A.; Nagai, Yoko; Gray, Marcus A.; Minati, Ludovico; Bernardi, Luciano

2015-01-01

Controlled slow breathing (at 6/min, a rate frequently adopted during yoga practice) can benefit cardiovascular function, including responses to hypoxia. We tested the neural substrates of cardiorespiratory control in humans during volitional controlled breathing and hypoxic challenge using functional magnetic resonance imaging (fMRI). Twenty healthy volunteers were scanned during paced (slow and normal rate) breathing and during spontaneous breathing of normoxic and hypoxic (13% inspired O2) air. Cardiovascular and respiratory measures were acquired concurrently, including beat-to-beat blood pressure from a subset of participants (N = 7). Slow breathing was associated with increased tidal ventilatory volume. Induced hypoxia raised heart rate and suppressed heart rate variability. Within the brain, slow breathing activated dorsal pons, periaqueductal grey matter, cerebellum, hypothalamus, thalamus and lateral and anterior insular cortices. Blocks of hypoxia activated mid pons, bilateral amygdalae, anterior insular and occipitotemporal cortices. Interaction between slow breathing and hypoxia was expressed in ventral striatal and frontal polar activity. Across conditions, within brainstem, dorsal medullary and pontine activity correlated with tidal volume and inversely with heart rate. Activity in rostroventral medulla correlated with beat-to-beat blood pressure and heart rate variability. Widespread insula and striatal activity tracked decreases in heart rate, while subregions of insular cortex correlated with momentary increases in tidal volume. Our findings define slow breathing effects on central and cardiovascular responses to hypoxic challenge. They highlight the recruitment of discrete brainstem nuclei to cardiorespiratory control, and the engagement of corticostriatal circuitry in support of physiological responses that accompany breathing regulation during hypoxic challenge. PMID:25973923

Experimental stroke protection induced by 4-hydroxybenzyl alcohol is cancelled by bacitracin.

PubMed

Descamps, Elodie; Petrault-Laprais, Maud; Maurois, Pierre; Pages, Nicole; Bac, Pierre; Bordet, Régis; Vamecq, Joseph

2009-06-01

Induction of protein disulfide isomerase (PDI) is validated as a main mechanism by which 4-hydroxybenzyl alcohol (4-HBA), an active principle of Gastrodia elata Blume, reduces cerebral infarct volumes in a murine model of focal brain ischemia/reperfusion. In contrast to its position isomers, i.e. 3-hydroxybenzyl alcohol (3-HBA) and 2-hydroxybenzyl alcohol (2-HBA), and to aliphatic diols (1,4-butanediol and 1,5-pentanediol), 4-HBA administered intravenously at 25 mg/kg protected mice, significantly reducing total, cortical and sub-cortical infarct volumes by 42, 28 and 55%, respectively. All compounds, 4-HBA included, were devoid of antioedematous properties. Only the stroke protective 4-HBA, but neither 3-HBA nor 2-HBA, was capable of significantly inducing PDI in intact mouse brains. Stroke protection was fully prevented by bacitracin (500 mg/kg), a known inhibitor of PDI, which, without affecting basal brain PDI levels, altered the ability of 4-HBA to induce significantly PDI in intact brains. Taken as a whole, our data indicate that stroke protection induced by 4-HBA involves PDI as a key player, making this protein a valuable target to control brain injury disorders. The fact that 4-HBA, at doses up to 200mg/kg, was devoid of neurotoxicity in the rotarod test is also a decisive element to promote the neuroprotective use of this plant compound.

Photochemoprevention of UVB-induced skin carcinogenesis in SKH-1 mice by brown algae polyphenols.

PubMed

Hwang, Hyejeong; Chen, Tong; Nines, Ronald G; Shin, Hyeon-Cheol; Stoner, Gary D

2006-12-15

Chronic exposure of the skin to ultraviolet B (UVB) radiation induces oxidative stress, which plays a crucial role in the induction of skin cancer. In this study, the effect of dietary feeding and topical application of brown algae polyphenols on UVB radiation-induced skin carcinogenesis in SKH-1 mice was investigated. SKH-1 hairless mice were randomly divided into 9 groups, including control, UVB control and treatment groups. They were treated orally (0.1% and 0.5% with AIN-76 diet, w/w) and topically (3 and 6 mg/0.2 ml of vehicle) with brown algae polyphenols and irradiated with UVB for 26 weeks. Dietary feeding (0.1% and 0.5%) of brown algae polyphenols significantly reduced tumor multiplicity (45% and 56%) and tumor volume (54% and 65%), and topical administration (3 and 6 mg) significantly decreased tumor multiplicity (60% and 46%) and tumor volume (66% and 57%), respectively, per tumor-bearing mouse. Dietary feeding and topical administration of the polyphenols also inhibited tumor incidence by 6% and 21%, respectively, but the results were not significant. Dietary and topical administration of the polyphenols markedly inhibited cyclooxygenase-2 activity and cell proliferation. These observations show that brown algae polyphenols have an antiphotocarcinogenic effect which may be associated with the prevention of UVB-induced oxidative stress, inflammation, and cell proliferation in the skin. Copyright 2006 Wiley-Liss, Inc.

Preoperative Renal Volume: A Surrogate Measure for Radical Nephrectomy-Induced Chronic Kidney Disease.

PubMed

Wu, Fiona Mei Wen; Tay, Melissa Hui Wen; Tai, Bee Choo; Chen, Zhaojin; Tan, Lincoln; Goh, Benjamin Yen Seow; Raman, Lata; Tiong, Ho Yee

2015-12-01

Surgically induced chronic kidney disease (CKD) has been found to have less impact on survival as well as function when compared to medical causes for CKD. The aim of this study is to evaluate whether preoperative remaining kidney volume correlates with renal function after nephrectomy, which represents an individual's renal reserve before surgically induced CKD. A retrospective review of 75 consecutive patients (29.3% females) who underwent radical nephrectomy (RN) (2000-2010) was performed. Normal side kidney parenchyma, excluding renal vessels and central sinus fat, was manually outlined in each transverse slice of CT image and multiplied by slice thickness to calculate volume. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease equation. CKD is defined as eGFR < 60 mL/min/1.73 m(2). Mean preoperative normal kidney parenchymal volume (mean age 55 [SD 13] years) is 150.7 (SD 36.4) mL. Over median follow-up of 36 months postsurgery, progression to CKD occurred in 42.6% (n = 32) of patients. On multivariable analysis, preoperative eGFR and preoperative renal volume <144 mL are independent predictors for postoperative CKD. On Kaplan-Meier analysis, median time to reach CKD postnephrectomy is 12.7 (range 0.03-43.66) months for renal volume <144 mL but not achieved if renal volume is >144 mL. Normal kidney parenchymal volume and preoperative eGFR are independent predictive factors for postoperative CKD after RN and may represent renal reserve for both surgically and medically induced CKD, respectively. Preoperative remaining kidney volume may be an adjunct representation of renal reserve postsurgery and predict later renal function decline due to perioperative loss of nephrons.

Quantitative structure-activity relationships (QSAR) of some 2,2-diphenyl propionate (DPP) derivatives of muscarinic antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gordon, R.K.; Breuer, E.; Padilla, F.N.

1987-05-01

QSAR between biological activities and molecular-chemical properties were investigated to aid in designing more effective and potent antimuscarinic pharmacophores. A molecular modeling program was used to calculate geometrical and topological values of a series of DPP pharmacophores. The newly synthesized pharmacophores were tested for their antagonist activities by: (1) inhibition of (N-methyl-/sup 3/H)scopolamine binding assay to the muscarinic receptors of N4TG1 neuroblastoma cells; (2) blocking of acetylcholine-induced contraction of guinea pig ileum; and (3) inhibition of carbachol-induced ..cap alpha..-amylase release from rat pancreas. The differences in the log of these biological activities were directly and significantly related to the distancesmore » between the carbonyl oxygen of the DPP and the quaternary nitrogen of the modified pharmacophores. The biological activities, while depending on each particular assay, varied between three and four logs of activity. The charge remained the same in all the pharmacophores. There were no QSAR correlations between molecular volume, molecular connectivity, or principle moments and their antagonistic activities, although multivariate QSAR was not employed. Thus, based on distance geometry, potent muscarinic pharmacophores can be predicted.« less

Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men

PubMed Central

Blondin, Denis P; Labbé, Sébastien M; Phoenix, Serge; Guérin, Brigitte; Turcotte, Éric E; Richard, Denis; Carpentier, André C; Haman, François

2015-01-01

Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-13C]-palmitate and [3-3H]-glucose tracer methodologies coupled with positron emission tomography using 11C-acetate and 18F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min−1, respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WAT lipolysis is closely associated with BAT metabolic activation upon acute cold exposure in healthy men. In humans, muscle glucose utilization during shivering contributes to a much greater extent than BAT to systemic glucose utilization during acute cold exposure. PMID:25384777

Hydraulic fracturing volume is associated with induced earthquake productivity in the Duvernay play.

PubMed

Schultz, R; Atkinson, G; Eaton, D W; Gu, Y J; Kao, H

2018-01-19

A sharp increase in the frequency of earthquakes near Fox Creek, Alberta, began in December 2013 in response to hydraulic fracturing. Using a hydraulic fracturing database, we explore relationships between injection parameters and seismicity response. We show that induced earthquakes are associated with completions that used larger injection volumes (10 4 to 10 5 cubic meters) and that seismic productivity scales linearly with injection volume. Injection pressure and rate have an insignificant association with seismic response. Further findings suggest that geological factors play a prominent role in seismic productivity, as evidenced by spatial correlations. Together, volume and geological factors account for ~96% of the variability in the induced earthquake rate near Fox Creek. This result is quantified by a seismogenic index-modified frequency-magnitude distribution, providing a framework to forecast induced seismicity. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1

PubMed Central

2013-01-01

Background Emerging studies have demonstrated that pretreatment with electroacupuncture (EA) induces significant tolerance to focal cerebral ischemia. The present study seeks to determine the involvement of monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified novel modulator of inflammatory reactions, in the cerebral neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of EA pretreatment-induced ischemic brain tolerance. Methods Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes in male C57BL/6 mice and MCPIP1 knockout mice. Transcription and expression of MCPIP1 gene was monitored by qRT-PCR, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, proinflammatory cytokines and leukocyte infiltration in brain and NF-κB signaling were evaluated after ischemia/reperfusion. Results MCPIP1 protein and mRNA levels significantly increased specifically in mouse brain undergoing EA pretreatment. EA pretreatment significantly attenuated the infarct volume, neurological deficits, upregulation of proinflammatory cytokines and leukocyte infiltration in the brain of wild-type mice after MCAO compared with that of the non-EA group. MCPIP1-deficient mice failed to evoke EA pretreatment-induced tolerance compared with that of the control MCPIP1 knockout group without EA treatment. Furthermore, the activation of NF-κB signaling was significantly reduced in EA-pretreated wild-type mice after MCAO compared to that of the non-EA control group and MCPIP1-deficient mice failed to confer the EA pretreatment-induced inhibition of NF-κB signaling after MCAO. Conclusions Our data demonstrated that MCPIP1 deficiency caused significant lack of EA pretreatment-induced cerebral protective effects after MCAO compared with the control group and that MCPIP1 is involved in EA pretreatment-induced delayed brain ischemia tolerance. PMID:23663236

Real-time detection of antibiotic activity by measuring nanometer-scale bacterial deformation

NASA Astrophysics Data System (ADS)

Iriya, Rafael; Syal, Karan; Jing, Wenwen; Mo, Manni; Yu, Hui; Haydel, Shelley E.; Wang, Shaopeng; Tao, Nongjian

2017-12-01

Diagnosing antibiotic-resistant bacteria currently requires sensitive detection of phenotypic changes associated with antibiotic action on bacteria. Here, we present an optical imaging-based approach to quantify bacterial membrane deformation as a phenotypic feature in real-time with a nanometer scale (˜9 nm) detection limit. Using this approach, we found two types of antibiotic-induced membrane deformations in different bacterial strains: polymyxin B induced relatively uniform spatial deformation of Escherichia coli O157:H7 cells leading to change in cellular volume and ampicillin-induced localized spatial deformation leading to the formation of bulges or protrusions on uropathogenic E. coli CFT073 cells. We anticipate that the approach will contribute to understanding of antibiotic phenotypic effects on bacteria with a potential for applications in rapid antibiotic susceptibility testing.

Escherichia coli α-Hemolysin Triggers Shrinkage of Erythrocytes via KCa3.1 and TMEM16A Channels with Subsequent Phosphatidylserine Exposure*

PubMed Central

Skals, Marianne; Jensen, Uffe B.; Ousingsawat, Jiraporn; Kunzelmann, Karl; Leipziger, Jens; Praetorius, Helle A.

2010-01-01

α-Hemolysin from Escherichia coli (HlyA) readily lyse erythrocytes from various species. We have recently demonstrated that this pore-forming toxin provokes distinct shrinkage and crenation before it finally leads to swelling and lysis of erythrocytes. The present study documents the underlying mechanism for this severe volume reduction. We show that HlyA-induced shrinkage and crenation of human erythrocytes occur subsequent to a significant rise in [Ca2+]i. The Ca2+-activated K+ channel KCa3.1 (or Gardos channel) is essential for the initial shrinkage, because both clotrimazole and TRAM-34 prevent the shrinkage and potentiate hemolysis produced by HlyA. Notably, the recently described Ca2+-activated Cl− channel TMEM16A contributes substantially to HlyA-induced cell volume reduction. Erythrocytes isolated from TMEM16A−/− mice showed significantly attenuated crenation and increased lysis compared with controls. Additionally, we found that HlyA leads to acute exposure of phosphatidylserine in the outer leaflet of the plasma membrane. This exposure was considerably reduced by KCa3.1 antagonists. In conclusion, this study shows that HlyA triggers acute erythrocyte shrinkage, which depends on Ca2+-activated efflux of K+ via KCa3.1 and Cl− via TMEM16A, with subsequent phosphatidylserine exposure. This mechanism might potentially allow HlyA-damaged erythrocytes to be removed from the bloodstream by macrophages and thereby reduce the risk of intravascular hemolysis. PMID:20231275

Platelet activation in pregnancy-induced hypertension.

PubMed

Karalis, Ioannis; Nadar, Sunil K; Al Yemeni, Eman; Blann, Andrew D; Lip, Gregory Y H

2005-01-01

Although excess platelet activation, as indicated by increased plasma beta thromboglobulin (beta-TG), has been shown in pregnancy-induced hypertension (PIH), platelet adhesion, platelet morphology and a comparison of platelet and soluble (plasma) levels of the adhesion molecules P-selectin (pPsel and sPsel, respectively) have not been studied. We conducted a cross-sectional study of 35 consecutive women with PIH (age 31+/-6 years), 31 consecutive women with normotensive pregnancies (age 29+/-5 years) and 30 normotensive non pregnant women (age 30+/-5 years). Platelet adhesion was studied in vitro by binding to fibrinogen-coated microwells, platelet morphology [mass and volume by flow cytometry], whole-platelet P-selectin (pPsel) by ELISA of the lysate of 2 x 10(8) cells, and the plasma markers soluble P-selectin (sP-sel) and beta-TG, by ELISA. The women with PIH had significantly raised sPsel, pPsel and (as expected) beta-TG (all p<0.05), when compared to the normotensive pregnant women and controls. However, in PIH platelet adhesion was similar to that in the normotensive pregnancy, but still higher than the normal controls (p<0.001). There was no difference among the three groups with respect to platelet mass and volume. pPsel and platelet adhesion correlated with gestational age and with systolic and diastolic blood pressure (all p<0.05). Increased platelet activation and adhesion develop during normal pregnancy, with some indices being further altered in PIH.

Escherichia coli alpha-hemolysin triggers shrinkage of erythrocytes via K(Ca)3.1 and TMEM16A channels with subsequent phosphatidylserine exposure.

PubMed

Skals, Marianne; Jensen, Uffe B; Ousingsawat, Jiraporn; Kunzelmann, Karl; Leipziger, Jens; Praetorius, Helle A

2010-05-14

alpha-Hemolysin from Escherichia coli (HlyA) readily lyse erythrocytes from various species. We have recently demonstrated that this pore-forming toxin provokes distinct shrinkage and crenation before it finally leads to swelling and lysis of erythrocytes. The present study documents the underlying mechanism for this severe volume reduction. We show that HlyA-induced shrinkage and crenation of human erythrocytes occur subsequent to a significant rise in [Ca(2+)](i). The Ca(2+)-activated K(+) channel K(Ca)3.1 (or Gardos channel) is essential for the initial shrinkage, because both clotrimazole and TRAM-34 prevent the shrinkage and potentiate hemolysis produced by HlyA. Notably, the recently described Ca(2+)-activated Cl(-) channel TMEM16A contributes substantially to HlyA-induced cell volume reduction. Erythrocytes isolated from TMEM16A(-/-) mice showed significantly attenuated crenation and increased lysis compared with controls. Additionally, we found that HlyA leads to acute exposure of phosphatidylserine in the outer leaflet of the plasma membrane. This exposure was considerably reduced by K(Ca)3.1 antagonists. In conclusion, this study shows that HlyA triggers acute erythrocyte shrinkage, which depends on Ca(2+)-activated efflux of K(+) via K(Ca)3.1 and Cl(-) via TMEM16A, with subsequent phosphatidylserine exposure. This mechanism might potentially allow HlyA-damaged erythrocytes to be removed from the bloodstream by macrophages and thereby reduce the risk of intravascular hemolysis.

SL4, a chalcone-based compound, induces apoptosis in human cancer cells by activation of the ROS/MAPK signalling pathway.

PubMed

Wang, L-H; Li, H-H; Li, M; Wang, S; Jiang, X-R; Li, Y; Ping, G-F; Cao, Q; Liu, X; Fang, W-H; Chen, G-L; Yang, J-Y; Wu, C-F

2015-12-01

SL4, a chalcone-based compound, exhibits clearly inhibitory effects on HIF-1 and has been shown to effectively suppress tumour invasion and angiogenesis in vitro and in vivo. Here, studies were conducted to determine SL4's anti-apoptotic effects and its underlying mechanisms, in human cancer cells. Cytotoxicity, apoptotic induction and its involved mechanisms of SL4 were investigated using normal cells, cancer cells and mouse xenograft models. The role of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) signalling in SL4-induced apoptosis was explored by manipulating specific scavenger or signalling inhibitors, in cultured cells. SL4 significantly inhibited cell population growth of human cancer cell lines but exhibited lower cytotoxicity against normal cells. In addition, SL4 effectively induced apoptosis of Hep3B and MDA-MB-435 cells by activating procaspase-8, -9 and -3, and down-regulating expression levels of XIAP, but did not affect HIF-1 apoptosis-related targets, Survivin and Bcl-XL. Further study showed that SL4 also reduced mitochondrial membrane potential and promoted generation of ROS. ROS generation and apoptotic induction by SL4 were blocked by NAC, a scavenger of ROS, suggesting SL4-induced apoptosis via ROS accumulation. We also found that MAPKs, JNK and p38, but not ERK1/2, to be critical mediators in SL4-induced apoptosis. SP600125 and SB203580, specific inhibitors of JNK kinase and p38 kinase, significantly retarded apoptosis induced by SL4. Moreover, anti-oxidant NAC blocked activation of JNK and p38 induced by SL4, indicating that ROS may act as upstream signalling of JNK and p38 activation. It is noteworthy that animal studies revealed dramatic reduction (49%) in tumour volume after 11 days SL4 treatment. These data demonstrate that SL4 induced apoptosis in human cancer cells through activation of the ROS/MAPK signalling pathway, suggesting that it may be a novel lead compound, as a cancer drug candidate, with polypharmacological characteristics. © 2015 John Wiley & Sons Ltd.

Detection of melting by X-ray imaging at high pressure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Li; Weidner, Donald J.

2014-06-15

The occurrence of partial melting at elevated pressure and temperature is documented in real time through measurement of volume strain induced by a fixed temperature change. Here we present the methodology for measuring volume strains to one part in 10{sup −4} for mm{sup 3} sized samples in situ as a function of time during a step in temperature. By calibrating the system for sample thermal expansion at temperatures lower than the solidus, the onset of melting can be detected when the melting volume increase is of comparable size to the thermal expansion induced volume change. We illustrate this technique withmore » a peridotite sample at 1.5 GPa during partial melting. The Re capsule is imaged with a CCD camera at 20 frames/s. Temperature steps of 100 K induce volume strains that triple with melting. The analysis relies on image comparison for strain determination and the thermal inertia of the sample is clearly seen in the time history of the volume strain. Coupled with a thermodynamic model of the melting, we infer that we identify melting with 2 vol.% melting.« less

Laser-Induced Incandescence Measurements in Low Gravity

NASA Technical Reports Server (NTRS)

VanderWal, R. L.

1997-01-01

A low-gravity environment offers advantages to investigations concerned with soot growth or flame radiation by eliminating of buoyancy-induced convection. Basic to each type of study is knowledge of spatially resolved soot volume fraction, (f(sub v). Laser-induced incandescence (LII) has emerged as a diagnostic for soot volume fraction determination because it possesses high temporal and spatial resolution, geometric versatility and high sensitivity. Implementation and system characterization of LII in a drop tower that provides 2.2 sec of low-gravity (micro)g) at the NASA Lewis Research Center are described here. Validation of LII for soot volume fraction determination in (micro)g is performed by comparison between soot volume fraction measurements obtained by light extinction [20] and LII in low-gravity for a 50/50 mixture (by volume) of 0 acetylene/nitrogen issuing into quiescent air. Quantitative soot volume fraction measurements within other laminar flames of ethane and propane and a turbulent diffusion flame in (micro)g via LII are also demonstrated. An analysis of LII images of a turbulent acetylene diffusion flame in 1-g and (micro)g is presented.

Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis

PubMed Central

El-Naa, Mona Mohamed; Othman, Mohamed; Younes, Sheren

2016-01-01

Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic, antiproliferative, and apoptotic activities of sildenafil. PMID:27895461

Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis.

PubMed

El-Naa, Mona Mohamed; Othman, Mohamed; Younes, Sheren

2016-01-01

Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic, antiproliferative, and apoptotic activities of sildenafil.

Unveiling the relationships among the viscosity equations of glass liquids and colloidal suspensions for obtaining universal equations with the generic free volume concept.

PubMed

Hao, Tian

2015-09-14

The underlying relationships among viscosity equations of glass liquids and colloidal suspensions are explored with the aid of free volume concept. Viscosity equations of glass liquids available in literature are focused and found to have a same physical basis but different mathematical expressions for the free volume. The glass transitions induced by temperatures in glass liquids and the percolation transition induced by particle volume fractions in colloidal suspensions essentially are a second order phase transition: both those two transitions could induce the free volume changes, which in turn determines how the viscosities are going to change with temperatures and/or particle volume fractions. Unified correlations of the free volume to both temperatures and particle volume fractions are thus proposed. The resulted viscosity equations are reducible to many popular viscosity equations currently widely used in literature; those equations should be able to cover many different types of materials over a wide temperature range. For demonstration purpose, one of the simplified versions of those newly developed equations is compared with popular viscosity equations and the experimental data: it can well fit the experimental data over a wide temperature range. The current work reveals common physical grounds among various viscosity equations, deepening our understanding on viscosity and unifying the free volume theory across many different systems.

Effects of positive end-expiratory pressure and recruitment maneuvers in a ventilator-induced injury mouse model

PubMed Central

Franzi, Lisa M.; Linderholm, Angela L.; Last, Jerold A.; Adams, Jason Y.; Harper, Richart W.

2017-01-01

Background Positive-pressure mechanical ventilation is an essential therapeutic intervention, yet it causes the clinical syndrome known as ventilator-induced lung injury. Various lung protective mechanical ventilation strategies have attempted to reduce or prevent ventilator-induced lung injury but few modalities have proven effective. A model that isolates the contribution of mechanical ventilation on the development of acute lung injury is needed to better understand biologic mechanisms that lead to ventilator-induced lung injury. Objectives To evaluate the effects of positive end-expiratory pressure and recruitment maneuvers in reducing lung injury in a ventilator-induced lung injury murine model in short- and longer-term ventilation. Methods 5–12 week-old female BALB/c mice (n = 85) were anesthetized, placed on mechanical ventilation for either 2 hrs or 4 hrs with either low tidal volume (8 ml/kg) or high tidal volume (15 ml/kg) with or without positive end-expiratory pressure and recruitment maneuvers. Results Alteration of the alveolar-capillary barrier was noted at 2 hrs of high tidal volume ventilation. Standardized histology scores, influx of bronchoalveolar lavage albumin, proinflammatory cytokines, and absolute neutrophils were significantly higher in the high-tidal volume ventilation group at 4 hours of ventilation. Application of positive end-expiratory pressure resulted in significantly decreased standardized histology scores and bronchoalveolar absolute neutrophil counts at low- and high-tidal volume ventilation, respectively. Recruitment maneuvers were essential to maintain pulmonary compliance at both 2 and 4 hrs of ventilation. Conclusions Signs of ventilator-induced lung injury are evident soon after high tidal volume ventilation (as early as 2 hours) and lung injury worsens with longer-term ventilation (4 hrs). Application of positive end-expiratory pressure and recruitment maneuvers are protective against worsening VILI across all time points. Dynamic compliance can be used guide the frequency of recruitment maneuvers to help ameloriate ventilator-induced lung injury. PMID:29112971

AMP-activated kinase mediates adipose stem cell-stimulated neuritogenesis of PC12 cells.

PubMed

Tan, B; Luan, Z; Wei, X; He, Y; Wei, G; Johnstone, B H; Farlow, M; Du, Y

2011-05-05

Adipose tissue stroma contains a population of mesenchymal stem cells, which support repair of damaged tissues through the protective effects of secreted trophic factors. Neurotrophic factors, including nerve growth factor (NGF) have been identified in media collected from cultured adipose-derived stem cells (ASC). We previously demonstrated that administration of cell-free ASC conditioned medium (ASC-CM) at 24 h after injury reduced lesion volume and promoted functional recovery in a rat model of neonatal brain hypoxic-ischemic (HI) injury. The timing of administration well after the peak in neural cell apoptosis in the affected region suggests that regeneration of lost neurons is promoted by factors in ASC-CM. In this study, we determined which of the factors in ASC-CM could induce neurogenesis by testing the ability of the mixture, either whole or after inactivating specific components, to stimulate neurite outgrowth in vitro using the neurogenic cell line PC12. Neuritogenesis in PC12 cells treated with ASC-CM was observed at a level comparable to that observed with purified recombinant NGF. It was observed that NGF in ASC-CM was mainly responsible for inducing PC12 cell neuritogenesis. Interestingly, both ASC-CM and NGF induced PC12 cell neuritogenesis through activation of the AMP-activated kinase (AMPK) pathway which is the central protein involved in controlling many critical functions in response to changes in the cellular energy status. Pharmacological and genetic inhibition of AMPK activity greatly reduced neuritogenesis in PC12 cells. These results suggest that, in addition to possessing neuroprotective properties, ASC-CM mediates repair of damaged tissues through inducing neuronal differentiation via NGF-induced AMPK activation. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Photothrombosis-Induced Infarction of the Mouse Cerebral Cortex Is Not Affected by the Nrf2-Activator Sulforaphane

PubMed Central

Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage. PMID:22911746

Photothrombosis-induced infarction of the mouse cerebral cortex is not affected by the Nrf2-activator sulforaphane.

PubMed

Porritt, Michelle J; Andersson, Helene C; Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage.

Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

PubMed

Tang, Jun; Chen, Qianwei; Guo, Jing; Yang, Liming; Tao, Yihao; Li, Lin; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

2016-04-01

Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes.

Effects of 5-hydroxymethyl-2-furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease

PubMed Central

Hannemann, Anke; Cytlak, Urszula M; Rees, David C; Tewari, Sanjay; Gibson, John S

2014-01-01

The heterocyclic aldehyde 5-hydroxymethyl-2-furfural (5HMF) interacts allosterically with the abnormal form of haemoglobin (Hb), HbS, in red blood cells (RBCs) from patients with sickle cell disease (SCD), thereby increasing oxygen affinity and decreasing HbS polymerization and RBC sickling during hypoxia. We hypothesized that should 5HMF also inhibit the main cation pathways implicated in the dehydration of RBCs from SCD patients – the deoxygenation-induced cation pathway (Psickle), the Ca2+-activated K+ channel (the Gardos channel) and the K+–Cl− cotransporter (KCC) – it would have a synergistic effect in protection against sickling, directly through interacting with HbS, and indirectly through maintaining hydration and reducing [HbS]. This study was therefore designed to investigate the effects of 5HMF on RBC volume and K+ permeability in vitro. 5HMF markedly reduced the deoxygenation-induced dehydration of RBCs whether in response to maintained deoxygenation or to cyclical deoxygenation/re-oxygenation. 5HMF was found to inhibit Psickle, an effect which correlated with its effects on sickling. Deoxygenation-induced activation of the Gardos channel and exposure of phosphatidylserine were also inhibited, probably indirectly via reduced entry of Ca2+ through the Psickle pathway. Effects of 5HMF on KCC were more modest with a slight inhibition in N-ethylmaleimide (NEM, 1 mm)-treated RBCs and stimulation in RBCs untreated with NEM. These findings support the hypothesis that 5HMF may also be beneficial through effects on RBC ion and water homeostasis. PMID:25015917

Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin-induced nephrotoxicity in rats.

PubMed

Ehsani, Vahid; Amirteimoury, Morteza; Taghipour, Zahra; Shamsizadeh, Ali; Bazmandegan, Gholamreza; Rahnama, Amir; Khajehasani, Fatemeh; Fatemi, Iman

2017-11-01

Pistacia vera is a plant of the family Anacardiaceae found in Central and West Asia. P. vera nut (Pistachio) possess multiple pharmacological effects such as antimicrobial, anti-hyperlipidemia, antioxidant and anti-inflammatory. This study is designed to evaluate the protective effect of the hydroalcoholic extract of pistachio on gentamicin-induced nephrotoxicity in rats. Nephrotoxicity was induced in rats by intraperitoneal injection of gentamicin (100 mg/kg/day for 7 days). Hydroalcoholic extract of pistachio (10, 50 and 100 mg/kg/p.o) was administered for 7 days. The nephroprotective activity was evaluated by determining creatinine clearance, serum creatinine, urine volume, urine glucose and blood urea nitrogen (BUN) levels. The kidneys were processed for histopathological examinations and all specimens were examined for morphologic parameters involving tubular degeneration, tubular necrosis and tubule interstitial nephritis. Results showed a significant increase in the levels of serum creatinine, urine volume, urine glucose and BUN and decrease of creatinine clearance by gentamicin (GA) administration. Co-administration with pistachio extract showed reduction in the levels of serum creatinine, urine volume, urine glucose and BUN and increase of creatinine clearance in all doses but the most significant alteration was observed in doses of 100 mg/kg. Also, the nephroprotective effect of the GA was confirmed by the histological examination of the kidneys. The study revealed the nephroprotective effect of the hydroalcoholic extract of pistachio. These findings suggest that pistachio treatment may attenuate renal dysfunction and structural damage through the reduction of oxidative stress and inflammation in the kidney.

[Participation of parasympathetic part of nervous system in realization of bioflavonoids action on gastric secretion in rats].

PubMed

Vovkun, T V; Yanchuk, P I; Shtanova, L Y; Veselskyy, S P; Shalamay, A S

2015-01-01

In this study we investigated the effects of corvitin--modified form of flavonoid quercetin on the stomach secretory function and physiological mechanisms involved in the maintenance of such effects in rat's pylorus-ligated model. In animals which corvitin was injected at a dose of 5 mg/kg, regardless of the route of administration--in the stomach or duodenum, did not observe any changes in the volume of gastric juice or general production of hydrochloric acid, compared with the control data. Dose of 40 mg/kg caused an increase in the volume of gastric juice and hydrochloric acid output as when administered in the stomach and in the duodenum. We also found that after the application of a large dose of corvitin (intragastrically) in the blood of experimental animals showed reduction in glucose levels, which was not detected when using the drug in a dose of 5 mg/kg. Nonspecific antagonist of M-cholinergic receptors--atropine almost completely blocked the enhancement of gastric secretion, which was caused by the introduction into the stomach of corvitin in large dose. From the present data, it is reasonable to conclude that intragastric administration of a large dose of corvitin to pylorus-ligated rats induces hypoglycemic reaction of blood, which may causes an increase in vagus nerve activity with subsequent stimulation of gastric secretion. The increase in gastric juice volume and gastric acid output induced by corvitin was completely inhibited by atropine. These results suggested that the increase in gastric secretion induced by intragastrically administered corvitin could be mediated by the parasympathetic nervous system.

Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin-induced nephrotoxicity in rats

PubMed Central

Ehsani, Vahid; Amirteimoury, Morteza; Taghipour, Zahra; Shamsizadeh, Ali; Bazmandegan, Gholamreza; Rahnama, Amir; Khajehasani, Fatemeh; Fatemi, Iman

2017-01-01

Abstract Purpose:Pistacia vera is a plant of the family Anacardiaceae found in Central and West Asia. P. vera nut (Pistachio) possess multiple pharmacological effects such as antimicrobial, anti-hyperlipidemia, antioxidant and anti-inflammatory. This study is designed to evaluate the protective effect of the hydroalcoholic extract of pistachio on gentamicin-induced nephrotoxicity in rats. Methods: Nephrotoxicity was induced in rats by intraperitoneal injection of gentamicin (100 mg/kg/day for 7 days). Hydroalcoholic extract of pistachio (10, 50 and 100 mg/kg/p.o) was administered for 7 days. The nephroprotective activity was evaluated by determining creatinine clearance, serum creatinine, urine volume, urine glucose and blood urea nitrogen (BUN) levels. The kidneys were processed for histopathological examinations and all specimens were examined for morphologic parameters involving tubular degeneration, tubular necrosis and tubule interstitial nephritis. Results: Results showed a significant increase in the levels of serum creatinine, urine volume, urine glucose and BUN and decrease of creatinine clearance by gentamicin (GA) administration. Co-administration with pistachio extract showed reduction in the levels of serum creatinine, urine volume, urine glucose and BUN and increase of creatinine clearance in all doses but the most significant alteration was observed in doses of 100 mg/kg. Also, the nephroprotective effect of the GA was confirmed by the histological examination of the kidneys. Conclusion: The study revealed the nephroprotective effect of the hydroalcoholic extract of pistachio. These findings suggest that pistachio treatment may attenuate renal dysfunction and structural damage through the reduction of oxidative stress and inflammation in the kidney. PMID:28558475

Left ventricular mass in elite olympic weight lifters.

PubMed

Lalande, Sophie; Baldi, James Christopher

2007-10-01

The existence of resistance training-induced left ventricular (LV) concentric hypertrophy is equivocal. Although some have described significant LV hypertrophy, others have suggested that training-induced LV hypertrophy is proportional to increased fat free mass (FFM) and thus a normal physiologic response to training. Method limitations, steroid use, and type of training may contribute to discrepant findings. Thus, LV structure and volumes are determined using magnetic resonance imaging. Body composition was determined using dual-energy x-ray absorptiometry in 9 elite Olympic weight lifters and 10 age- and weight-matched recreationally active controls. LV structure and volumes were determined by acquiring 6 short- and 3 long-axis magnetic resonance imaging scans of the left ventricle, whereas LV wall thickness was defined as the average of 6 midventricular segment thickness measurements. Weight lifters had the same age, weight, and FFM, but were shorter and had a greater body mass index than controls. LV mass was not different in weight lifters and controls, but was lower in weight lifters when indexed to FFM (2.56 +/- 0.07 vs 2.30 +/- 0.05, p = 0.01). LV mass correlated with FFM (r = 0.49, p = 0.04). However, LV mass was lower in weight lifters for a given FFM. LV wall thickness, as well as end-diastolic, end-systolic, and stroke volumes, were not different between groups. In conclusion, these results refute the hypothesis that resistance training induces LV concentric hypertrophy and suggest that Olympic weight lifting is associated with increases in FFM without a concomitant increase in LV mass.

Absolute versus relative intensity of physical activity in a dose-response context.

PubMed

Shephard, R J

2001-06-01

To examine the importance of relative versus absolute intensities of physical activity in the context of population health. A standard computer-search of the literature was supplemented by review of extensive personal files. Consensus reports (Category D Evidence) have commonly recommended moderate rather than hard physical activity in the context of population health. Much of the available literature provides Category C Evidence. It has often confounded issues of relative intensity with absolute intensity or total weekly dose of exercise. In terms of cardiovascular health, there is some evidence for a threshold intensity of effort, perhaps as high as 6 METs, in addition to a minimum volume of physical activity. Decreases in blood pressure and prevention of stroke seem best achieved by moderate rather than high relative intensities of physical activity. Many aspects of metabolic health depend on the total volume of activity; moderate relative intensities of effort are more effective in mobilizing body fat, but harder relative intensities may help to increase energy expenditures postexercise. Hard relative intensities seem needed to augment bone density, but this may reflect an associated increase in volume of activity. Hard relative intensities of exercise induce a transient immunosuppression. The optimal intensity of effort, relative or absolute, for protection against various types of cancer remains unresolved. Acute effects of exercise on mood state also require further study; long-term benefits seem associated with a moderate rather than a hard relative intensity of effort. The importance of relative versus absolute intensity of effort depends on the desired health outcome, and many issues remain to be resolved. Progress will depend on more precise epidemiological methods of assessing energy expenditures and studies that equate total energy expenditures between differing relative intensities. There is a need to focus on gains in quality-adjusted life expectancy.

Interactions Between IGFBP-3 and Nuclear Receptors in Prostate Cancer Apoptosis

DTIC Science & Technology

2010-01-01

flavonoid found in grapes, green vegetables, and onions, induced apoptosis of PC-3 cells (240). This was accompanied with a decrease in IGF-1 and -2 and...stabilized integrin receptor complexes (27). In vivo. GROWTH INHIBITION. Mice bearing human prostate 22RV1 tumor xenografts were fed apigenin, a flavonoid ...the active component of flavonoid antioxidant silymarin (milk thistle extract) significantly inhib- ited tumor volume in DU145 tumor xenograft nude

Piezoelectric energy harvesting in coupling-chamber excited by the vortex-induced pressure

NASA Astrophysics Data System (ADS)

Cheng, Tinghai; Wang, Yingting; Qin, Feng; Song, Zhaoyang; Lu, Xiaohui; Bao, Gang; Zhao, Xilu

2016-08-01

The performance of a piezoelectric energy harvester with a coupling chamber was investigated under vortex-induced pressure. The harvester consisted of a power chamber, a buffer, and a storage chamber. Different types of vortex (i.e., clockwise or counter-clockwise) could be induced by changing the volume ratio between the power chamber and the storage chamber. The peak voltage of the harvester could be tuned by changing the volume ratio. For example, under a pressure of 0.30 MPa, input cycle of 2.0 s, and flow rate of 200 l/min, the peak voltage decreased from 79.20 to 70.80 V with increasing volume ratio. The optimal volume ratio was 2.03, which resulted in the formation of a clockwise vortex. The corresponding effective power through a 600 kΩ resistor was 1.97 mW.

The anti-gastric ulcer effect of Gynostemma pentaphyllum Makino.

PubMed

Rujjanawate, C; Kanjanapothi, D; Amornlerdpison, D

2004-07-01

Gynostemma pentaphyllum is an oriental medicinal herb reputed to have broad-spectrum activities. The plant's principal saponin components are structurally similar to those found in ginseng plants and this similarity is assumed to be responsible for the claimed activities. The present study was undertaken to evaluate a G. pentaphyllum butanol fraction (GPB) for its anti-gastric ulcer activity using experimental models. Oral administration of the GPB at 200 and 400 mg/kg body wt. significantly inhibited gastric ulcer formation induced by indomethacin, HCl/EtOH and water-immersion restraint stress in rats. In pylorus-ligated rats, pretreatment with the GPB had no effect on gastric volume, pH or acidity output, thus indicating a lack of anti-secretory effect. In ethanol-induced ulcerated rats, gastric wall mucus and hexosamine content were markedly preserved by GPB pretreatment. The findings indicate that the butanol fraction of G. pentaphyllum possesses gastroprotective potential related to the preservation of gastric mucus synthesis and secretion.

DELFIC: Department of Defense Fallout Prediction System. Volume II. User’s Manual

DTIC Science & Technology

1979-12-31

code, and it strives to include as much of the physics of fallout transport and activity calculation, without resorting to short cuts, as is...fission may be specified. Induced activity in soil material in the fallout and in 2 3BU may be accounted for. Physical and mathematical bases for...900o) *GTo 1.) GO TO 150 ATMR 140 ALT(13=-i003. ATAR 14± GO TO 20O ATNR ±42 15C WRITE(IRISE)ATMSU8 ATMR ±43 160 IGG=IGO+i ATMR 144 C ATMR 145 C CO THE

From MIPS to Vicsek: A comprehensive phase diagram for self-propelled rods

NASA Astrophysics Data System (ADS)

Shi, Xiaqing

Self-propelled rods interacting by volume exclusion is one of the simplest active matter systems. Despite years of effort, no comprehensive picture of their phase diagram is available. Furthermore, results on explicit rods are so far largely disconnected from those obtained on the relatively better understood cases of motility induced phase separation (MIPS) of (usually) isotropic active particles, and from our current knowledge of Vicsek-style aligning point particles. In this talk, I will present a complete phase diagram of a generic model of self-propelled rods and show how it is connected to both MIPS and Vicsek worlds.

Solute induced relaxation in glassy polymers: Experimental measurements and nonequilibrium thermodynamic model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minelli, Matteo; Doghieri, Ferruccio

2014-05-15

Data for kinetics of mass uptake from vapor sorption experiments in thin glassy polymer samples are here interpreted in terms of relaxation times for volume dilation. To this result, both models from non-equilibrium thermodynamics and from mechanics of volume relaxation contribute. Different kind of sorption experiments have been considered in order to facilitate the direct comparison between kinetics of solute induced volume dilation and corresponding data from process driven by pressure or temperature jumps.

Ferulic acid attenuates the down-regulation of MEK/ERK/p90RSK signaling pathway in focal cerebral ischemic injury.

PubMed

Koh, Phil-Ok

2015-02-19

Ferulic acid provides neuroprotective effects against a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia. Mitogen-activated protein kinases can regulate extensive intracellular processes including cell differentiation, growth, and death. This study further investigated whether ferulic acid modulates a protective mechanism through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad during cerebral ischemic injury. Male Sprague-Dawley rats were treated with ferulic acid (100mg/kg) or vehicle after the onset of MCAO and brain tissues were collected 24h after MCAO. These results indicated that ferulic acid decreases the volume of the infarct area and the number of cells positive in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Although MCAO injury induces a decrease in the phosphorylation of Raf-1, MEK1/2, and ERK1/2, ferulic acid treatment prevents the injury-induced decrease in these phosphorylation levels. Ferulic acid also attenuates the injury-induced decrease in p90RSK and Bad phosphorylation levels. These findings suggest that ferulic acid prevents MCAO-induced neuronal cell death and that the MEK-ERK-p90RSK-Bad signaling pathway is involved in these neuroprotective effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mechanochemical Association Reaction of Interfacial Molecules Driven by Shear.

PubMed

Khajeh, Arash; He, Xin; Yeon, Jejoon; Kim, Seong H; Martini, Ashlie

2018-05-29

Shear-driven chemical reaction mechanisms are poorly understood because the relevant reactions are often hidden between two solid surfaces moving in relative motion. Here, this phenomenon is explored by characterizing shear-induced polymerization reactions that occur during vapor phase lubrication of α-pinene between sliding hydroxylated and dehydroxylated silica surfaces, complemented by reactive molecular dynamics simulations. The results suggest that oxidative chemisorption of the α-pinene molecules at reactive surface sites, which transfers oxygen atoms from the surface to the adsorbate molecule, is the critical activation step. Such activation takes place more readily on the dehydroxylated surface. During this activation, the most strained part of the α-pinene molecules undergoes a partial distortion from its equilibrium geometry, which appears to be related to the critical activation volume for mechanical activation. Once α-pinene molecules are activated, association reactions occur between the newly attached oxygen and one of the carbon atoms in another molecule, forming ether bonds. These findings have general implications for mechanochemistry because they reveal that shear-driven reactions may occur through reaction pathways very different from their thermally induced counterparts and specifically the critical role of molecular distortion in such reactions.

Platelet size and density affect shear-induced thrombus formation in tortuous arterioles

NASA Astrophysics Data System (ADS)

Chesnutt, Jennifer K. W.; Han, Hai-Chao

2013-10-01

Thrombosis accounts for 80% of deaths in patients with diabetes mellitus. Diabetic patients demonstrate tortuous microvessels and larger than normal platelets. Large platelets are associated with increased platelet activation and thrombosis, but the physical effects of large platelets in the microscale processes of thrombus formation are not clear. Therefore, the objective of this study was to determine the physical effects of mean platelet volume (MPV), mean platelet density (MPD) and vessel tortuosity on platelet activation and thrombus formation in tortuous arterioles. A computational model of the transport, shear-induced activation, collision, adhesion and aggregation of individual platelets was used to simulate platelet interactions and thrombus formation in tortuous arterioles. Our results showed that an increase in MPV resulted in a larger number of activated platelets, though MPD and level of tortuosity made little difference on platelet activation. Platelets with normal MPD yielded the lowest amount of mural thrombus. With platelets of normal MPD, the amount of mural thrombus decreased with increasing level of tortuosity but did not have a simple monotonic relationship with MPV. The physical mechanisms associated with MPV, MPD and arteriole tortuosity play important roles in platelet activation and thrombus formation.

Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential

PubMed Central

ALAM, BADRUL; MAJUMDER, RAJIB; AKTER, SHAHINA; LEE, SANG-HAN

2015-01-01

The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (P<0.05). Hematological and serum biochemical profiles were restored to normal levels in the extract-treated mice compared with the EAC control mice. MPBL and EPBL treatment significantly decreased lipid peroxidation (P<0.05) and restored GSH, SOD and CAT levels towards normal compared with the EAC control. Taken together, the results of the present study demonstrated that Piper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential. PMID:25624910

Piper betle extracts exhibit antitumor activity by augmenting antioxidant potential.

PubMed

Alam, Badrul; Majumder, Rajib; Akter, Shahina; Lee, Sang-Han

2015-02-01

The present study was conducted to evaluate the methanolic extract of Piper betle leaves (MPBL) and its organic fractions with regard to antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice and to confirm their antioxidant activities. At 24 h post-intraperitoneal inoculation of tumor cells into mice, extracts were administered at 25, 50 and 100 mg/kg body weight for nine consecutive days. The antitumor effects of the extracts were then assessed according to tumor volume, packed cell count, viable and non-viable tumor cell count, median survival time and increase in life span of EAC-bearing mice. Next, hematological profiles and serum biochemical parameters were calculated, and antioxidant properties were assessed by estimating lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels. MPBL and the ethylacetate fraction (EPBL) at a dose of 100 mg/kg induced a significant decrease in tumor volume, packed cell volume and viable cell count and increased the life span of the EAC-bearing mice (P<0.05). Hematological and serum biochemical profiles were restored to normal levels in the extract-treated mice compared with the EAC control mice. MPBL and EPBL treatment significantly decreased lipid peroxidation (P<0.05) and restored GSH, SOD and CAT levels towards normal compared with the EAC control. Taken together, the results of the present study demonstrated that Piper betle extracts exhibit significant antitumor activity, which may be attributed to the augmentation of endogenous antioxidant potential.

Overendocytosis of superparamagnetic iron oxide particles increases apoptosis and triggers autophagic cell death in human osteosarcoma cell under a spinning magnetic field

PubMed Central

Du, Chonghua; Huang, Zhongming; Chen, Guangnan; Yan, Weiqi

2017-01-01

The toxicity of superparamagnetic iron oxide nanoparticles (SPIONs) is still a vital topic of debate and the mechanisms remain unclear. In the present study, overdose SPIONs could induce osteosarcoma cell death and the effects were exaggerated when combined with spinning magnetic field (SMF). In the combination group, mitochondrial transmembrane potential decrease more obviously and reactive oxygen species (ROS) was found to generate much higher in line with that of the apoptosis ratio. Meantime, amount of autophagy was induced. Inhibiting the autophagy generation by 3-methyladenine (3-MA) increase cell viability but decrease the caspase 3/7 and caspase 8 activities in combination groups, and inhibiting apoptosis took the same effect. In the end, the SPIONs effects on xenograft mice was examed by intratumoral injection. The result showed that the combination group could greatly decrease the tumor volume and prolong the lifespan of mice. In sum, the result indicated that overdose SPIONs induced ROS generation, and excessive ROS induced by combination of SPIONs and SMF contribute to autophagy formation, which play a apoptosis-promoting role that formed as a platform to recruits initiate the caspase activities. PMID:28031531

Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells.

PubMed

Shi, Wei; Deng, Jiagang; Tong, Rongsheng; Yang, Yong; He, Xia; Lv, Jianzhen; Wang, Hailian; Deng, Shaoping; Qi, Ping; Zhang, Dingding; Wang, Yi

2016-04-01

Mangiferin, which is a C‑glucosylxanthone (1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside) purified from plant sources, has recently gained attention due to its various biological activities. The present study aimed to determine the apoptotic effects of mangiferin on A549 human lung adenocarcinoma cells. In vitro studies demonstrated that mangiferin exerted growth‑inhibitory and apoptosis-inducing effects against A549 cells. In addition, mangiferin exhibited anti-tumor properties in A549 xenograft mice in vivo. Mangiferin triggered G2/M phase cell cycle arrest via downregulating the cyclin-dependent kinase 1-cyclin B1 signaling pathway, and induced apoptotic cell death by inhibiting the protein kinase C-nuclear factor-κB pathway. In addition, mangiferin was able to enhance the antiproliferative effects of cisplatin on A549 cells, thus indicating the potential for a combined therapy. Notably, mangiferin exerted anticancer effects in vivo, where it was able to markedly decrease the volume and weight of subcutaneous tumor mass, and expand the lifespan of xenograft mice. The present study clarified the molecular mechanisms underlying mangiferin-induced antitumor activities, and suggested that mangiferin may be considered a potential antineoplastic drug for the future treatment of cancer.

Differential regulation of Smad3 and of the type II transforming growth factor-β receptor in mitosis: implications for signaling.

PubMed

Hirschhorn, Tal; Barizilay, Lior; Smorodinsky, Nechama I; Ehrlich, Marcelo

2012-01-01

The response to transforming growth factor-β (TGF-β) depends on cellular context. This context is changed in mitosis through selective inhibition of vesicle trafficking, reduction in cell volume and the activation of mitotic kinases. We hypothesized that these alterations in cell context may induce a differential regulation of Smads and TGF-β receptors. We tested this hypothesis in mesenchymal-like ovarian cancer cells, arrested (or not) in mitosis with 2-methoxyestradiol (2ME2). In mitosis, without TGF-β stimulation, Smad3 was phosphorylated at the C-terminus and linker regions and localized to the mitotic spindle. Phosphorylated Smad3 interacted with the negative regulators of Smad signaling, Smurf2 and Ski, and failed to induce a transcriptional response. Moreover, in cells arrested in mitosis, Smad3 levels were progressively reduced. These phosphorylations and reduction in the levels of Smad3 depended on ERK activation and Mps1 kinase activity, and were abrogated by increasing the volume of cells arrested in mitosis with hypotonic medium. Furthermore, an Mps1-dependent phosphorylation of GFP-Smad3 was also observed upon its over-expression in interphase cells, suggesting a mechanism of negative regulation which counters increases in Smad3 concentration. Arrest in mitosis also induced a block in the clathrin-mediated endocytosis of the type II TGF-β receptor (TβRII). Moreover, following the stimulation of mitotic cells with TGF-β, the proteasome-mediated attenuation of TGF-β receptor activity, the degradation and clearance of TβRII from the plasma membrane, and the clearance of the TGF-β ligand from the medium were compromised, and the C-terminus phosphorylation of Smad3 was prolonged. We propose that the reduction in Smad3 levels, its linker phosphorylation, and its association with negative regulators (observed in mitosis prior to ligand stimulation) represent a signal attenuating mechanism. This mechanism is balanced by the retention of active TGF-β receptors at the plasma membrane. Together, both mechanisms allow for a regulated cellular response to TGF-β stimuli in mitosis.

Differential Regulation of Smad3 and of the Type II Transforming Growth Factor-β Receptor in Mitosis: Implications for Signaling

PubMed Central

Hirschhorn, Tal; Barizilay, Lior; Smorodinsky, Nechama I.; Ehrlich, Marcelo

2012-01-01

The response to transforming growth factor-β (TGF-β) depends on cellular context. This context is changed in mitosis through selective inhibition of vesicle trafficking, reduction in cell volume and the activation of mitotic kinases. We hypothesized that these alterations in cell context may induce a differential regulation of Smads and TGF-β receptors. We tested this hypothesis in mesenchymal-like ovarian cancer cells, arrested (or not) in mitosis with 2-methoxyestradiol (2ME2). In mitosis, without TGF-β stimulation, Smad3 was phosphorylated at the C-terminus and linker regions and localized to the mitotic spindle. Phosphorylated Smad3 interacted with the negative regulators of Smad signaling, Smurf2 and Ski, and failed to induce a transcriptional response. Moreover, in cells arrested in mitosis, Smad3 levels were progressively reduced. These phosphorylations and reduction in the levels of Smad3 depended on ERK activation and Mps1 kinase activity, and were abrogated by increasing the volume of cells arrested in mitosis with hypotonic medium. Furthermore, an Mps1-dependent phosphorylation of GFP-Smad3 was also observed upon its over-expression in interphase cells, suggesting a mechanism of negative regulation which counters increases in Smad3 concentration. Arrest in mitosis also induced a block in the clathrin-mediated endocytosis of the type II TGF-β receptor (TβRII). Moreover, following the stimulation of mitotic cells with TGF-β, the proteasome-mediated attenuation of TGF-β receptor activity, the degradation and clearance of TβRII from the plasma membrane, and the clearance of the TGF-β ligand from the medium were compromised, and the C-terminus phosphorylation of Smad3 was prolonged. We propose that the reduction in Smad3 levels, its linker phosphorylation, and its association with negative regulators (observed in mitosis prior to ligand stimulation) represent a signal attenuating mechanism. This mechanism is balanced by the retention of active TGF-β receptors at the plasma membrane. Together, both mechanisms allow for a regulated cellular response to TGF-β stimuli in mitosis. PMID:22927969

Specialized physiological studies in support of manned space flight

NASA Technical Reports Server (NTRS)

Luft, U. C.; Loeppky, J. A.; Venters, M. D.; Kobayashi, Y.

1978-01-01

The effects of a diuretic (Lasix) induced dehydration on the cardiovascular and hematological responses to lower body negative pressure (LBNP) were analyzed and compared to previous observations on dehydration following exercise in the heat. During LBNP runs the subjects were monitored for changes in blood volume, heart rate, blood pressure, and variations in the volume of the left calf. It was concluded that Lasix dehydration produced a depletion of the body electrolytes at the expense of both the plasma and extravascular compartments. Striking differences were found between those subjects who were physically active (Runners: R) and those who did not engage in any regular physical activity (Non-runners: NR). Tolerance to LBNP (Torr x min) was significantly lower in the R's than the NR's before and after dehydration, however the R's lost more of their tolerance after dehydration with Lasix than after exercise in the heat for about the same fluid loss. The opposite was true for the NR's. Two factors appear to be responsible for the lower LBNP tolerance in R's: parasympathetic inhibition of cardiac activity during LBNP and a greater propensity to pool blood in the lower extremities.

[Temperature sensitivity and the indicators of respiration in humans in the normal state and during local cooling].

PubMed

Kozyreva, T V; Simonova, T G

1991-01-01

The examination has shown that people who have many cold spots on the forearm possess high ventilation volume and breathing frequency and low value of oxygen utilization. These facts can evidence for the effect of cold skin receptors on the respiratory patterns. The skin temperature, at which the maximal cooling-induced changes of respiratory parameters are observed depends on the dynamic activity of cold skin thermoreceptors: the greater number of cold spots in the hand and forearm, the lesser cooling is necessary to cause the maximal increase of oxygen consumption and change of respiratory volume. The latter increased in the case of hand cooling and decreased in the case of the forearm cooling.

Multipolar radiofrequency ablation with internally cooled electrodes: experimental study in ex vivo bovine liver with mathematic modeling.

PubMed

Clasen, Stephan; Schmidt, Diethard; Boss, Andreas; Dietz, Klaus; Kröber, Stefan M; Claussen, Claus D; Pereira, Philippe L

2006-03-01

To evaluate the size and geometry of thermally induced coagulation by using multipolar radiofrequency (RF) ablation and to determine a mathematic model to predict coagulation volume. Multipolar RF ablations (n = 80) were performed in ex vivo bovine livers by using three internally cooled bipolar applicators with two electrodes on the same shaft. Applicators were placed in a triangular array (spacing, 2-5 cm) and were activated in multipolar mode (power output, 75-225 W). The size and geometry of the coagulation zone, together with ablation time, were assessed. Mathematic functions were fitted, and the goodness of fit was assessed by using r(2). Coagulation volume, short-axis diameter, and ablation time were dependent on power output and applicator distance. The maximum zone of coagulation (volume, 324 cm(3); short-axis diameter, 8.4 cm; ablation time, 193 min) was induced with a power output of 75 W at an applicator distance of 5 cm. Coagulation volume and ablation time decreased as power output increased. Power outputs of 100-125 W at applicator distances of 2-4 cm led to a reasonable compromise between coagulation volume and ablation time. At 2 cm (100 W), coagulation volume, short-axis diameter, and ablation time were 66 cm(3), 4.5 cm, and 19 min, respectively; at 3 cm (100 W), 90 cm(3), 5.2 cm, and 22 min, respectively; at 4 cm (100 W), 132 cm(3), 6.1 cm, and 27 min, respectively; at 2 cm (125 W), 56 cm(3), 4.2 cm, and 9 min, respectively; at 3 cm (125 W), 73 cm(3), 4.9 cm, and 12 min, respectively; and at 4 cm (125 W), 103 cm(3), 5.5 cm, and 16 min, respectively. At applicator distances of 4 cm (>125 W) and 5 cm (>100 W), the zones of coagulation were not confluent. Coagulation volume (r(2) = 0.80) and RF ablation time (r(2) = 0.93) were determined by using the mathematic model. Multipolar RF ablation with three bipolar applicators may produce large volumes of confluent coagulation ex vivo. A compromise is necessary between prolonged RF ablations at lower power outputs, which produce larger volumes of coagulation, and faster RF ablations at higher power outputs, which produce smaller volumes of coagulation. Copyright RSNA, 2006.

Effectiveness of centrifuge-induced artificial gravity with ergometric exercise as a countermeasure during simulated microgravity exposure in humans.

PubMed

Iwase, Satoshi

2005-01-01

To test the effectiveness of centrifuge-induced artificial gravity with ergometric exercise, 12 healthy young men (20.7 +/- 1.9 yr) were exposed to simulated microgravity for 14 days of -6 degrees head-down bedrest. Half the subjects were randomly selected and loaded 1.2 G artificial gravity with 60 W (four out of six subjects) or 40 W (two out of six subjects) of ergometric workload on days 1, 2, 3, 5, 7, 9, 11, 12, 13, 14 (CM group). The rest of the subjects served as the control. Anti-G score, defined as the G-load x running time to the endpoint, was significantly elongated by the load of the centrifuge-ergometer. Plasma volume loss was suppressed (-5.0 +/- 2.4 vs. -16.4 +/- 1.9%), and fluid volume shift was prevented by the countermeasure load. Elevated heart rate and muscle sympathetic nerve activity after bedrest were counteracted, and exaggerated response to head-up tilt was also suppressed. Centrifuge-induced artificial gravity with exercise is effective in preventing cardiovascular deconditioning due to microgravity exposure, however, an effective and appropriate regimen (magnitude of G-load and exercise workload) should be determined in future studies. c2005 Elsevier Ltd. All rights reserved.

Effectiveness of centrifuge-induced artificial gravity with ergometric exercise as a countermeasure during simulated microgravity exposure in humans

NASA Astrophysics Data System (ADS)

Iwase, Satoshi

2005-07-01

To test the effectiveness of centrifuge-induced artificial gravity with ergometric exercise, 12 healthy young men (20.7±1.9yr) were exposed to simulated microgravity for 14 days of -6∘ head-down bedrest. Half the subjects were randomly selected and loaded 1.2 G artificial gravity with 60 W (four out of six subjects) or 40 W (two out of six subjects) of ergometric workload on days 1,2,3,5,7,9,11,12,13,14 (CM group). The rest of the subjects served as the control. Anti-G score, defined as the G-load×running time to the endpoint, was significantly elongated by the load of the centrifuge-ergometer. Plasma volume loss was suppressed ( -5.0±2.4 vs. -16.4±1.9%), and fluid volume shift was prevented by the countermeasure load. Elevated heart rate and muscle sympathetic nerve activity after bedrest were counteracted, and exaggerated response to head-up tilt was also suppressed. Centrifuge-induced artificial gravity with exercise is effective in preventing cardiovascular deconditioning due to microgravity exposure, however, an effective and appropriate regimen (magnitude of G-load and exercise workload) should be determined in future studies.

White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism.

PubMed

Xiu, Yun; Kong, Xiang-Ru; Zhang, Lei; Qiu, Xuan; Chao, Feng-Lei; Peng, Chao; Gao, Yuan; Huang, Chun-Xia; Wang, San-Rong; Tang, Yong

2014-08-01

The etiology of schizophrenia (SZ) is complex and largely unknown. Neuroimaging and postmortem studies have suggested white matter disturbances in SZ. In the present study, we tested the white matter deficits hypothesis of SZ using a mouse model of SZ induced by NMDA receptor antagonist MK-801. We found that mice with repeated chronic MK-801 administration showed increased locomotor activity in the open field test, less exploration of a novel environment in the hole-board test, and increased anxiety in the elevated plus maze but no impairments were observed in coordination or motor function on accelerating rota-rod. The total white matter volume and corpus callosum volume in mice treated with MK-801 were significantly decreased compared to control mice treated with saline. Myelin basic protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase were also significantly decreased in the mouse model of SZ. Furthermore, we observed degenerative changes of myelin sheaths in the mouse model of SZ. These results provide further evidence of white matter deficits in SZ and indicate that the animal model of SZ induced by MK-801 is a useful model to investigate mechanisms underlying white matter abnormalities in SZ. Copyright © 2014 Wiley Periodicals, Inc.

A Sphingosine-1 Phosphate agonist (FTY720) limits trauma/hemorrhagic shock induced multiple organ dysfunction syndrome

PubMed Central

Bonitz, Joyce A.; Son, Julie Y.; Chandler, Benjamin; Tomaio, Jacquelyn N.; Qin, Yong; Prescott, Lauriston M.; Feketeova, Eleonora; Deitch, Edwin A.

2014-01-01

BACKGROUND Trauma/hemorrhagic shock is one of the major consequences of battlefield injury as well as civilian trauma. FTY720 (sphingosine-1 phosphate agonist) has the capability to decrease the activity of the innate and adaptive immune systems and, at the same time, maintain endothelial cell barrier function and vascular homeostasis during stress. For this reason, we hypothesize that FTY720, as part of resuscitation therapy, would limit T/HS induced multiple organ dysfunction syndrome (MODS) in a rodent trauma-hemorrhagic shock (T/HS) model. METHODS Rats subjected to trauma/sham-shock (T/SS) or T/HS (30 mm Hg × 90 min), were administered FTY720 (1 mg/kg) post-T/HS during volume resuscitation. Lung injury (permeability to Evans Blue dye), PMN priming (respiratory burst activity), and RBC rigidity were measured. In addition, lymph duct cannulated rats were used to quantify the effect of FTY720 on gut injury (permeability and morphology) and the biologic activity of T/HS vs. T/SS lymph on PMN-RB and RBC deformability. RESULTS T/HS-induced increased lung permeability, PMN priming and RBC rigidity were all abrogated by FTY720. The systemic protective effect of FTY720 was only partially at the gut level, since FTY720 did not prevent T/HS-induced gut injury (morphology or permeability,) however, it did abrogate T/HS lymph-induced increased respiratory burst and RBC rigidity. CONCLUSION FTY720 limited T/HS-induced MODS (lung injury, red cell injury, and neutrophil priming) as well as T/HS lymph bioactivity, although it did not limit gut injury. PMID:25004059

Sensorimotor cortex ablation induces time-dependent response of ACTH cells in adult rats: behavioral, immunohistomorphometric and hormonal study.

PubMed

Lavrnja, Irena; Trifunovic, Svetlana; Ajdzanovic, Vladimir; Pekovic, Sanja; Bjelobaba, Ivana; Stojiljkovic, Mirjana; Milosevic, Verica

2014-02-10

Traumatic brain injury (TBI) represents a serious event with far reaching complications, including pituitary dysfunction. Pars distalis corticotropes (ACTH cells), that represent the active module of hypothalamo-pituitary-adrenocortical axis, seem to be affected as well. Since pituitary failure after TBI has been associated with neurobehavioral impairments the aim of this study was to evaluate the effects of TBI on recovery of motor functions, morphology and secretory activity of ACTH cells in the pituitary of adult rats. Wistar male rats, initially exposed to sensorimotor cortex ablation (SCA), were sacrificed at the 2nd, 7th, 14th and 30th days post-surgery (dps). A beam walking test was used to evaluate the recovery of motor functions. Pituitary glands and blood were collected for morphological and hormonal analyses. During the first two weeks post-injury increased recovery of locomotor function was detected, reaching almost the control value at day 30. SCA induces significant increase of pituitary weights compared to their time-matched controls. The volume of ACTH-immunopositive cells was reduced at the 7th dps, while at the 14th dps their volume was enlarged, in comparison to corresponding sham controls. Volume density of ACTH cells was increased only at 14th dps, while at day 30 this increase was insignificant. The plasma level of ACTH transiently increased after the injury. The most pronounced changes were observed at the 7th and 14th dps, and were followed by decrease toward control levels at the 30th dps. Thus, temporal changes in the hypothalamic-pituitary-adrenal axis after traumatic brain injury appear to correlate with the recovery process. Copyright © 2013 Elsevier Inc. All rights reserved.

Continuous infusion of substance P into rat striatum alleviates nociceptive behavior via phosphorylation of extracellular signal-regulated kinase 1/2.

PubMed

Nakamura, Yoki; Izumi, Hiroki; Fukushige, Ryo; Shimizu, Takumi; Watanabe, Kyohei; Morioka, Norimitsu; Hama, Aldric; Takamatsu, Hiroyuki; Nakata, Yoshihiro

2014-12-01

Intraplantar injection of 0.4% formalin into the rat hind paw leads to a biphasic nociceptive response; an 'acute' phase (0-15 min) and 'tonic' phase (16-120 min), which is accompanied by significant phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the contralateral striatum at 120 min post-formalin injection. To uncover a possible relationship between the slow-onset substance P (SP) release and increased ERK1/2 phosphorylation in the striatum, continuous infusion of SP into the striatum by reverse microdialysis (0.4 μg/mL in microdialysis fiber, 1 μL/min) was performed to mimic volume neurotransmission of SP. Continuous infusion for 3 h of SP reduced the duration of 'tonic' phase nociception, and this SP effect was mediated by neurokinin 1 (NK1) receptors since pre-treatment with NK1 receptor antagonist CP96345 (10 μM) blocked the effect of SP infusion. However, formalin-induced 'tonic' phase nociception was significantly prolonged following acute injection of the MAP/ERK kinase 1/2 inhibitor PD0325901 (100 pmol) by microinjection. The coinfusion of SP and PD0325901 significantly increased the 'tonic' phase of nociception. These data demonstrate that volume transmission of striatal SP triggered by peripheral nociceptive stimulation does not lead to pain facilitation but a significant decrease of tonic nociception by the activation of the SP-NK1 receptor-ERK1/2 system. Noxious stimulation induces a slow-onset substance P (SP) release as a volume transmitter, activating extra-synaptic NK1 receptors, and evokes phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The SP-NK1-ERK1/2 system in the striatum decreases tonic nociception. © 2014 International Society for Neurochemistry.

GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury.

PubMed

Zhou, Xiaogang; Zhou, Jian; Li, Xilei; Guo, Chang'an; Fang, Taolin; Chen, Zhengrong

2011-07-29

Previous studies have shown that GSK-3β inhibitor could reduce infarct volume after ischemia brain injury. However, the underlying mechanisms of GSK-3β inhibitor involving neuroprotection remain poorly understood. In the present study, we demonstrated that GSK-3β inhibitor suppressed insult-induced neuroinflammation in rat cortex by increasing autophagy activation in ischemic injury. Male rats were subjected to pMCAO (permanent middle cerebral artery occlusion) followed by treating with SB216763, a GSK-3β inhibitor. We found that insult-induced inflammatory response was significantly decreased by intraperitoneal infusion of SB216763 in rat cortex. A higher level of autophagy was also detected after SB216763 treatment. In the cultured primary microglia, SB216763 activated autophagy and suppressed inflammatory response. Importantly, inhibition of autophagy by Beclin1-siRNA increased inflammatory response in the SB216763-treated microglia. These data suggest that GSK-3β inhibitor suppressed neuroinflammation by activating autophagy after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury. Copyright © 2011 Elsevier Inc. All rights reserved.

A non-ionotropic activity of NMDA receptors contributes to glycine-induced neuroprotection in cerebral ischemia-reperfusion injury.

PubMed

Chen, Juan; Hu, Rong; Liao, Huabao; Zhang, Ya; Lei, Ruixue; Zhang, Zhifeng; Zhuang, Yang; Wan, Yu; Jin, Ping; Feng, Hua; Wan, Qi

2017-06-15

NMDA receptor (NMDAR) is known for its ionotropic function. But recent evidence suggests that NMDAR also has a non-ionotropic property. To determine the role of non-ionotropic activity of NMDARs in clinical relevant conditions, we tested the effect of glycine, a co-agonist of NMDARs, in rat middle cerebral artery occlusion (MCAO), an animal model of cerebral ischemia-reperfusion injury after the animals were injected with the NMDAR channel blocker MK-801 and the glycine receptor antagonist strychnine. We show that glycine reduces the infarct volume in the brain of ischemic stroke animals pre-injected with MK-801 and strychnine. The effect of glycine is sensitive to the antagonist of glycine-GluN1 binding site and blocked by Akt inhibition. In the neurobehavioral tests, glycine improves the functional recovery of stroke animals pre-injected with MK-801 and strychnine. This study suggests that glycine-induced neuroprotection is mediated in part by the non-ionotropic activity of NMDARs via Akt activation in cerebral ischemia-reperfusion injury.

Angiotensin II stimulates calcineurin activity in proximal tubule epithelia through AT-1 receptor-mediated tyrosine phosphorylation of the PLC-gamma1 isoform.

PubMed

Lea, Janice P; Jin, Shao G; Roberts, Brian R; Shuler, Michael S; Marrero, Mario B; Tumlin, James A

2002-07-01

Angiotensin II (AngII) contributes to the maintenance of extracellular fluid volume by regulating sodium transport in the nephron. In nonepithelial cells, activation of phospholipase C (PLC) by AT-1 receptors stimulates the generation of 1,4,5-trisphosphate (IP(3)) and the release of intracellular calcium. Calcineurin, a serine-threonine phosphatase, is activated by calcium and calmodulin, and both PLC and calcineurin have been linked to sodium transport in the proximal tubule. An examination of whether AngII activates calcineurin in a model of proximal tubule epithelia (LLC-PK1 cells) was performed; AngII increased calcineurin activity within 30 s. An examination of whether AngII activates PLC in proximal tubule epithelia was also performed after first showing that all three families of PLC isoforms are present in LLC-PK1 cells. Application of AngII increased IP(3) generation by 60% within 15 s, which coincided with AngII-induced tyrosine phosphorylation of the PLC-gamma1 isoform also observed at 15 s. AngII-induced tyrosine phosphorylation was blocked by the AT-1 receptor antagonist, Losartan. Subsequently, an inhibitor of tyrosine phosphorylation blocked the AngII-induced activation of calcineurin, as did coincubation with an inhibitor of PLC activity and with an antagonist of the AT-1 receptor. It is therefore concluded that AngII stimulates calcineurin phosphatase activity in proximal tubule epithelial cells through a mechanism involving AT-1 receptor-mediated tyrosine phosphorylation of the PLC isoform.

Improved activity of α-chymotrypsin on silica particles - A high-pressure stopped-flow study.

PubMed

Schuabb, Vitor; Winter, Roland; Czeslik, Claus

2016-11-01

Pressure is well known to affect the catalytic rate of enzymes dissolved in solution. To better understand enzyme kinetics at aqueous-solid interfaces, we have carried out a high-pressure stopped-flow activity study of α-chymotrypsin (α-CT) that is adsorbed on silica particles and, for comparison, dissolved in solution. The enzyme reaction was modulated using pressures up to 2000bar and recorded using the high-pressure stopped-flow technique. The results indicate an 8-fold enhancement of the turnover number upon α-CT adsorption and a further increase of the catalytic rate in the pressure range up to 1000bar. From the pressure dependence of the catalytic rate, apparent activation volumes have been determined. In the adsorbed state of α-CT, a pronounced change of the activation volume is found with increasing pressure. Furthermore, owing to suppression of its autolysis, a significantly longer storage time of α-CT can be achieved when the enzyme is adsorbed on silica particles. The results obtained are discussed in terms of a surface-induced selection of conformational substates of the enzyme-substrate complex. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimal arrangement of magnetic coils for functional magnetic stimulation of the inspiratory muscles in dogs.

PubMed

Lin, Vernon Weh-Hau; Zhu, Ercheng; Sasse, Scott A; Sassoon, Catherine; Hsiao, Ian N

2005-12-01

In an attempt to maximize inspiratory pressure and volume, the optimal position of a single or of dual magnetic coils during functional magnetic stimulation (FMS) of the inspiratory muscles was evaluated in twenty-three dogs. Unilateral phrenic magnetic stimulation (UPMS) or bilateral phrenic magnetic stimulation (BPMS), posterior cervical magnetic stimulation (PCMS), anterior cervical magnetic stimulation (ACMS) as well as a combination of PCMS and ACMS were performed. Trans-diaphragmatic pressure (Pdi), flow, and lung volume changes with an open airway were measured. Transdiaphragmatic pressure was also measured with an occluded airway. Changes in inspiratory parameters during FMS were compared with 1) electrical stimulation of surgically exposed bilateral phrenic nerves (BPES) and 2) ventral root electrical stimulation at C5-C7 (VRES C5-C7). Relative to the Pdi generated by BPES of 36.3 +/- 4.5 cm H2O (Mean +/- SEM), occluded Pdi(s) produced by UPMS, BPMS, PCMS, ACMS, and a combined PCMS + ACMS were 51.7%, 61.5%, 22.4%, 100.3%, and 104.5% of the maximal Pdi, respectively. Pdi(s) produced by UPMS, BPMS, PCMS, ACMS, and combined ACMS + PCMS were 38.0%, 45.2%, 16.5%, 73.8%, and 76.8%, respectively, of the Pdi induced by VRES (C5-C7) (48.0 +/- 3.9 cm H2O). The maximal Pdi(s) generated during ACMS and combined PCMS + ACMS were higher than the maximal Pdi(s) generated during UPMS, BPMS, or PCMS (p < 0.05). ACMS alone induced 129.8% of the inspiratory flow (73.0 +/- 9.4 L/ min) and 77.5% of the volume (626 +/- 556 ml) induced by BPES. ACMS and combined PCMS + ACMS produce a greater inspiratory pressure than UPMS, BPMS or PCMS. ACMS can be used to generate sufficient inspiratory pressure, flow, and volume for activation of the inspiratory muscles.

Effects and interactions of medium components on laccase from a marine-derived fungus using response surface methodology.

PubMed

D'Souza-Ticlo, Donna; Garg, Sandeep; Raghukumar, Chandralata

2009-11-25

The effects of various synthetic medium components and their interactions with each other ultimately impact laccase production in fungi. This was studied using a laccase-hyper-producing marine-derived basidiomycete, Cerrena unicolor MTCC 5159. Inducible laccases were produced in the idiophase only after addition of an inducer such as CuSO(4). Concentration of carbon and nitrogen acted antagonistically with respect to laccase production. A combination of low nitrogen and high carbon concentration favored both biomass and laccase production. The most favorable combination resulted in 917 U L(-1) of laccase. After sufficient growth had occurred, addition of a surfactant such as Tween 80 positively impacted biomass and increased the laccase activity to around 1,300 U L(-1). Increasing the surface to volume ratio of the culture vessel further increased its activity to almost 2,000 U L(-1).

Specific α7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol-induced cardiac remodelling in mice through TGF-β1/Smad3 pathway.

PubMed

Yang, Yong-Hua; Fang, Huan-Le; Zhao, Ming; Wei, Xiang-Lan; Zhang, Ning; Wang, Shun; Lu, Yi; Yu, Xiao-Jiang; Sun, Lei; He, Xi; Li, Dong-Ling; Liu, Jin-Jun; Zang, Wei-Jin

2017-12-01

It is well-accepted that inflammation plays an important role in the development of cardiac remodelling and that therapeutic approaches targeting inflammation can inhibit cardiac remodelling. Although a large amount of evidence indicates that activation of α7 nicotinic acetylcholine receptor (α7nAChR) causes an anti-inflammatory effect, the role of α7nAChR in cardiac remodelling and the underlying mechanism have not been established. To investigate the effect of the specific α7nAChR agonist, PNU282987, on cardiac remodelling induced by isoproterenol (ISO 60 mg/kg per day) in mice, the cardiomyocyte cross-sectional area (CSA) and collagen volume fraction were evaluated by hematoxylin and eosin (HE) and Masson staining, respectively. Cardiac function and ventricular wall thickness were measured by echocardiography. The protein expressions of collagen I, matrix metalloproteinase 9 (MMP-9), transforming growth factor β1 (TGF-β1), and Smad3 were analyzed by Western blot. ISO-induced cardiac hypertrophy, characterized by an increase in the heart weight/body weight ratio, CSA and ventricular wall thickness. Moreover, cardiac fibrosis indices, such as collagen volume fraction, MMP-9 and collagen I protein expression, were also increased by ISO. PNU282987 not only attenuated cardiac hypertrophy but also decreased the cardiac fibrosis induced by ISO. Furthermore, PNU282987 suppressed TGF-β1 protein expression and the phosphorylation of Smad3 induced by ISO. In conclusion, PNU282987 ameliorated the cardiac remodelling induced by ISO, which may be related to the TGF-β1/Smad3 pathway. These data imply that the α7nAChR may represent a novel therapeutic target for cardiac remodelling in many cardiovascular diseases. © 2017 John Wiley & Sons Australia, Ltd.

Regression of experimentally induced endometriosis with a new selective cyclooxygenase-2 enzyme inhibitor.

PubMed

Kilico, Ismail; Kokcu, Arif; Kefeli, Mehmet; Kandemir, Bedri

2014-01-01

Cyclooxygenase-2 (COX-2) levels increase in women with endometriosis. COX-2, via increasing prostaglandin E2, contributes to an increase in vascular endothelial growth factor. In this way, COX-2 may contribute to the progression and continuity of endometriosis. We investigated the effect of dexketoprofen trometamol, a new selective COX-2 enzyme inhibitor, on experimentally induced endometriotic cysts. Experimental endometriotic cysts were created in 60 adult female Wistar albino rats. The rats were randomized to 2 equal groups, a control (group Con) and a dexketoprofen (group Dex) group. Six weeks later, cyst volumes were measured as in vivo (volume 1). Following volume 1 measurement, for 4 weeks group Con received 0.1 ml distilled water; group Dex received 0.375 mg dexketoprofen trometamol/0.1 ml distilled water, intramuscularly, twice a day. At the end of administration, the cyst volumes were remeasured (volume 2), and the cysts totally excised and weighed. Glandular (GT) and stromal tissues (ST) and natural killer (NK) cell contents in the cyst wall were scored. NK cell content and volume 1 were not different between the 2 groups. Volume 2, cyst weight, and GT and ST contents in group Dex were significantly lower than those in group Con. Dexketoprofen trometamol significantly reduced the development of experimentally induced endometriotic cysts both macroscopically and microscopically.

Inhibiting effects of rhynchophylline on zebrafish methamphetamine dependence are associated with amelioration of neurotransmitters content and down-regulation of TH and NR2B expression.

PubMed

Jiang, Mingjin; Chen, Yifei; Li, Chan; Peng, Qiuxian; Fang, Miao; Liu, Wei; Kang, Qunzhao; Lin, Yingbo; Yung, Ken Kin Lam; Mo, Zhixian

2016-07-04

Others and we have reported that rhynchophylline reverses amphetamine-induced conditioned place preference (CPP) effect which may be partly mediated by amelioration of central neurotransmitters and N-methyl-d-aspartate receptor 2B (NR2B) levels in the rat brains. The current study investigated the inhibiting effects of rhynchophylline on methamphetamine-induced (METH-induced) CPP in adult zebrafish and METH-induced locomotor activity in tyrosine hydroxylase-green fluorescent protein (TH-GFP) transgenic zebrafish larvae and attempted to confirm the hypothesis that these effects were mediated via regulation of neurotransmitters and dopaminergic and glutamatergic systems. After baseline preference test (on days 1-3), zebrafish were injected intraperitoneally METH (on days 4, 6 and 8) or the same volume of fish physiological saline (on days 5 and 7) and were immediately conditioned. Rhynchophylline was administered at 12h after injection of METH. On day 9, zebrafish were tested for METH-induced CPP. Results revealed that rhynchophylline (100mg/kg) significantly inhibited the acquisition of METH-induced CPP, reduced the content of dopamine and glutamate and down-regulated the expression of TH and NR2B in the CPP zebrafish brains. Furthermore, the influence of rhynchophylline on METH-induced locomotor activity was also observed in TH-GFP transgenic zebrafish larvae. Results showed that rhynchophylline (50mg/L) treatment led to a significant reduction on the locomotor activity and TH expression in TH-GFP transgenic zebrafish larvae. Taken together, these data indicate that the inhibition of the formation of METH dependence by rhynchophylline in zebrafish is associated with amelioration of the neurotransmitters dopamine and glutamate content and down-regulation of TH and NR2B expression. Copyright © 2016 Elsevier Inc. All rights reserved.

Evidence of root zone hypoxia in Brassica rapa L. grown in microgravity.

PubMed

Stout, S C; Porterfield, D M; Briarty, L G; Kuang, A; Musgrave, M E

2001-03-01

A series of experiments was conducted aboard the U.S. space shuttle and the Mir space station to evaluate microgravity-induced root zone hypoxia in rapid-cycling Brassica (Brassica rapa L.), using both root and foliar indicators of low-oxygen stress to the root zone. Root systems from two groups of plants 15 and 30 d after planting, grown in a phenolic foam nutrient delivery system on the shuttle (STS-87), were harvested and fixed for microscopy or frozen for enzyme assays immediately postflight or following a ground-based control. Activities of fermentative enzymes were measured as indicators of root zone hypoxia and metabolism. Following 16 d of microgravity, ADH (alcohol dehydrogenase) activity was increased in the spaceflight roots 47% and 475% in the 15-d-old and 30-d-old plants, respectively, relative to the ground control. Cytochemical localization showed ADH activity in only the root tips of the space-grown plants. Shoots from plants that were grown from seed in flight in a particulate medium on the Mir station were harvested at 13 d after planting and quick-frozen and stored in flight in a gaseous nitrogen freezer or chemically fixed in flight for subsequent microscopy. When compared to material from a high-fidelity ground control, concentrations of shoot sucrose and total soluble carbohydrate were significantly greater in the spaceflight treatment according to enzymatic carbohydrate analysis. Stereological analysis of micrographs of sections from leaf and cotyledon tissue fixed in flight and compared with ground controls indicated no changes in the volume of protoplast, cell wall, and intercellular space in parenchyma cells. Within the protoplasm, the volume occupied by starch was threefold higher in the spaceflight than in the ground control, with a concomitant decrease in vacuolar volume in the spaceflight treatment. Both induction of fermentative enzyme activity in roots and accumulation of carbohydrates in foliage have been repeatedly shown to occur in response to root zone oxygen deprivation. These results indicate that root zone hypoxia is a persistent challenge in spaceflight plant growth experiments and may be caused by microgravity-induced changes in fluid and gas distribution.

Evidence of root zone hypoxia in Brassica rapa L. grown in microgravity

NASA Technical Reports Server (NTRS)

Stout, S. C.; Porterfield, D. M.; Briarty, L. G.; Kuang, A.; Musgrave, M. E.

2001-01-01

A series of experiments was conducted aboard the U.S. space shuttle and the Mir space station to evaluate microgravity-induced root zone hypoxia in rapid-cycling Brassica (Brassica rapa L.), using both root and foliar indicators of low-oxygen stress to the root zone. Root systems from two groups of plants 15 and 30 d after planting, grown in a phenolic foam nutrient delivery system on the shuttle (STS-87), were harvested and fixed for microscopy or frozen for enzyme assays immediately postflight or following a ground-based control. Activities of fermentative enzymes were measured as indicators of root zone hypoxia and metabolism. Following 16 d of microgravity, ADH (alcohol dehydrogenase) activity was increased in the spaceflight roots 47% and 475% in the 15-d-old and 30-d-old plants, respectively, relative to the ground control. Cytochemical localization showed ADH activity in only the root tips of the space-grown plants. Shoots from plants that were grown from seed in flight in a particulate medium on the Mir station were harvested at 13 d after planting and quick-frozen and stored in flight in a gaseous nitrogen freezer or chemically fixed in flight for subsequent microscopy. When compared to material from a high-fidelity ground control, concentrations of shoot sucrose and total soluble carbohydrate were significantly greater in the spaceflight treatment according to enzymatic carbohydrate analysis. Stereological analysis of micrographs of sections from leaf and cotyledon tissue fixed in flight and compared with ground controls indicated no changes in the volume of protoplast, cell wall, and intercellular space in parenchyma cells. Within the protoplasm, the volume occupied by starch was threefold higher in the spaceflight than in the ground control, with a concomitant decrease in vacuolar volume in the spaceflight treatment. Both induction of fermentative enzyme activity in roots and accumulation of carbohydrates in foliage have been repeatedly shown to occur in response to root zone oxygen deprivation. These results indicate that root zone hypoxia is a persistent challenge in spaceflight plant growth experiments and may be caused by microgravity-induced changes in fluid and gas distribution.

Electric field characteristics of electroconvulsive therapy with individualized current amplitude: a preclinical study.

PubMed

Lee, Won Hee; Lisanby, Sarah H; Laine, Andrew F; Peterchev, Angel V

2013-01-01

This study examines the characteristics of the electric field induced in the brain by electroconvulsive therapy (ECT) with individualized current amplitude. The electric field induced by bilateral (BL), bifrontal (BF), right unilateral (RUL), and frontomedial (FM) ECT electrode configurations was computed in anatomically realistic finite element models of four nonhuman primates (NHPs). We generated maps of the electric field strength relative to an empirical neural activation threshold, and determined the stimulation strength and focality at fixed current amplitude and at individualized current amplitudes corresponding to seizure threshold (ST) measured in the anesthetized NHPs. The results show less variation in brain volume stimulated above threshold with individualized current amplitudes (16-36%) compared to fixed current amplitude (30-62%). Further, the stimulated brain volume at amplitude-titrated ST is substantially lower than that for ECT with conventional fixed current amplitudes. Thus individualizing the ECT stimulus current could compensate for individual anatomical variability and result in more focal and uniform electric field exposure across different subjects compared to the standard clinical practice of using high, fixed current for all patients.

Laser-induced incandescence calibration via gravimetric sampling

NASA Technical Reports Server (NTRS)

Choi, M. Y.; Vander Wal, R. L.; Zhou, Z.

1996-01-01

Absolute calibration of laser-induced incandescence (LII) is demonstrated via comparison of LII signal intensities with gravimetrically determined soot volume fractions. This calibration technique does not rely upon calculated or measured optical characteristics of soot. The variation of the LII signal with gravimetrically measured soot volume fractions ranging from 0.078 to 1.1 ppm established the linearly of the calibration. With the high spatial and temporal resolution capabilities of laser-induced incandescence (LII), the spatial and temporal fluctuations of the soot field within a gravimetric chimney were characterized. Radial uniformity of the soot volume fraction, f(sub v) was demonstrated with sufficient averaging of the single laser-shot LII images of the soot field thus confirming the validity of the calibration method for imaging applications. As illustration, instantaneous soot volume fractions within a Re = 5000 ethylene/air diffusion flame measured via planar LII were established quantitatively with this calibration.

Fluid shear stress regulates vascular remodeling via VEGFR-3 activation, although independently of its ligand, VEGF-C, in the uterus during pregnancy

PubMed Central

Park, Yang-Gyu; Choi, Jawun; Jung, Hye-Kang; Song, In Kyu; Shin, Yongwhan; Park, Sang-Youel; Seol, Jae-Won

2017-01-01

Early pregnancy is characterized by an increase in the blood volume of the uterus for embryonic development, thereby exerting fluid shear stress (FSS) on the vascular walls. The uterus experiences vascular remodeling to accommodate the increased blood flow. The blood flow-induced FSS elevates the expression of vascular endothelial growth factors (VEGFs) and their receptors, and regulates vascular remodeling through the activation of VEGF receptor-3 (VEGFR-3). However, the mechanisms responsible for FSS-induced VEGFR-3 expression in the uterus during pregnancy are unclear. In this study, we demonstrate that vascular remodeling in the uterus during pregnancy is regulated by FSS-induced VEGFR-3 expression. We examined the association between VEGFR-3 and FSS through in vivo and in vitro experiments. In vivo experiments revealed VEGFR-3 expression in the CD31-positive region of the uterus of pregnant mice; VEGF-C (ligand for VEGFR-3) was undetected in the uterus. These results confirmed that VEGFR-3 expression in the endometrium is independent of its ligand. In vitro studies experiments revealed that FSS induced morphological changes and increased VEGFR-3 expression in human uterine microvascular endothelial cells. Thus, VEGFR-3 activation by FSS is associated with vascular remodeling to allow increased blood flow in the uterus during pregnancy. PMID:28849193

Fluid shear stress regulates vascular remodeling via VEGFR-3 activation, although independently of its ligand, VEGF-C, in the uterus during pregnancy.

PubMed

Park, Yang-Gyu; Choi, Jawun; Jung, Hye-Kang; Song, In Kyu; Shin, Yongwhan; Park, Sang-Youel; Seol, Jae-Won

2017-10-01

Early pregnancy is characterized by an increase in the blood volume of the uterus for embryonic development, thereby exerting fluid shear stress (FSS) on the vascular walls. The uterus experiences vascular remodeling to accommodate the increased blood flow. The blood flow‑induced FSS elevates the expression of vascular endothelial growth factors (VEGFs) and their receptors, and regulates vascular remodeling through the activation of VEGF receptor-3 (VEGFR-3). However, the mechanisms responsible for FSS-induced VEGFR-3 expression in the uterus during pregnancy are unclear. In this study, we demonstrate that vascular remodeling in the uterus during pregnancy is regulated by FSS-induced VEGFR-3 expression. We examined the association between VEGFR-3 and FSS through in vivo and in vitro experiments. In vivo experiments revealed VEGFR-3 expression in the CD31-positive region of the uterus of pregnant mice; VEGF-C (ligand for VEGFR‑3) was undetected in the uterus. These results confirmed that VEGFR-3 expression in the endometrium is independent of its ligand. In vitro studies experiments revealed that FSS induced morphological changes and increased VEGFR-3 expression in human uterine microvascular endothelial cells. Thus, VEGFR-3 activation by FSS is associated with vascular remodeling to allow increased blood flow in the uterus during pregnancy.

Cell volume changes regulate slick (Slo2.1), but not slack (Slo2.2) K+ channels.

PubMed

Tejada, Maria A; Stople, Kathleen; Hammami Bomholtz, Sofia; Meinild, Anne-Kristine; Poulsen, Asser Nyander; Klaerke, Dan A

2014-01-01

Slick (Slo2.1) and Slack (Slo2.2) channels belong to the family of high-conductance K+ channels and have been found widely distributed in the CNS. Both channels are activated by Na+ and Cl- and, in addition, Slick channels are regulated by ATP. Therefore, the roles of these channels in regulation of cell excitability as well as ion transport processes, like regulation of cell volume, have been hypothesized. It is the aim of this work to evaluate the sensitivity of Slick and Slack channels to small, fast changes in cell volume and to explore mechanisms, which may explain this type of regulation. For this purpose Slick and Slack channels were co-expressed with aquaporin 1 in Xenopus laevis oocytes and cell volume changes of around 5% were induced by exposure to hypotonic or hypertonic media. Whole-cell currents were measured by two electrode voltage clamp. Our results show that Slick channels are dramatically stimulated (196% of control) by cell swelling and inhibited (57% of control) by a decrease in cell volume. In contrast, Slack channels are totally insensitive to similar cell volume changes. The mechanism underlining the strong volume sensitivity of Slick channels needs to be further explored, however we were able to show that it does not depend on an intact actin cytoskeleton, ATP release or vesicle fusion. In conclusion, Slick channels, in contrast to the similar Slack channels, are the only high-conductance K+ channels strongly sensitive to small changes in cell volume.

Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine

PubMed Central

Doloff, J.C.; Khan, N.; Ma, J.; Demidenko, E.; Swartz, H.M.; Jounaidi, Y.

2010-01-01

Metronomic cyclophosphamide treatment is associated with anti-angiogenic activity and is anticipated to generate exploitable hypoxia using hypoxia-activated prodrugs. Weekly administration of tirapazamine (TPZ; 5 mg/kg body weight i.p.) failed to inhibit the growth of 9L gliosarcoma tumors grown s.c. in scid mice. However, the anti-tumor effect of weekly cyclophosphamide (CPA) treatment (140 mg/kg BW i.p.) was substantially enhanced by weekly TPZ administration. An extended tumor free period and increased frequency of tumor eradication without overt toxicity were observed when TPZ was given 3, 4 or 5 days after each weekly CPA treatment. Following the 2nd CPA injection, Electron Paramagnetic Resonance (EPR) Oximetry indicated significant increases in tumor pO2, starting at 48 hr, which further increased after the 3rd CPA injection. pO2 levels were, however, stable in growing untreated tumors. A strong negative correlation (−0.81) between tumor pO2 and tumor volume during 21 days of weekly CPA chemotherapy was observed, indicating increasing tumor pO2 with decreasing tumor volume. Furthermore, CPA treatment resulted in increased tumor uptake of activated CPA. CPA induced increases in VEGF RNA, which reached a maximum on day 1, and in PLGF RNA which was sustained throughout the treatment, while anti-angiogenic host thrombospondin-1 increased dramatically through day 7 post-CPA treatment. Weekly cyclophosphamide treatment was anticipated to generate exploitable hypoxia. However, our findings suggest that weekly CPA treatment induces a functional improvement of tumor vasculature, which is characterized by increased tumor oxygenation and drug uptake in tumors, thus counter-intuitively, benefiting intratumoral activation of TPZ and perhaps other bioreductive drugs. PMID:19754361

Role of Orexin in Respiratory and Sleep Homeostasis during Upper Airway Obstruction in Rats

PubMed Central

Tarasiuk, Ariel; Levi, Avishag; Berdugo-Boura, Nilly; Yahalom, Ari; Segev, Yael

2014-01-01

Study Objectives: Chronic upper airway obstruction (UAO) elicits a cascade of complex endocrine derangements that affect growth, sleep, and energy metabolism. We hypothesized that elevated hypothalamic orexin has a role in maintaining ventilation during UAO, while at the same time altering sleep-wake activity and energy metabolism. Here, we sought to explore the UAO-induced changes in hypothalamic orexin and their role in sleep-wake balance, respiratory activity, and energy metabolism. Interventions: The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed; UAO and sham-operated control animals were monitored for 7 weeks. We measured food intake, body weight, temperature, locomotion, and sleep-wake activity. Magnetic resonance imaging was used to quantify subcutaneous and visceral fat tissue volumes. In week 7, the rats were sacrificed and levels of hypothalamic orexin, serum leptin, and corticosterone were determined. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and respiration was also explored. Measurements and Results: UAO increased hypothalamic orexin mRNA and protein content by 64% and 65%, respectively. UAO led to 30% chronic sleep loss, excessive active phase sleepiness, decreased body temperature, increased food intake, reduction of abdominal and subcutaneous fat tissue volume, and growth retardation. Administration of almorexant normalized sleep but induced severe breathing difficulties in UAO rats, while it had no effect on sleep or on breathing of control animals. Conclusions: In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth. Citation: Tarasiuk A, Levi A, Berdugo-Boura N, Yahalom A, Segev Y. Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats. SLEEP 2014;37(5):987-998. PMID:24790278

Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase.

PubMed

Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

2015-10-01

Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 µM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl(-) and the decreased HCO3 (-) concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na-K-2Cl electroneutral cotransporter or Cl(-)/HCO3 (-) anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells.

Synergistic effect of the combination of gallic acid and famotidine in protection of rat gastric mucosa.

PubMed

Asokkumar, K; Sen, Saikat; Umamaheswari, M; Sivashanmugam, A T; Subhadradevi, V

2014-08-01

Antioxidant supplements with existing drugs may confer better therapeutic efficacy in oxidative stress related diseases. The purpose of the present work was to characterize the interaction and investigate the protective effect of H2 blocker famotidine and gallic acid in combination against experimentally induced peptic ulcer. Preventive effect of gallic acid and famotidine in different combinations was investigated against aspirin plus pyloric ligation induced ulcer in rat. Ulcer index, gastric juice volume, pH, other biochemical parameters of gastric juice and antioxidant activity using stomach tissue were estimated. Pretreatment with gallic acid and famotidine in combinations for 7 days, protected the gastric mucosa significantly (p<0.05, 0.01), which was evidenced by decrease in ulcer index, gastric juice volume, free and total acidity, total protein, pepsin and DNA content, and increase in pH, carbohydrates concentration in gastric juice. Combination treatment increases levels of superoxide dismutase, catalase, reduced glutathione, glutathione reductase and glucose-6-phosphate dehydrogenase, and decreases lipid peroxidation, myloperoxidase in stomach tissue. Along with higher dose combination, lower dose combinations like gallic acid (50mg/kg) plus famotidine (10mg/kg) also offered better antiulcer activity than their individual effect. Histopathological studies confirmed their antiulcer activity. Combination treatments confer synergistic protective effect against peptic ulcer in rats, which was related to the gastroprotective, antisecratory and antioxidant activity of combination treatment. Results proved that use of gallic acid with existing antiulcer drug will be more useful in the prevention/management of peptic ulcer. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Intravenous superoxide dismutase as a protective agent to prevent impairment of lung function induced by high tidal volume ventilation.

PubMed

Wu, Nan-Chun; Liao, Fan-Ting; Cheng, Hao-Min; Sung, Shih-Hsien; Yang, Yu-Chun; Wang, Jiun-Jr

2017-07-26

Positive-pressure mechanical ventilation is essential in assisting patients with respiratory failure in the intensive care unit and facilitating oxygenation in the operating room. However, it was also recognized as a primary factor leading to hospital-acquired pulmonary dysfunction, in which pulmonary oxidative stress and lung inflammation had been known to play important roles. Cu/Zn superoxide dismutase (SOD) is an important antioxidant, and possesses anti-inflammatory capacity. In this study, we aimed to study the efficacy of Cu/Zn SOD, administered intravenously during high tidal volume (HTV) ventilation, to prevent impairment of lung function. Thirty-eight male Sprague-Dawley rats were divided into 3 groups: 5 h ventilation with (A) low tidal volume (LTV; 8 mL/kg; n = 10), (B) high tidal volume (HTV; 18 mL/kg; n = 14), or (C) HTV and intravenous treatment of Cu/Zn SOD at a dose of 1000 U/kg/h (HTV + SOD; n = 14). Lung function was evaluated both at baseline and after 5-h ventilation. Lung injury was assessed by histological examination, lung water and protein contents in the bronchoalveolar lavage fluid (BALF). Pulmonary oxidative stress was examined by concentrations of methylguanidine (MG) and malondialdehyde (MDA) in BALF, and antioxidative activity by protein expression of glutathione peroxidase-1 (GPx-1) in the lung. Severity of lung inflammation was evaluated by white blood cell and differential count in BALF, and protein expression of inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), and mRNA expression of nuclear factor-κB (NF-κB) in the lung. We also examined protein expression of surfactant protein (SP)-A and D and we measured hourly changes in serum nitric oxide (NO) level. Five hours of LTV ventilation did not induce a major change in lung function, whereas 5 h of HTV ventilation induced apparent combined restrictive and obstructive lung disorder, together with increased pulmonary oxidative stress, decreased anti-oxidative activity and increased lung inflammation (P < 0.05). HTV ventilation also decreased SP-A and SP-D expression and suppressed serum NO level during the time course of ventilation. Cu/Zn SOD administered intravenously during HTV ventilation effectively reversed associated pulmonary oxidative stress and lung inflammation (P < 0.05); moreover, it preserved SP-A and SP-D expressions in the lung and increased serum nitric oxide (NO) level, enhancing vascular NO bioavailability. HTV ventilation can induce combined restrictive and obstructive lung disorders. Intravenous administration of Cu/Zn SOD during HTV ventilation can prevent lung function impairment and lung injury via reducing pulmonary oxidative stress and lung inflammation, preserving pulmonary surfactant expression, and enhancing vascular NO bioavailability.

Maternal Active Mastication during Prenatal Stress Ameliorates Prenatal Stress-Induced Lower Bone Mass in Adult Mouse Offspring

PubMed Central

Azuma, Kagaku; Ogura, Minori; Kondo, Hiroko; Suzuki, Ayumi; Hayashi, Sakurako; Iinuma, Mitsuo; Onozuka, Minoru; Kubo, Kin-ya

2017-01-01

Chronic psychological stress is a risk factor for osteoporosis. Maternal active mastication during prenatal stress attenuates stress response. The aim of this study is to test the hypothesis that maternal active mastication influences the effect of prenatal stress on bone mass and bone microstructure in adult offspring. Pregnant ddY mice were randomly divided into control, stress, and stress/chewing groups. Mice in the stress and stress/chewing groups were placed in a ventilated restraint tube for 45 minutes, 3 times a day, and was initiated on day 12 of gestation and continued until delivery. Mice in the stress/chewing group were allowed to chew a wooden stick during the restraint stress period. The bone response of 5-month-old male offspring was evaluated using quantitative micro-CT, bone histomorphometry, and biochemical markers. Prenatal stress resulted in significant decrease of trabecular bone mass in both vertebra and distal femur of the offspring. Maternal active mastication during prenatal stress attenuated the reduced bone formation and increased bone resorption, improved the lower trabecular bone volume and bone microstructural deterioration induced by prenatal stress in the offspring. These findings indicate that maternal active mastication during prenatal stress can ameliorate prenatal stress-induced lower bone mass of the vertebra and femur in adult offspring. Active mastication during prenatal stress in dams could be an effective coping strategy to prevent lower bone mass in their offspring. PMID:28553167

Maternal Active Mastication during Prenatal Stress Ameliorates Prenatal Stress-Induced Lower Bone Mass in Adult Mouse Offspring.

PubMed

Azuma, Kagaku; Ogura, Minori; Kondo, Hiroko; Suzuki, Ayumi; Hayashi, Sakurako; Iinuma, Mitsuo; Onozuka, Minoru; Kubo, Kin-Ya

2017-01-01

Chronic psychological stress is a risk factor for osteoporosis. Maternal active mastication during prenatal stress attenuates stress response. The aim of this study is to test the hypothesis that maternal active mastication influences the effect of prenatal stress on bone mass and bone microstructure in adult offspring. Pregnant ddY mice were randomly divided into control, stress, and stress/chewing groups. Mice in the stress and stress/chewing groups were placed in a ventilated restraint tube for 45 minutes, 3 times a day, and was initiated on day 12 of gestation and continued until delivery. Mice in the stress/chewing group were allowed to chew a wooden stick during the restraint stress period. The bone response of 5-month-old male offspring was evaluated using quantitative micro-CT, bone histomorphometry, and biochemical markers. Prenatal stress resulted in significant decrease of trabecular bone mass in both vertebra and distal femur of the offspring. Maternal active mastication during prenatal stress attenuated the reduced bone formation and increased bone resorption, improved the lower trabecular bone volume and bone microstructural deterioration induced by prenatal stress in the offspring. These findings indicate that maternal active mastication during prenatal stress can ameliorate prenatal stress-induced lower bone mass of the vertebra and femur in adult offspring. Active mastication during prenatal stress in dams could be an effective coping strategy to prevent lower bone mass in their offspring.

HCO3(-) secretion by murine nasal submucosal gland serous acinar cells during Ca2+-stimulated fluid secretion.

PubMed

Lee, Robert J; Harlow, Janice M; Limberis, Maria P; Wilson, James M; Foskett, J Kevin

2008-07-01

Airway submucosal glands contribute to airway surface liquid (ASL) composition and volume, both important for lung mucociliary clearance. Serous acini generate most of the fluid secreted by glands, but the molecular mechanisms remain poorly characterized. We previously described cholinergic-regulated fluid secretion driven by Ca(2+)-activated Cl(-) secretion in primary murine serous acinar cells revealed by simultaneous differential interference contrast (DIC) and fluorescence microscopy. Here, we evaluated whether Ca(2+)-activated Cl(-) secretion was accompanied by secretion of HCO(3)(-), possibly a critical ASL component, by simultaneous measurements of intracellular pH (pH(i)) and cell volume. Resting pH(i) was 7.17 +/- 0.01 in physiological medium (5% CO(2)-25 mM HCO(3)(-)). During carbachol (CCh) stimulation, pH(i) fell transiently by 0.08 +/- 0.01 U concomitantly with a fall in Cl(-) content revealed by cell shrinkage, reflecting Cl(-) secretion. A subsequent alkalinization elevated pH(i) to above resting levels until agonist removal, whereupon it returned to prestimulation values. In nominally CO(2)-HCO(3)(-)-free media, the CCh-induced acidification was reduced, whereas the alkalinization remained intact. Elimination of driving forces for conductive HCO(3)(-) efflux by ion substitution or exposure to the Cl(-) channel inhibitor niflumic acid (100 microM) strongly inhibited agonist-induced acidification by >80% and >70%, respectively. The Na(+)/H(+) exchanger (NHE) inhibitor dimethylamiloride (DMA) increased the magnitude (greater than twofold) and duration of the CCh-induced acidification. Gene expression profiling suggested that serous cells express NHE isoforms 1-4 and 6-9, but pharmacological sensitivities demonstrated that alkalinization observed during both CCh stimulation and pH(i) recovery from agonist-induced acidification was primarily due to NHE1, localized to the basolateral membrane. These results suggest that serous acinar cells secrete HCO(3)(-) during Ca(2+)-evoked fluid secretion by a mechanism that involves the apical membrane secretory Cl(-) channel, with HCO(3)(-) secretion sustained by activation of NHE1 in the basolateral membrane. In addition, other Na(+)-dependent pH(i) regulatory mechanisms exist, as evidenced by stronger inhibition of alkalinization in Na(+)-free media.

Evidence for increased cardiac compliance during exposure to simulated microgravity

NASA Technical Reports Server (NTRS)

Koenig, S. C.; Convertino, V. A.; Fanton, J. W.; Reister, C. A.; Gaffney, F. A.; Ludwig, D. A.; Krotov, V. P.; Trambovetsky, E. V.; Latham, R. D.

1998-01-01

We measured hemodynamic responses during 4 days of head-down tilt (HDT) and during graded lower body negative pressure (LBNP) in invasively instrumented rhesus monkeys to test the hypotheses that exposure to simulated microgravity increases cardiac compliance and that decreased stroke volume, cardiac output, and orthostatic tolerance are associated with reduced left ventricular peak dP/dt. Six monkeys underwent two 4-day (96 h) experimental conditions separated by 9 days of ambulatory activities in a crossover counterbalance design: 1) continuous exposure to 10 degrees HDT and 2) approximately 12-14 h per day of 80 degrees head-up tilt and 10-12 h supine (control condition). Each animal underwent measurements of central venous pressure (CVP), left ventricular and aortic pressures, stroke volume, esophageal pressure (EsP), plasma volume, alpha1- and beta1-adrenergic responsiveness, and tolerance to LBNP. HDT induced a hypovolemic and hypoadrenergic state with reduced LBNP tolerance compared with the control condition. Decreased LBNP tolerance with HDT was associated with reduced stroke volume, cardiac output, and peak dP/dt. Compared with the control condition, a 34% reduction in CVP (P = 0.010) and no change in left ventricular end-diastolic area during HDT was associated with increased ventricular compliance (P = 0.0053). Increased cardiac compliance could not be explained by reduced intrathoracic pressure since EsP was unaltered by HDT. Our data provide the first direct evidence that increased cardiac compliance was associated with headward fluid shifts similar to those induced by exposure to spaceflight and that reduced orthostatic tolerance was associated with lower cardiac contractility.

Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study.

PubMed

Bakker, Leontine E H; Boon, Mariëtte R; van der Linden, Rianne A D; Arias-Bouda, Lenka Pereira; van Klinken, Jan B; Smit, Frits; Verberne, Hein J; Jukema, J Wouter; Tamsma, Jouke T; Havekes, Louis M; van Marken Lichtenbelt, Wouter D; Jazet, Ingrid M; Rensen, Patrick C N

2014-03-01

Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups. We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473. Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0°C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0.0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0.04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (β=0.44, p=0.04). Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals. Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500). Copyright © 2014 Elsevier Ltd. All rights reserved.

Annual Progress Report FY-92. Volume 1

DTIC Science & Technology

1993-01-21

Billups, L Flow Cytom Resh Psychologist 12 0180 CS Hamm, C DCI 7 DESCRIPTION GRADE MOS BRANCH NAME ACTIVITY Kyle Metabolic Unit Nursing Service Supv...3349 Salata, Kalman PhD. Mitogen-Inducible T Suppressor Cell 13 Assay by Flow Cytometry (12/89) 3350 Salata, Kalman PhD. Flow Cytometric Analysis of...17 Immunotherapy (3/90) 3354 Salata, Kalman PhD. Two Way Mixed Lymphocyte Culture: 18 Analysis by Two Color Flow Cytometry (4/90) 3355 Salata, Kalman

SU-F-J-86: Method to Include Tissue Dose Response Effect in Deformable Image Registration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, J; Liang, J; Chen, S

Purpose: Organ changes shape and size during radiation treatment due to both mechanical stress and radiation dose response. However, the dose response induced deformation has not been considered in conventional deformable image registration (DIR). A novel DIR approach is proposed to include both tissue elasticity and radiation dose induced organ deformation. Methods: Assuming that organ sub-volume shrinkage was proportional to the radiation dose induced cell killing/absorption, the dose induced organ volume change was simulated applying virtual temperature on each sub-volume. Hence, both stress and heterogeneity temperature induced organ deformation. Thermal stress finite element method with organ surface boundary condition wasmore » used to solve deformation. Initial boundary correspondence on organ surface was created from conventional DIR. Boundary condition was updated by an iterative optimization scheme to minimize elastic deformation energy. The registration was validated on a numerical phantom. Treatment dose was constructed applying both the conventional DIR and the proposed method using daily CBCT image obtained from HN treatment. Results: Phantom study showed 2.7% maximal discrepancy with respect to the actual displacement. Compared with conventional DIR, subvolume displacement difference in a right parotid had the mean±SD (Min, Max) to be 1.1±0.9(−0.4∼4.8), −0.1±0.9(−2.9∼2.4) and −0.1±0.9(−3.4∼1.9)mm in RL/PA/SI directions respectively. Mean parotid dose and V30 constructed including the dose response induced shrinkage were 6.3% and 12.0% higher than those from the conventional DIR. Conclusion: Heterogeneous dose distribution in normal organ causes non-uniform sub-volume shrinkage. Sub-volume in high dose region has a larger shrinkage than the one in low dose region, therefore causing more sub-volumes to move into the high dose area during the treatment course. This leads to an unfavorable dose-volume relationship for the normal organ. Without including this effect in DIR, treatment dose in normal organ could be underestimated affecting treatment evaluation and planning modification. Acknowledgement: Partially Supported by Elekta Research Grant.« less

Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity.

PubMed

van der Stelt, M; Veldhuis, W B; Bär, P R; Veldink, G A; Vliegenthart, J F; Nicolay, K

2001-09-01

Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Delta(9)-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB(1) cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Delta(9)-THC, indicating that Delta(9)-THC afforded protection to neurons via the CB(1) receptor. In Delta(9)-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB(1) receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration.

Vitamin K3 induces antiproliferative effect in cervical epithelial cells transformed by HPV 16 (SiHa cells) through the increase in reactive oxygen species production.

PubMed

de Carvalho Scharf Santana, Natália; Lima, Natália Alves; Desoti, Vânia Cristina; Bidóia, Danielle Lazarin; de Souza Bonfim Mendonça, Patrícia; Ratti, Bianca Altrão; Nakamura, Tânia Ueda; Nakamura, Celso Vataru; Consolaro, Marcia Edilaine Lopes; Ximenes, Valdecir Farias; de Oliveira Silva, Sueli

2016-10-01

Cervical cancer is characterized as an important public health problem. According to latest estimates, cancer of the cervix is the fourth most common cancer among women. Due to its high prevalence, the search for new and efficient drugs to treat this infection is continuous. The progression of HPV-associated cervical cancer involves the expression of two viral proteins, E6 and E7, which are rapidly degraded by the ubiquitin-proteasome system through the increase in reactive oxygen species generation. Vitamins are essential to human substances, participate in the regulation of metabolism, and facilitate the process of energy transfer. Some early studies have indicated that vitamin K3 exerts antitumor activity by inducing cell death by apoptosis through an increase in the generation of reactive oxygen species. Thus, we evaluated the antiproliferative effect and a likely mechanism of action of vitamin K3 against cervical epithelial cells transformed by HPV 16 (SiHa cells) assessing the production of total ROS, the mitochondrial membrane potential, the cell morphology, the cell volume, and the cell membrane integrity. Our results show that vitamin K3 induces an increase in ROS production in SiHa cells, triggering biochemical and morphological events, such as depolarization of mitochondrial membrane potential and decreasing cell volume. Our data showed that vitamin K3 generates an oxidative imbalance in SiHa cells, leading to mechanisms that induce cell death by apoptosis.

The Effect of the Wastewater of Penicillin and Amoxicillin on the Antioxidant Indexes of Limnodrilus Hoffmeisteri

NASA Astrophysics Data System (ADS)

Dong, Yuxin; Shen, Hongyan

2018-01-01

In order to obtain some basic data for ecological risk assessment, an exposure experiment was carried out to study the effect of different volume of mixed penicillin and amoxicillin wastewater on Superoxide Dismutase (SOD) and Malondialdehyde (MDA) in Limnodrilus hoffmeisteri. Limnodrilus hoffmeisteri was exposed to different volume (10%, 20%, 30%, 40%, and 50%) of mixed wastewater for 15 days. According to the experimental data, the MDA contents and SOD activities in Limnodrilus hoffmeisteri muscle tissue had seen significant change significantly during the period of exposure. The results showed that the trend of SOD activities in low concentration groups (10% and 20%) increased at first, then decreased and increased at last. As exposure concentration increased (40% and 50%), SOD activities were inhibited in the early days (3 d), and was gradually induced in the later phase. The change of MDA content in muscle tissue of Limnodrilus hoffmeisteri was further investigated. It was found to be negatively correlated with the activity of SOD, and the high concentration group (50%) was in a remarkable induction state and reached the maximum at 6 d. According to the experimental data, the MDA contents and SOD activities in Limnodrilus hoffmeisteri muscle tissue had changed significantly and caused the oxidative damage.

Atrazine Triggers Mitochondrial Dysfunction and Oxidative Stress in Quail ( Coturnix C. coturnix) Cerebrum via Activating Xenobiotic-Sensing Nuclear Receptors and Modulating Cytochrome P450 Systems.

PubMed

Lin, Jia; Zhao, Hua-Shan; Qin, Lei; Li, Xue-Nan; Zhang, Cong; Xia, Jun; Li, Jin-Long

2018-06-14

The residues from the widely used broad-spectrum environmental herbicide, atrazine (ATR), result in the exposure of nontarget organisms and persist as a global major public health hazard. ATR is neurotoxic and may cause adverse health effects in mammals, birds, and fishes. Nevertheless, the molecular mechanism of ATR induced neurotoxicity remains unclear. To assess the molecular mechanisms of ATR-induced cerebral toxicity through potential oxidative damage, quail were treated with ATR by oral gavage administration at doses of 0, 50, 250, and 500 mg/kg body weight daily for 45 days. Markedly, increases in the amount of swelling of neuronal cells, the percentage of mean damaged mitochondria, mitochondrial malformation, and mitochondrial vacuolar degeneration as well as decreases in the mitochondrial cristae and mitochondrial volume density were observed by light and electron microscopy in the cerebrum of quail. ATR induced toxicities in the expression of mitochondrial function-related genes and promoted oxidative damage, as indicated by effects on oxidative stress indices. These results indicated that ATR exposure can cause neurological disorders and cerebral injury. ATR may initiate apoptosis by activating Bcl-2, Bax, and Caspase3 protein expression but failed to induce autophagy (LC3B has not cleaved to LC3BI/II). Furthermore, ATR induced CYP-related enzymes metabolism disorders by activating the nuclear xenobiotic receptors response (NXRs including AHR, CAR, and PXR) and increased expression of several CYP isoforms (including CYP1B1 and CYP2C18) and thereby producing mitochondrial dysfunction. In this study, we observed ATR exposure resulted in oxidative stress and mitochondrial dysfunction by activating the NXR response and interfering the CYP450s homeostasis in quail cerebrum that supported the molecular mechanism of ATR induced cerebrum toxicity. In conclusion, these results provided new evidence on molecular mechanism of ATR induced neurotoxicity.

Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss.

PubMed

Gautam, Jyoti; Khedgikar, Vikram; Kushwaha, Priyanka; Choudhary, Dharmendra; Nagar, Geet Kumar; Dev, Kapil; Dixit, Preety; Singh, Divya; Maurya, Rakesh; Trivedi, Ritu

2017-03-01

Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of β-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/β-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.

Sex-linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula.

PubMed

Červenka, Luděk; Škaroupková, Petra; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz

2016-10-01

The role of hypertension and the renin-angiotensin system (RAS) in sex-related differences in the course of chronic kidney disease (CKD) and congestive heart failure (CHF) remain unclear, especially when the two diseases are combined. In male and female Ren-2 transgenic rats (TGR), a model of hypertension with activation of endogenous RAS, CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of an aorto-caval fistula (ACF). The primary aim of the study was to examine long-term CKD- and CHF-related mortality, especially in animals with CKD and CHF combined, with particular interest in the potential sex-related differences. The follow-up period was 23 weeks after the first intervention (5/6 NX). We found, first, that TGR did not exhibit sexual dimorphism in the course of 5/6 NX-induced CKD. Second, in contrast, TGR exhibited important sex-related differences in the course of ACF-induced CHF-related mortality: intact female TGR showed higher survival rate than male TGR. This situation is reversed in the course of combined 5/6 NX-induced CKD and ACF-induced CHF-related mortality: intact female TGR exhibited poorer survival than male TGR. Third, the survival rate in animals with combined 5/6 NX-induced CKD and ACF-induced CHF was significantly worsened as compared with rat groups that were exposed to 'single organ disease'. Collectively, our present results clearly show that CKD aggravates long-term mortality of animals with CHF. In addition, TGR exhibit remarkable sexual dimorphism with respect to CKD- and CHF-related mortality, especially in animals with combined CKD and CHF. © 2016 John Wiley & Sons Australia, Ltd.

Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1.

PubMed

Wang, Yan-Xiang; Pang, Wei-Qiang; Zeng, Qing-Xuan; Deng, Zhe-Song; Fan, Tian-Yun; Jiang, Jian-Dong; Deng, Hong-Bin; Song, Dan-Qing

2018-01-01

To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation. Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Effect of cold pressor stimulation (4 degrees C) on human masseter muscle haemodynamics during and after sustained isometric contraction.

PubMed

Maekawa, K; Kuboki, T; Yamashita, A; Clark, G T

1999-11-01

The effect of cold pressor (CP) stimulation and sustained isometric contraction on the blood volume of the right masseter muscle was examined in seven healthy males, who performed 1 min of isometric jaw clenching at 50% of their maximum voluntary contraction without, with and again without a 4 degrees C CP stimulation. Total haemoglobin was measured in the masseter before, during and after the contraction task using near-infrared spectroscopy. CP stimulation during the isometric contraction diminished the magnitude of the contraction-induced decrease of blood volume when compared to the trials without CP stimulation. However, in the immediate post-contraction period (while the CP stimulation was still in place), no increase in blood volume above the usual post-contraction hyperaemia was evident. Once the CP stimulation had been removed, there was a clear decrease (faster return to baseline) in the vasodilation occurring in the post-contraction period. This diminished period of vasodilation occurred in spite of the fact that the vascular resistance (blood pressure) and heart rate were still substantially elevated by the CP effect during this same period. These data suggest that the strong CP stimulation produced a biphasic response. First, there was an early-onset strong vasodilation (during CP), which was followed by a period of diminished vasodilation, suggesting that an active, but delayed, vasoconstrictive drive may be induced by the CP stimulus.

Antihyperglycemic effect of the traditional Chinese scutellaria-coptis herb couple and its main components in streptozotocin-induced diabetic rats.

PubMed

Liu, Sheng-Zi; Deng, Yuan-Xiong; Chen, Bo; Zhang, Xiao-Jie; Shi, Qun-Zhi; Qiu, Xi-Min

2013-01-30

Scutellaria-coptis herb couple (SC) is the main herb couple in many traditional Chinese compound formulas used for the treatment of diabetes mellitus, which has been used to treat diabetes mellitus for thousands of years in China. In this study we provide experimental evidence for the clinical use of SC in the treatment of diabetes mellitus. To confirm the anti-diabetic effect of SC extract and its main components, and to explore its mechanism from the effect on intestinal disaccharidases by in vivo and in vitro experiment. SC extract was prepared and the main components (namely berberine and baicalin) contained in the extract were assayed with high performance liquid chromatography (HPLC). And diabetic model rats were induced by intraperitoneal injection of streptozotocin (STZ). After grouped randomly, diabetic rats were administered SC extract, berberine, baicalin, berberine+baicalin, acarbose and vehicle for 33d, respectively. Body weight, food intake, urine volume, urine sugars, fasting plasma glucose and fasting plasma insulin were monitored to evaluate the antidiabetic effects on diabetic rats. Intestinal mucosa homogenate was prepared and the activities of intestinal disaccharidases were assayed. Moreover, oral sucrose tolerance test (OSTT) was performed and the inhibitory effects of SC extract and its main components (berberine and baicalin) on the maltase and sucrase in vitro was evaluated. After the treatment of SC extract and its main components, the body weight and the fasting plasma insulin level were found to be increased while food intake, urine volume, urine sugars and fasting plasma were decreased. OSTT showed that SC extract and its main components could lower the postprandial plasma glucose level of diabetic rats. Furthermore, SC extract and its main components could inhibit the activities of intestinal disaccharidases in diabetic rats, whereas only SC extract and berberine could inhibit the activity of maltase in vitro. According to our present findings, scutellaria-coptis herb couple (SC) possessed potent anti-hyperglycemic effect on STZ-induced diabetic rats. And SC extract and its main components exerted anti-hyperglycemic effect partly via inhibiting the increased activities of intestinal disaccharidases and elevating the level of plasma insulin in diabetic rats induced by STZ. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Exogenous surfactant preserves lung function and reduces alveolar Evans blue dye influx in a rat model of ventilation-induced lung injury.

PubMed

Verbrugge, S J; Vazquez de Anda, G; Gommers, D; Neggers, S J; Sorm, V; Böhm, S H; Lachmann, B

1998-08-01

Changes in pulmonary edema infiltration and surfactant after intermittent positive pressure ventilation with high peak inspiratory lung volumes have been well described. To further elucidate the role of surfactant changes, the authors tested the effect of different doses of exogenous surfactant preceding high peak inspiratory lung volumes on lung function and lung permeability. Five groups of Sprague-Dawley rats (n = 6 per group) were subjected to 20 min of high peak inspiratory lung volumes. Before high peak inspiratory lung volumes, four of these groups received intratracheal administration of saline or 50, 100, or 200 mg/kg body weight surfactant; one group received no intratracheal administration. Gas exchange was measured during mechanical ventilation. A sixth group served as nontreated, nonventilated controls. After death, all lungs were excised, and static pressure-volume curves and total lung volume at a transpulmonary pressure of 5 cm H2O were recorded. The Gruenwald index and the steepest part of the compliance curve (Cmax) were calculated. A bronchoalveolar lavage was performed; surfactant small and large aggregate total phosphorus and minimal surface tension were measured. In a second experiment in five groups of rats (n = 6 per group), lung permeability for Evans blue dye was measured. Before 20 min of high peak inspiratory lung volumes, three groups received intratracheal administration of 100, 200, or 400 mg/ kg body weight surfactant; one group received no intratracheal administration. A fifth group served as nontreated, nonventilated controls. Exogenous surfactant at a dose of 200 mg/kg preserved total lung volume at a pressure of 5 cm H2O, maximum compliance, the Gruenwald Index, and oxygenation after 20 min of mechanical ventilation. The most active surfactant was recovered in the group that received 200 mg/kg surfactant, and this dose reduced minimal surface tension of bronchoalveolar lavage to control values. Alveolar influx of Evans blue dye was reduced in the groups that received 200 and 400 mg/kg exogenous surfactant. Exogenous surfactant preceding high peak inspiratory lung volumes prevents impairment of oxygenation, lung mechanics, and minimal surface tension of bronchoalveolar lavage fluid and reduces alveolar influx of Evans blue dye. These data indicate that surfactant has a beneficial effect on ventilation-induced lung injury.

ELABELA Improves Cardio-Renal Outcome in Fatal Experimental Septic Shock.

PubMed

Coquerel, David; Chagnon, Frédéric; Sainsily, Xavier; Dumont, Lauralyne; Murza, Alexandre; Côté, Jérôme; Dumaine, Robert; Sarret, Philippe; Marsault, Éric; Salvail, Dany; Auger-Messier, Mannix; Lesur, Olivier

2017-11-01

Apelin-13 was recently proposed as an alternative to the recommended β-adrenergic drugs for supporting endotoxin-induced myocardial dysfunction. Since Apelin-13 signals through its receptor (Apelin peptide jejunum) to exert singular inotropic/vasotropic actions and to optimize body fluid balance, this candidate pathway might benefit septic shock management. Whether the newly discovered ELABELA (ELA), a second endogenous ligand of the Apelin peptide jejunum receptor highly expressed in the kidney, further improves cardio-renal impairment remains unknown. Interventional study in a rat model of septic shock (128 adult males) to assess the effects of ELA and Apelin-13 on vascular and cardio-renal function. Experiments were performed in a tertiary care University-based research institute. Polymicrobial sepsis-induced cardiac dysfunction was produced by cecal ligation puncture to assess hemodynamic efficacy, cardioprotection, and biomechanics under acute or continuous infusions of the apelinergic agonists ELA or Apelin-13 (39 and 15 µg/kg/hr, respectively) versus normal saline. Apelinergic agonists improved 72-hour survival after sepsis induction, with ELA providing the best clinical outcome after 24 hours. Apelinergic agonist infusion counteracted cecal ligation puncture-induced myocardial dysfunction by improving left ventricular pressure-volume relationship. ELA-treated cecal ligation puncture rats were the only group to 1) display a significant improvement in left ventricular filling as shown by increased E-wave velocity and left ventricular end-diastolic volume, 2) exhibit a higher plasma volume, and 3) limit kidney injury and free-water clearance. These beneficial renal effects were superior to Apelin-13, likely because full-length ELA enabled a distinctive regulation of pituitary vasopressin release. Activation of the apelinergic system by exogenous ELA or Apelin-13 infusion improves cardiovascular function and survival after cecal ligation puncture-induced sepsis. However, ELA proved better than Apelin-13 by improving fluid homeostasis, cardiovascular hemodynamics recovery, and limiting kidney dysfunction in a vasopressinergic-dependent manner.

A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats.

PubMed

Allan, George; Lai, Muh-Tsann; Sbriscia, Tifanie; Linton, Olivia; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Dodds, Robert; Fiordeliso, James; Lanter, James; Sui, Zhihua; Lundeen, Scott

2007-01-01

The pharmacological activity of JNJ-26146900 is described. JNJ-26146900 is a nonsteroidal androgen receptor (AR) ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the androgen antagonist bicalutamide (Casodex). In intact rats, JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of bicalutamide. JNJ-26146900 prevented prostate tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed tumor growth significantly in a CWR22-LD1 mouse xenograft model of human prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg, JNJ-26146900 significantly reduced castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of hydroxyapatite to 166+/-26mg/cm(3) following orchidectomy, and was maintained at 194+/-20mg/cm(3) with JNJ-26146900 treatment (P<0.05 relative to orchidectomy alone). Using magnetic resonance imaging, the compound was found to partially prevent orchidectomy-induced loss of lean body mass. Our data show that selective androgen receptor modulators (SARMs) have the potential for anabolic effects on bone and muscle while maintaining therapeutic efficacy in prostate cancer.

Rationale for the development and the mechanism of action of endoscopic thermal vapor ablation (InterVapor) for the treatment of emphysema.

PubMed

Kesten, Steven; Anderson, Joseph C; Tuck, Stephanie A

2012-07-01

Emphysema remains a disabling disease despite current treatment. Novel approaches to the underlying physiological abnormalities responsible for symptom generation are warranted. A review of current hypotheses and preclinical and clinical data on the utility of endoscopic thermal vapor ablation (InterVapor) in the treatment of emphysema. In animal studies, thermal energy in the form of heated water vapor both in healthy and in papain-induced emphysema in dogs and sheep leads to an inflammatory response followed by healing with airway and parenchymal fibrosis. The fibrosis and associated distal atelectasis result in volume reduction. The amount of thermal energy delivered has been based on the amount of target tissue mass determined from a high-resolution computed tomogram. Early human studies indicated the feasibility of InterVapor with 5 cal/g tissue; however, the dose appeared insufficient to induce lobar volume reduction. A study using 10 cal/g to 1 upper lobe (n=44) induced a mean of 46% lobar volume reduction at 12 months along with significant improvements in the physiology and health outcomes. InterVapor induces lung volume reduction in patients with emphysema. The mechanism of action is through a thermally induced inflammatory response followed by healing with subsequent remodeling of tissue (fibrosis and distal atelectasis).

Wasabi-derived 6-(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human breast cancer by possible involvement of the NF-κB pathways.

PubMed

Fuke, Yoko; Hishinuma, Madoka; Namikawa, Mayumi; Oishi, Yoshie; Matsuzaki, Takeshi

2014-01-01

6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a bioactive ingredient of wasabi (Wasabia japonica), which is a popular spice in Japan. 6-MSITC has been reported to inhibit the proliferation of breast cancer and melanoma cell lines. We inoculated 30 female Balb-nu/nu mice with MDA-MB-231 or -453 cells, and orally administered varying concentrations of 6-MSITC for 12 days following tumor growth. The tumor volumes and tumor weights from mice inoculated with MDA-MB-231 cells, and the tumor volumes of MDA-MB-453 cells were significantly inhibited by 6-MSITC on Days 9 and 11 after drug administration. DNA fragmentation, DNA ladder, and caspase 3/7 activity performed in vitro revealed that 6-MSITC induced apoptosis of MDA-MB-231, MDA-MB-453, and MCF-7 cells. Furthermore, nuclear factor-κB (NF-κB) expression in the nuclei and phosphorylation of inhibitor κBα (IκBα) was downregulated by 6-MSITC in a concentration-dependent manner; however, this activity was not observed in MCF-7 cells. Moreover, this downregulation of phosphorylated IκBα by 6-MSITC in MDA-MB-231 and -453 cells supports its inhibitory effects on NF-κB activity. The expression of phosphorylated AKT (pAKT) reduced by 6-MSITC was confirmed in MDA-MB-231 cells. Thus, we conclude that 6-MITC promotes apoptosis of breast cancer cells by inhibiting NF-kB and therefore releasing its control of the PI3K/AKT pathway.

Characterization and Demonstrations of Laser-Induced Incandescence in both Normal and Low-Gravity

NASA Technical Reports Server (NTRS)

VanderWal, Randall L.

1997-01-01

Knowledge of soot volume fraction is important to a wide range of combustion studies in microgravity. Laser-induced incandescence (LII) offers high sensitivity, high temporal and spatial resolution in addition to geometric versatility for real-time determination of soot volume fraction. Implementation of LII into the 2.2 see drop tower at The NASA-Lewis Research Center along with system characterization is described. Absolute soot volume fraction measurements are presented for laminar and turbulent gas-jet flames in microgravity to illustrate the capabilities of LII in microgravity. Comparison between LII radial intensity profiles with soot volume fraction profiles determined through a full-field light extinction technique are also reported validating the accuracy of LII for soot volume fraction measurements in a microgravity environment.

Evaluation of the antiulcerogenic and analgesic activities of Cordia verbenacea DC. (Boraginaceae).

PubMed

Roldão, Erika de Freitas; Witaicenis, Aline; Seito, Leonardo Noboru; Hiruma-Lima, Clélia Akiko; Di Stasi, Luiz Claudio

2008-09-02

Cordia verbenacea is a medicinal plant popularly used in Brazil as anti-inflammatory, antiulcer and anti-rheumatic agent without detailed pharmacological and toxicological studies. The study was aimed to investigate the effects of Cordia verbenacea in antiulcer, analgesic and antioxidant assays, as well as to evaluate its toxic effects and phytochemical profile. Antiulcer activity of plant extract was evaluated using ethanol/HCl, ethanol and piroxican-induced gastric lesions methods. The pH, volume and total acid of gastric juice were determined by pylorus-ligated assay. Analgesic activity was evaluated by writhing, tail-flick and hot-plate tests. Antioxidant activity was determined by in vitro lipoperoxidation assay. Acute toxicity and number of deaths were evaluated by Hippocratic screening. The ethanol leaf extract shows a potent antiulcer activity in the ethanol/HCl and absolute ethanol-induced gastric lesions. The IC(50) value of plant extract on the lipid peroxidation was 76.11mug/ml. Preliminary phytochemical tests were positive for flavonoids, steroids, saponins, fixed acids, alkaloids and phenols. In the analgesic models the extract did not present any activity. Cordial verbenaceae showed a potent antiulcer activity at the dose of 125mg/kg and this effect may be associated with an improvement in stomach antioxidant mechanisms.

The Effect of Increasing Volume of Exercise on Activation Pattern of Vastus Medialis and Lateralis and its Correlation With Anterior Knee Pain in Karate Elites

PubMed Central

Safar Cherati, Afsaneh; Lotfian, Sara; Jamshidi, Aliashraf; Sanjari, Mohammad Ali; Razi, Mohammad

2016-01-01

Background The effects of exercise volume on the pattern of muscle activity is one of the most important factors in training management and injury risk reduction. In the lower limb, the quadriceps muscle which plays a determining role in performing the stance and other karate techniques could be injured in intensive exercise and may induce anterior knee pain in athletes. Objectives The aim of this study was to determine the relationship between training volume and muscle activity of vastus medialis and vastus lateralis and its association with anterior knee pain in karate elites. Patients and Methods Male and female athletes from national junior and cadet karate team (14 to 18 years) were invited to participate in the study at the beginning and the end of the training camps. Studies involved measurement of electromyographic muscle activity of vastus medialis and vastus lateralis in both lower extremities with surface electromyography device and assessment of movement by electrogoniometery. Muscle activity was recorded in three tests of dachi, walking up and walking down stairs. Simultaneously, anterior knee pain was evaluated using visual analogue scale and anterior knee pain scale questionnaire. Results Eight athletes of a total number of 23 reported increased ratings of pain in their right knees. No differences in muscle activity were observed in tests of Dachi and stairs between the groups with and without pain. Comparing Dachi task pattern at the beginning and end of training camps, there was no significant difference in pattern of biomechanical movement; however, reducing the amount of muscle activity in early and late phases of tasks was observed in electromyographic assessment. Conclusions The results showed that performing the same task after a six-week training period, less muscle activity was required in all phases in two groups of tasks, including karate-specific movement (dachi) and activities of daily living (up or down stairs). PMID:27826403

The Effect of Increasing Volume of Exercise on Activation Pattern of Vastus Medialis and Lateralis and its Correlation With Anterior Knee Pain in Karate Elites.

PubMed

Safar Cherati, Afsaneh; Lotfian, Sara; Jamshidi, Aliashraf; Sanjari, Mohammad Ali; Razi, Mohammad

2016-09-01

The effects of exercise volume on the pattern of muscle activity is one of the most important factors in training management and injury risk reduction. In the lower limb, the quadriceps muscle which plays a determining role in performing the stance and other karate techniques could be injured in intensive exercise and may induce anterior knee pain in athletes. The aim of this study was to determine the relationship between training volume and muscle activity of vastus medialis and vastus lateralis and its association with anterior knee pain in karate elites. Male and female athletes from national junior and cadet karate team (14 to 18 years) were invited to participate in the study at the beginning and the end of the training camps. Studies involved measurement of electromyographic muscle activity of vastus medialis and vastus lateralis in both lower extremities with surface electromyography device and assessment of movement by electrogoniometery. Muscle activity was recorded in three tests of dachi, walking up and walking down stairs. Simultaneously, anterior knee pain was evaluated using visual analogue scale and anterior knee pain scale questionnaire. Eight athletes of a total number of 23 reported increased ratings of pain in their right knees. No differences in muscle activity were observed in tests of Dachi and stairs between the groups with and without pain. Comparing Dachi task pattern at the beginning and end of training camps, there was no significant difference in pattern of biomechanical movement; however, reducing the amount of muscle activity in early and late phases of tasks was observed in electromyographic assessment. The results showed that performing the same task after a six-week training period, less muscle activity was required in all phases in two groups of tasks, including karate-specific movement (dachi) and activities of daily living (up or down stairs).

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease

PubMed Central

Nyman, Jeffry S.; Merkel, Alyssa R.; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J.; Oyajobi, Babatunde O.; Sterling, Julie A.

2016-01-01

Multiplemyeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2 −/−) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4 weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. PMID:27423464

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.

PubMed

Nyman, Jeffry S; Merkel, Alyssa R; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J; Oyajobi, Babatunde O; Sterling, Julie A

2016-10-01

Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. Published by Elsevier Inc.

Topical sodium cromoglicate relieves allergen- and histamine-induced dermal pruritus.

PubMed

Vieira Dos Santos, R; Magerl, M; Martus, P; Zuberbier, T; Church, M K; Escribano, L; Maurer, M

2010-03-01

Sodium cromoglicate (SCG) has long been used in the management of allergic diseases, including as an ointment for atopic dermatitis. Although mast cell stabilization was initially considered as its mechanism of action, anti-inflammatory actions and modulation of sensory nerve function have also been suggested. To investigate the mechanism(s) by which SCG relieves allergen- and histamine-induced dermal inflammation by assessing its effects on pruritus, flare, skin temperature and weal volume. Aqueous cream containing 0.2%, 1% or 4% SCG or no SCG (placebo) was applied in a randomized single-blind manner to four areas on each forearm (two sites per arm) and covered with an occlusive dressing. One hour later, skin-prick tests were performed in 20 allergic subjects with allergens to which they had previously shown sensitization, and in 40 nonallergic subjects with codeine (9 mg mL(-1), 20 subjects) and histamine (10 mg mL(-1), 20 subjects). Weal volume, skin temperature increase, erythema area and pruritus intensity were assessed at 0, 5, 10 and 15 min. SCG significantly (P < 0.05 to P < 0.001) reduced pruritus induced by all stimuli, with 4% SCG being most effective. Significant (P < 0.05 to P < 0.01) reductions of erythema area were also seen but there was no inhibition of weal volume or temperature increase. SCG is effective in reducing pruritus but has no effect on weals, supporting the proposition that, in the skin, SCG inhibits sensory C-fibre nerve activation rather than preventing mast cell degranulation. We suggest that topical SCG treatment, delivered in an appropriate vehicle, may be beneficial for symptomatic relief of pruritus in patients with cutaneous mastocytosis and other pruritic dermatoses.

Evaluating the Gutenberg-Richter Relationship for Induced Seismicity

NASA Astrophysics Data System (ADS)

Tymchak, M. P.; Flewelling, S. A.

2013-12-01

Large volumes of flowback and produced water generated from hydraulic fracturing and oil and gas production have led to increased wastewater disposal through underground injection wells. Several recent studies have linked recently felt seismic events to underground injection wells in Arkansas, Ohio, Texas and Oklahoma, among others. However, in some cases, such as in Oklahoma, there is a lack of consensus as to whether the earthquakes were the result of fluid injection (Keranan et al., 2013), natural tectonic processes (Oklahoma Geological Survey, 2013), or were related to remote events (van der Elst et al., 2013). Moreover, it is unclear why earthquakes have occurred near some injection wells but not others, with apparently similar geology, target reservoirs, and injection rates (e.g., Frohlich, 2012). In instances where injection occurred near a fault (e.g., Rangely, CO), the timing and distribution of seismic events was well correlated to fluid volumes, and the interaction between injection and induced seismicity was easily resolved. In other cases (e.g., Oklahoma, Texas), it appears more difficult to interpret whether a particular injection well was related to observed seismic events. Therefore, metrics are needed as diagnostic tools to help differentiate between natural and induced seismicity. It has been well established that the frequency-magnitude distribution of earthquakes follows the Gutenberg-Richter distribution log N(M) = a - bM, where the slope (b-value) is typically near one. However, in some instances of deep fluid injection, b-values may vary, depending on specific injection activities, such as enhanced geothermal or hydraulic fracturing (Dinske and Shapiro, 2013). In some cases, b-values may vary during successive fracture stages of a single horizontal well (e.g., Williams and Calvarez, 2013), and seismicity associated with hydraulic fracturing may deviate from the Gutenberg-Richter relationship altogether (Hurd and Zoback, 2012). We evaluate whether frequency magnitude distributions could be used as a method to distinguish between natural and induced seismicity, drawing from a number of datasets compiled from different types of injection activities.

D-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB.

PubMed

Rengarajan, Thamaraiselvan; Nandakumar, Natarajan; Rajendran, Peramaiyan; Ganesh, Mohanraj Karthik; Balasubramanian, Maruthaiveeran Periyasamy; Nishigaki, Ikuo

2015-06-01

Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 ± 0.56, which was significantly reduced to 5.74 ± 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-κB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D-pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above-mentioned parameters along with NF-κB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis.

Brown Adipose Tissue Is Linked to a Distinct Thermoregulatory Response to Mild Cold in People

PubMed Central

Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Chao, Tony; Porter, Craig; Annamalai, Palam; Yfanti, Christina; Labbe, Sebastien M.; Hurren, Nicholas M.; Malagaris, Ioannis; Cesani, Fernardo; Sidossis, Labros S.

2016-01-01

Brown adipose tissue (BAT) plays an important role in thermoregulation in rodents. Its role in temperature homeostasis in people is less studied. To this end, we recruited 18 men [8 subjects with no/minimal BAT activity (BAT−) and 10 with pronounced BAT activity (BAT+)]. Each volunteer participated in a 6 h, individualized, non-shivering cold exposure protocol. BAT was quantified using positron emission tomography/computed tomography. Body core and skin temperatures were measured using a telemetric pill and wireless thermistors, respectively. Core body temperature decreased during cold exposure in the BAT− group only (−0.34°C, 95% CI: −0.6 to −0.1, p = 0.03), while the cold-induced change in core temperature was significantly different between BAT+ and BAT− subjects (BAT+ vs. BAT−, 0.43°C, 95% CI: 0.20–0.65, p = 0.0014). BAT volume was associated with the cold-induced change in core temperature (p = 0.01) even after adjustment for age and adiposity. Compared to the BAT− group, BAT+ subjects tolerated a lower ambient temperature (BAT−: 20.6 ± 0.3°C vs. BAT+: 19.8 ± 0.3°C, p = 0.035) without shivering. The cold-induced change in core temperature (r = 0.79, p = 0.001) and supraclavicular temperature (r = 0.58, p = 0.014) correlated with BAT volume, suggesting that these non-invasive measures can be potentially used as surrogate markers of BAT when other methods to detect BAT are not available or their use is not warranted. These results demonstrate a physiologically significant role for BAT in thermoregulation in people. This trial has been registered with Clinaltrials.gov: NCT01791114 (https://clinicaltrials.gov/ct2/show/NCT01791114). PMID:27148068

Protective effects of ghrelin in ventilator-induced lung injury in rats.

PubMed

Li, Guang; Liu, Jiao; Xia, Wen-Fang; Zhou, Chen-Liang; Lv, Li-Qiong

2017-11-01

Ghrelin has exhibited potent anti-inflammatory effects on various inflammatory diseases. The aim of this study was to investigate the potential effects of ghrelin on a model of ventilator-induced lung injury (VILI) established in rats. Male Sprague-Dawley rats were randomly divided into three groups: low volume ventilation (LV, Vt=8ml/kg) group, a VILI group (Vt=30ml/kg), and a VILI group pretreated with ghrelin (GH+VILI). For the LV group, for the VILI and GH+VILI groups, the same parameters were applied except the tidal volume was increased to 40ml/kg. After 4h of MV, blood gas, lung elastance, and levels of inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and (MIP)-2 and total protein in bronchoalveolar lavage fluid (BALF) were analyzed. Myeloperoxidase (MPO), (TLR)-4, and NF-κB, were detected in lung tissues. Water content (wet-to-dry ratio) and lung morphology were also evaluated. The VILI group had a higher acute lung injury (ALI) score, wet weight to dry ratio, MPO activity, and concentrations of inflammatory mediators (TNF-α, IL-6, IL-1β, and MIP-2) in BALF, as well as higher levels of TLR4 and NF-κB expression than the LV group (P<0.05). All histopathologic ALI, the inflammatory profile, and pulmonary dynamics have been improved by ghrelin pretreatment (P<0.05). Ghrelin pretreatment also decreased TLR4 expression and NF-κB activity compared with the VILI group (P<0.05). Ghrelin pretreatment attenuated VILI in rats by reducing MV-induced pulmonary inflammation and might represent a novel therapeutic candidate for protection against VILI. Copyright © 2017 Elsevier B.V. All rights reserved.

Rosiglitazone, a Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, Attenuates Inflammation Via NF-κB Inhibition in Lipopolysaccharide-Induced Peritonitis.

PubMed

Zhang, Yun-Fang; Zou, Xun-Liang; Wu, Jun; Yu, Xue-Qing; Yang, Xiao

2015-12-01

We assessed the anti-inflammatory effect of peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, in a lipopolysaccharide (LPS)-induced peritonitis rat model. LPS was intraperitoneally injected into rats to establish peritonitis model. Male Sprague-Dawley (SD) rats were assigned to normal saline (the solvent of LPS), LPS, rosiglitazone plus LPS, and rosiglitazone alone. A simple peritoneal equilibrium test was performed with 20 ml 4.25 % peritoneal dialysis fluid. We measured the leukocyte count in dialysate and ultrafiltration volume. Peritoneal membrane histochemical staining was performed, and peritoneal thickness was assessed. CD40 and intercellular adhesion molecule-1 messenger RNA (ICAM-1 mRNA) levels in rat visceral peritoneum were detected by reverse transcription (RT)-PCR. IL-6 in rat peritoneal dialysis effluent was measured using enzyme-linked immunosorbent assay. The phosphorylation of NF-κB-p65 and IκBα was analyzed by Western blot. LPS administration resulted in increased peritoneal thickness and decreased ultrafiltration volume. Rosiglitazone pretreatment significantly decreased peritoneal thickness. In addition to CD40 and ICAM-1 mRNA expression, the IL-6, p-p65, and p-IκBα protein expressions were enhanced in LPS-administered animals. Rosiglitazone pretreatment significantly decreased ICAM-1 mRNA upregulation, secretion of IL-6 protein, and phosphorylation of NF-κB-p65 and IκBα without decreasing CD40 mRNA expression. Rosiglitazone has a protective effect in peritonitis, simultaneously decreasing NF-κB phosphorylation, suggesting that NF-κB signaling pathway mediated peritoneal inflammation induced by LPS. PPAR-γ might be considered a potential therapeutic target against peritonitis.

Effects of 5-hydroxymethyl-2-furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease.

PubMed

Hannemann, Anke; Cytlak, Urszula M; Rees, David C; Tewari, Sanjay; Gibson, John S

2014-09-15

The heterocyclic aldehyde 5-hydroxymethyl-2-furfural (5HMF) interacts allosterically with the abnormal form of haemoglobin (Hb), HbS, in red blood cells (RBCs) from patients with sickle cell disease (SCD), thereby increasing oxygen affinity and decreasing HbS polymerization and RBC sickling during hypoxia. We hypothesized that should 5HMF also inhibit the main cation pathways implicated in the dehydration of RBCs from SCD patients - the deoxygenation-induced cation pathway (Psickle), the Ca(2+)-activated K(+) channel (the Gardos channel) and the K(+)-Cl(-) cotransporter (KCC) - it would have a synergistic effect in protection against sickling, directly through interacting with HbS, and indirectly through maintaining hydration and reducing [HbS]. This study was therefore designed to investigate the effects of 5HMF on RBC volume and K(+) permeability in vitro. 5HMF markedly reduced the deoxygenation-induced dehydration of RBCs whether in response to maintained deoxygenation or to cyclical deoxygenation/re-oxygenation. 5HMF was found to inhibit Psickle, an effect which correlated with its effects on sickling. Deoxygenation-induced activation of the Gardos channel and exposure of phosphatidylserine were also inhibited, probably indirectly via reduced entry of Ca(2+) through the Psickle pathway. Effects of 5HMF on KCC were more modest with a slight inhibition in N-ethylmaleimide (NEM, 1 mm)-treated RBCs and stimulation in RBCs untreated with NEM. These findings support the hypothesis that 5HMF may also be beneficial through effects on RBC ion and water homeostasis. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Elevated central venous pressure: A consequence of exercise training-induced hypervolemia

NASA Technical Reports Server (NTRS)

Convertino, Victor A.; Mack, Gary W.; Nadel, Ethan R.

1990-01-01

Resting plasma volumes, and arterial and central venous pressures (CVP) were measured in 16 men before and after exercise training to determine if training-induced hypervolemia could be explained by a change in total vascular capacitance. In addition, resting levels of plasma vasopressin (AVP), atrial natriuretic peptide (ANP), aldosterone (ALD), and norepinephrine (NE) were measured before and after training. The same measurements of vacular volume, pressures, and plasma hormones were measured in 8 subjects who did not undergo exercise and acted as controls. The exercise training program consisted of 10 weeks of controlled cycle exercise for 30 min/d, 4 d/wk at 75 to 80 percent of maximal oxygen uptake (VO2max). A training effect was verified by a 20 percent increase in VO2max, a resting bradycardia, and a 370 ml (9 percent) increase in blood volume. Mean arterial blood pressure was unaltered by exercise training, but resting CVP increased. The percent change in blood volume from before to after training was linearly related to the percent change in CVP. As a consequence of elevations in both blood volume and CVP, the volume-to-pressure ratio was essentially unchanged following exercise training. Plasma AVP, ANP, ALD, and NE were unaltered. Results indicate that elevated CVP is a consequence of training-induced hypervolemia without alteration in total effective venous capacitance. This may represent a resetting of the pressure-volume stimulus-response relation for regulation of blood volume.

Active micromixer using surface acoustic wave streaming

DOEpatents

Branch,; Darren W. , Meyer; Grant D. , Craighead; Harold, G [Ithaca, NY

2011-05-17

An active micromixer uses a surface acoustic wave, preferably a Rayleigh wave, propagating on a piezoelectric substrate to induce acoustic streaming in a fluid in a microfluidic channel. The surface acoustic wave can be generated by applying an RF excitation signal to at least one interdigital transducer on the piezoelectric substrate. The active micromixer can rapidly mix quiescent fluids or laminar streams in low Reynolds number flows. The active micromixer has no moving parts (other than the SAW transducer) and is, therefore, more reliable, less damaging to sensitive fluids, and less susceptible to fouling and channel clogging than other types of active and passive micromixers. The active micromixer is adaptable to a wide range of geometries, can be easily fabricated, and can be integrated in a microfluidic system, reducing dead volume. Finally, the active micromixer has on-demand on/off mixing capability and can be operated at low power.

Parallel changes in intracellular water volume and pH induced by NH(3)/NH(4)(+) exposure in single neuroblastoma cells.

PubMed

Blanco, Víctor M; Márquez, Martín S; Alvarez-Leefmans, Francisco J

2013-01-01

Increased blood levels of ammonia (NH3) and ammonium (NH4(+)), i.e. hyperammonemia, leads to cellular brain edema in humans with acute liver failure. The pathophysiology of this edema is poorly understood. This is partly due to incomplete understanding of the osmotic effects of the pair NH3/NH4(+) at the cellular and molecular levels. Cell exposure to solutions containing NH3/NH4(+) elicits changes in intracellular pH (pHi), which can in turn affect cell water volume (CWV) by activating transport mechanisms that produce net gain or loss of solutes and water. The occurrence of CWV changes caused by NH3/NH4(+) has long been suspected, but the mechanisms, magnitude and kinetics of these changes remain unknown. Using fluorescence imaging microscopy we measured, in real time, parallel changes in pHi and CWV caused by brief exposure to NH3/NH4(+) of single cells (N1E-115 neuroblastoma or NG-108 neuroblastoma X glioma ) loaded with the fluorescent indicator BCECF. Changes in CWV were measured by exciting BCECF at its intracellular isosbestic wavelength (∼438 nm), and pHi was measured ratiometrically. Brief exposure to isosmotic solutions (i.e. having the same osmolality as that of control solutions) containing NH4Cl (0.5- 30 mM) resulted in a rapid, dose-dependent swelling, followed by isosmotic regulatory volume decrease (iRVD). NH4Cl solutions in which either extracellular [NH3] or [NH4(+)] was kept constant while the other was changed by varying the pH of the solution, demonstrated that [NH3]o rather than [NH4(+)]o is the main determinant of the NH4Cl-induced swelling. The iRVD response was sensitive to the anion channel blocker NPPB, and partly dependent on external Ca(2+). Upon removal of NH4Cl, cells shrank and displayed isosmotic regulatory volume increase (iRVI). Regulatory volume responses could not be activated by comparable CWV changes produced by anisosmotic solutions, suggesting that membrane stretch or contraction by themselves are not sufficient to trigger these responses. Inhibition of glutamine synthetase partially blocked the NH4Cl-induced swelling. A quantitative description of the osmotic changes produced by exposure to NH3/NH4(+) in single neurons and glial cells shows that ∼35 to 45% of the initial cell swelling can be explained by intracellular accumulation of NH4(+) due to rapid permeation and protonation of NH3. Another∼23% of the swelling can be accounted for by rapid glutamine accumulation. The results are discussed in terms of basic cell physiology and their potential relevance to the pathophysiology of hyperammonemic cellular brain edema. © 2014 S. Karger AG, Basel.

Protective effects of oleuropein against renal injury oxidative damage in alloxan-induced diabetic rats; a histological and biochemical study.

PubMed

Ahmadvand, Hassan; Shahsavari, Gholamreza; Tavafi, Majid; Bagheri, Shahrokh; Moradkhani, Mohamad Reza; Kkorramabadi, Reza Mohammadrezaei; Khosravi, Peyman; Jafari, Maryam; Zahabi, Khadije; Eftekhar, Reza; Soleimaninejad, Maryam; Moghadam, Sanaz

2017-07-01

Oleuropein is a potent antioxidant and free-radical scavenger with antiinflammatory properties. In the present study, we evaluated the protective effects of oleuropein on myeloperoxidase (MPO) activity, nitrite, urea, creatinine and glomerulosclerosis in alloxan-induced type 1 diabetic rats. Thirty Sprague-Dawley male rats were randomly divided into 3 groups: group 1 as control; group 2 as untreated diabetic; and group 3 as treated with oleuropein 15 mg/kg i.p daily. Diabetes was induced in the second and third groups by subcutaneous alloxan injection. After 48 days, the animals were anaesthetized and then the livers and kidneys were removed immediately and used fresh or kept frozen until MPO activity analysis. Blood samples were also collected before sacrificing to measure nitrite, urea, and creatinine. Kidney paraffin sections were prepared to estimate glomerular volume, leukocyte infiltration, and glomerulosclerosis. Oleuropein significantly decreased leukocyte infiltration and glomerulosclerosis in the treated group compared with the diabetic untreated group. Oleuropein significantly decreased the levels of urea, nitrite, and creatinine in the treated group compared with the diabetic untreated group. Moreover, oleuropein significantly decreased MPO activity in the treated group compared with the diabetic untreated group. Oleuropein has antioxidative and antiatherogenic activities and exerts beneficial effects on inflammation and kidney function test and decreases diabetic complication in diabetic rats.

Peptidyl Prolyl Isomerase PIN1 Directly Binds to and Stabilizes Hypoxia-Inducible Factor-1α

PubMed Central

Han, Hyeong-jun; Kwon, Nayoung; Choi, Min-A; Jung, Kyung Oh; Piao, Juan-Yu; Ngo, Hoang Kieu Chi; Kim, Su-Jung; Kim, Do-Hee; Chung, June-Key; Cha, Young-Nam; Youn, Hyewon; Choi, Bu Young; Min, Sang-Hyun; Surh, Young-Joon

2016-01-01

Peptidyl prolyl isomerase (PIN1) regulates the functional activity of a subset of phosphoproteins through binding to phosphorylated Ser/Thr-Pro motifs and subsequently isomerization of the phosphorylated bonds. Interestingly, PIN1 is overexpressed in many types of malignancies including breast, prostate, lung and colon cancers. However, its oncogenic functions have not been fully elucidated. Here, we report that PIN1 directly interacts with hypoxia-inducible factor (HIF)-1α in human colon cancer (HCT116) cells. PIN1 binding to HIF-1α occurred in a phosphorylation-dependent manner. We also found that PIN1 interacted with HIF-1α at both exogenous and endogenous levels. Notably, PIN1 binding stabilized the HIF-1α protein, given that their levels were significantly increased under hypoxic conditions. The stabilization of HIF-1α resulted in increased transcriptional activity, consequently upregulating expression of vascular endothelial growth factor, a major contributor to angiogenesis. Silencing of PIN1 or pharmacologic inhibition of its activity abrogated the angiogenesis. By utilizing a bioluminescence imaging technique, we were able to demonstrate that PIN1 inhibition dramatically reduced the tumor volume in a subcutaneous mouse xenograft model and angiogenesis as well as hypoxia-induced transcriptional activity of HIF-1α. These results suggest that PIN1 interacting with HIF-1α is a potential cancer chemopreventive and therapeutic target. PMID:26784107

Cardiovascular responses during orthostasis - Effect of an increase in maximal O2 uptake

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Montgomery, L. D.; Greenleaf, J. E.

1984-01-01

A study is described which tests the hypothesis that changes in aerobic activity (increases in maximum oxygen uptake) will reduce the effectiveness of cardiovascular reflexes to regulate blood pressure during orthostasis. The hypothesis was tested by measuring heart rate, blood pressure and blood volume responses in eight healthy male subjects before and after an eight-day endurance regimen. The results of the study suggest that the physiologic responses to orthostasis are dependent upon the rate of plasma volume loss and pooling, and are associated with training-induced hypervolemia. It is indicated that endurance type exercise training enhances cardiovascular adjustments during tilt. The implications of these results for the use of exercise training as a countermeasure and/or therapeutic method for the prevention of cardiovascular instability during orthostatic stress are discussed.

Role of cardiac volume receptors in the control of ADH release during acute simulated weightlessness in man

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Benjamin, B. A.; Keil, L. C.; Sandler, H.

1984-01-01

Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes, designed to induce central blood volume shifts in ten cardiac and one heart-lung transplant recipients, to assess the contribution of cardiac volume receptors in the control of ADH release during the initial acute phase of exposure to weightlessness. Each subject underwent 15 min of a sitting-control period (C) followed by 30 min of 6 deg headdown tilt (T) and 30 min of resumed sitting (S). Venous blood samples and cardiac dimensions were taken at 0 and 15 min of C; 5, 15, and 30 min of T; and 5, 15, and 30 min of S. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Heart rate and blood pressure were recorded every two min. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 ml in C to 106 ml in T and returned to 87 ml in S. Plasma ADH was reduced by 20 percent (P less than 0.05) with T, and returned to control levels with S. These responses were similar in six normal cardiac-innervated control subjects. These data may suggest that cardiac volume receptors are not the primary mechanism for the control of ADH release during acute central volume shifts in man.

Cardioprotection activity and mechanism of Astragalus polysaccharide in vivo and in vitro.

PubMed

Liu, Debin; Chen, Lei; Zhao, Jianye; Cui, Kang

2018-05-01

Astragalus polysaccharides (ASP) is extracted from Astragalus, and is the main active ingredient of Astragalus membranaceus. The purpose of this study was to investigate the protective effect of ASP on rat cardiomyocytes damage induced by myocardial ischemia and reperfusion injury (MVRI) and isoprenaline(ISO) in vivo and in vitro. The model of cardiomyocytes damage was induced using MVRI in a rat in vivo and also using ISO in cell. After ASP intervention, the protective effect of ASP on cardiomyocytes was evaluated by animal experimental and cell experimental. The results show that ASP can relieve the increase of cell volume in myocardium, reduce the apoptosis of cell in myocardial tissue caused by MVRI in vivo. At the cellular level, ASP can reverse the decrease of cell activity induced by ISO, inhibit the apoptosis, and decrease the levels of intracellular reactive oxygen species. Mechanistically at the molecular level, these effects are elicited via down-regulation of the protein levels of caspase-3 and bax and up-regulation of the protein levels of bcl-2 in both in vivo and in vitro. These results demonstrate that ASP has a protective efficacy in MVRI/ISO-treated cardiomyocytes by inhibiting the apoptosis. Copyright © 2018 Elsevier B.V. All rights reserved.

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

PubMed Central

Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

2015-01-01

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells. PMID:26396176

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

PubMed

Feys, Lynn; Descamps, Benedicte; Vanhove, Christian; Vral, Anne; Veldeman, Liv; Vermeulen, Stefan; De Wagter, Carlos; Bracke, Marc; De Wever, Olivier

2015-09-29

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

Axl acts as a tumor suppressor by regulating LIGHT expression in T lymphoma

PubMed Central

Young, Kon-Ji; Park, A-Reum; Choi, Ha-Rim; Lee, Hwa-Youn; Kim, Su-Man; Chung, Byung Yeoup; Park, Chul-Hong; Choi, Hyo Jin; Ko, Young-Hyeh; Bai, Hyoung-Woo; Kang, Hyung-Sik

2017-01-01

Axl is an oncogenic receptor tyrosine kinase that plays a role in many cancers. LIGHT (Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is a ligand that induces robust anti-tumor immunity by enhancing the recruitment and activation of effector immune cells at tumor sites. We observed that mouse EL4 and human Jurkat T lymphoma cells that stably overexpressed Axl also showed high expression of LIGHT. When Jurkat-Axl cells were treated with Gas6, a ligand for Axl, LIGHT expression was upregulated through activation of the PI3K/AKT signaling pathway and transcriptional induction by Sp1. The lytic activity of cytotoxic T lymphocytes and natural killer cells was enhanced by EL4-Axl cells. In addition, tumor volume and growth were markedly reduced due to enhanced apoptotic cell death in EL4-Axl tumor-bearing mice as compared to control mice. We also observed upregulated expression of CCL5 and its receptor, CCR5, and enhanced intratumoral infiltration of cytotoxic T lymphocytes and natural killer cells in EL4-Axl-bearing mice as compared to mock controls. These data strongly suggested that Axl exerts novel tumor suppressor effects by inducing upregulation of LIGHT in the tumor microenvironment of T lymphoma. PMID:28423548

Axl acts as a tumor suppressor by regulating LIGHT expression in T lymphoma.

PubMed

Lee, Eun-Hee; Kim, Eun-Mi; Ji, Kon-Young; Park, A-Reum; Choi, Ha-Rim; Lee, Hwa-Youn; Kim, Su-Man; Chung, Byung Yeoup; Park, Chul-Hong; Choi, Hyo Jin; Ko, Young-Hyeh; Bai, Hyoung-Woo; Kang, Hyung-Sik

2017-03-28

Axl is an oncogenic receptor tyrosine kinase that plays a role in many cancers. LIGHT (Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is a ligand that induces robust anti-tumor immunity by enhancing the recruitment and activation of effector immune cells at tumor sites. We observed that mouse EL4 and human Jurkat T lymphoma cells that stably overexpressed Axl also showed high expression of LIGHT. When Jurkat-Axl cells were treated with Gas6, a ligand for Axl, LIGHT expression was upregulated through activation of the PI3K/AKT signaling pathway and transcriptional induction by Sp1. The lytic activity of cytotoxic T lymphocytes and natural killer cells was enhanced by EL4-Axl cells. In addition, tumor volume and growth were markedly reduced due to enhanced apoptotic cell death in EL4-Axl tumor-bearing mice as compared to control mice. We also observed upregulated expression of CCL5 and its receptor, CCR5, and enhanced intratumoral infiltration of cytotoxic T lymphocytes and natural killer cells in EL4-Axl-bearing mice as compared to mock controls. These data strongly suggested that Axl exerts novel tumor suppressor effects by inducing upregulation of LIGHT in the tumor microenvironment of T lymphoma.

An experimental study on the impacts of inspiratory and expiratory muscles activities during mechanical ventilation in ARDS animal model

PubMed Central

Zhang, Xianming; Du, Juan; Wu, Weiliang; Zhu, Yongcheng; Jiang, Ying; Chen, Rongchang

2017-01-01

In spite of intensive investigations, the role of spontaneous breathing (SB) activity in ARDS has not been well defined yet and little has been known about the different contribution of inspiratory or expiratory muscles activities during mechanical ventilation in patients with ARDS. In present study, oleic acid-induced beagle dogs’ ARDS models were employed and ventilated with the same level of mean airway pressure. Respiratory mechanics, lung volume, gas exchange and inflammatory cytokines were measured during mechanical ventilation, and lung injury was determined histologically. As a result, for the comparable ventilator setting, preserved inspiratory muscles activity groups resulted in higher end-expiratory lung volume (EELV) and oxygenation index. In addition, less lung damage scores and lower levels of system inflammatory cytokines were revealed after 8 h of ventilation. In comparison, preserved expiratory muscles activity groups resulted in lower EELV and oxygenation index. Moreover, higher lung injury scores and inflammatory cytokines levels were observed after 8 h of ventilation. Our findings suggest that the activity of inspiratory muscles has beneficial effects, whereas that of expiratory muscles exerts adverse effects during mechanical ventilation in ARDS animal model. Therefore, for mechanically ventilated patients with ARDS, the demands for deep sedation or paralysis might be replaced by the strategy of expiratory muscles paralysis through epidural anesthesia. PMID:28230150

A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability.

PubMed

Royes, Luiz Fernando Freire; Gabbi, Patrícia; Ribeiro, Leandro Rodrigo; Della-Pace, Iuri Domingues; Rodrigues, Fernanda Silva; de Oliveira Ferreira, Ana Paula; da Silveira Junior, Mauro Eduardo Porto; da Silva, Luís Roberto Hart; Grisólia, Alan Barroso Araújo; Braga, Danielle Valente; Dobrachinski, Fernando; da Silva, Anderson Manoel Herculano Oliveira; Soares, Félix Alexandre Antunes; Marchesan, Sara; Furian, Ana Flavia; Oliveira, Mauro Schneider; Fighera, Michele Rechia

2016-06-01

Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH4Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 µmol/2 µL, i.c.v.) were observed in mice. After, ammonia, TNF-α, IL1β, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (ΔΨ), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na(+), K(+)-ATPase activity levels were measured in the cerebral cortex. The binding of [(3)H]flunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage [opening of blood brain barrier (BBB) permeability and cellular death volume] were also measured. EEG recordings showed that an intermediate dose of NH4Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 μmol/2 μL i.c.v). NH4Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na(+), K(+)-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [(3)H]flunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate (GABA) cycle and contribute to MMA-induced excitability.

Zone-specific cell biosynthetic activity in mature bovine articular cartilage: a new method using confocal microscopic stereology and quantitative autoradiography.

PubMed

Wong, M; Wuethrich, P; Eggli, P; Hunziker, E

1996-05-01

A new methodology was developed to measure spatial variations in chondrocyte/matrix structural parameters and chondrocyte biosynthetic activity in articular cartilage. This technique is based on the use of a laser scanning confocal microscope that can "optically" section chemically fixed, unembedded tissue. The confocal images are used for morphometric measurement of stereologic parameters such as cell density (cells/mm3), cell volume fraction (%), surface density (l/cm), mean cell volume (micron3), and mean cell surface area (micron2). Adjacent pieces of tissue are simultaneously processed for conventional liquid emulsion autoradiography, and a semiautomated grain counting program is used to measure the silver grain density at regions corresponding to the same sites used for structural measurements. An estimate of chondrocyte biosynthetic activity in terms of grains per cell is obtained by dividing the value for grain density by that for cell density. In this paper, the newly developed methodology was applied to characterize the zone-specific behavior of adult articular cartilage in the free-swelling state. Cylinders of young adult bovine articular cartilage were labelled with either [3H]proline or [35S]sulfate, and chondrocyte biosynthesis and structural parameters were measured from the articular surface to the tidemark. The results showed that chondrocytes of the radial zone occupied twice the volume and surface area of the chondrocytes of the superficial zone but were 10 times more synthetically active. This efficient and unbiased technique may prove useful in studying the correlation between mechanically induced changes in cell form and biosynthetic activity within inhomogeneous tissue as well as metabolic changes in cartilage due to ageing and disease.

Regulating the Membrane Transport Activity and Death of Cells via Electroosmotic Manipulation.

PubMed

Hui, Tsz Hin; Kwan, Kin Wah; Chun Yip, Timothy Tak; Fong, Hong Wai; Ngan, Kai Cheong; Yu, Miao; Yao, Shuhuai; Wan Ngan, Alfonso Hin; Lin, Yuan

2016-06-21

Although the volume of living cells has been known to heavily influence their behavior and fate, a method allowing us to control the cell size in a programmable manner is still lacking. Here, we develop a technique in which precise changes in the cellular volume can be conveniently introduced by varying the voltage applied across a Nafion membrane that separates the culture medium from a reservoir. It is found that, unlike sudden osmotic shocks, active ion transport across the membrane of leukemia K562 cells will not be triggered by a gradual change in the extracellular osmolarity. Furthermore, when subjected to the same applied voltage, different lung and nasopharyngeal epithelial cancer cells will undergo larger volumetric changes and have a 5-10% higher death rate compared to their normal counterparts. We show that such distinct response is largely caused by the overexpression of aquaporin-4 in tumor cells, with knockout of this water channel protein resulting in a markedly reduced change in the cellular volume. Finally, by taking into account the exchange of water/ion molecules across the Nafion film and the cell membrane, a theoretical model is also proposed to describe the voltage-induced size changes of cells, which explain our experimental observations very well. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Effects of pinealectomy and melatonin supplementation on endometrial explants in a rat model.

PubMed

Koc, Onder; Gunduz, Bülent; Topcuoglu, Ata; Bugdayci, Güler; Yilmaz, Fahri; Duran, Bülent

2010-11-01

To determine the effects of pinealectomy on endometrial explants in rats and evaluate the activity of superoxide dismutase (SOD) and catalase (CAT) and the levels of malondialdehyde (MDA) in the rat endometriosis model. Rats with experimentally induced endometriosis were randomly divided into three groups after second-look laparotomies. Group 1 (pinealectomy, n = 8) and Group 2 (pinealectomy+melatonin, n = 8) underwent pinealectomies after the second-look laparotomies. Group 3 was presented as control group (vehicle solution+without pinealectomy (n = 6)). Melatonin was administered intraperitoneally for 4 weeks in Group 2, whereas an equal volume of vehicle solution was given to Groups 1 and 3. Evaluation of the volume of the endometrial explants, histopathological examination and preservation of explant epitheliums according to the scoring system were undertaken. There was a statistically significant increase in spherical explant volumes of Group 1 compared to Groups 2 and 3. In Group 1, the level of MDA was significantly higher and SOD and CAT activity was significantly lower compared to Groups 2 and 3. A statistically significant increase in the epithelial lining scores of explants was noted in Group 1 compared to Groups 2 and 3. The effects of pinealectomy on the progression of endometriosis explants were reversed by melatonin. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice.

PubMed

Wang, Shiquan; Wei, Haidong; Cai, Min; Lu, Yan; Hou, Wugang; Yang, Qianzi; Dong, Hailong; Xiong, Lize

2014-01-01

Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.

Arachidonic Acid Metabolism in the Nervous System; Physiological and Pathological Significance. Annals of the New York Academy of Science. Volume 5

DTIC Science & Technology

1989-01-01

CEREBRAL INJURY 351 23. YOUNG, W. 1980. H2 clearance measurement of blood flow: A review of technique andpolarographic principles. Stroke 11: 552-564.24...Gerbil Brain: Inhibition of Ischemia-Reperfusion-Induced Cerebral Injury by a Platelet-Activating Factor Antagonist (BN 52021). By THOMAS PANETTA, VICTOR L...and in the complex pathophysiology of cerebral ischemia, stroke , and brain trauma has been a subject of increasing interest. These problems are of

Spectroscopic Constants for Selected Homonuclear Diatomic Molecules. Volume 2. K through Z

DTIC Science & Technology

1976-02-16

in Active Nitrogen, Part 1. - Mercury Hg(63P1)," J. Chem. Soc. Faraday Trans, II 68, 2023-30 R. S. Hickman and L. Liang, "Comment...and G. M. Skardis, "Quenching of Mercury -Sensitized Fluorescence in Sodium induced in Collisions With N2 Molecules, " Can. J. Phys. 51...34 Nature 210, 1034-5 (67. 87) N. Basco and A. E. Pearson, "Reactions of Sulphur Atoms in Presence of Carbon Disulphide, Carbonyl Sulphide and

[The effect of tachykinins microinjections into the solitary tract nucleus on respiration and blood circulation in rats].

PubMed

Chepurnov, S A; Iniushkin, A N

1997-04-01

Administration of substance P and kassinin into the solitary tract nucleus of anesthetized rats induced a dose-dependent increase in ventilation, tidal volume, inspiratory muscle activity, and a decrease in the mean blood pressure and heart rate. Microinjections of peptides caused a decrease in ventilatory response to hypoxia and an inhibition of the Breuer-Hering reflex. The data obtained suggest involvement of tachykinins in the respiratory and circulatory control via the solitary tract nucleus.

Membrane hydraulic permeability changes during cooling of mammalian cells.

PubMed

Akhoondi, Maryam; Oldenhof, Harriëtte; Stoll, Christoph; Sieme, Harald; Wolkers, Willem F

2011-03-01

In order to predict optimal cooling rates for cryopreservation of cells, the cell-specific membrane hydraulic permeability and corresponding activation energy for water transport need to be experimentally determined. These parameters should preferably be determined at subzero temperatures in the presence of ice. There is, however, a lack of methods to study membrane properties of cells in the presence of ice. We have used Fourier transform infrared spectroscopy to study freezing-induced membrane dehydration of mouse embryonic fibroblast (3T3) cells and derived the subzero membrane hydraulic permeability and the activation energy for water transport from these data. Coulter counter measurements were used to determine the suprazero membrane hydraulic permeability parameters from cellular volume changes of cells exposed to osmotic stress. The activation energy for water transport in the ice phase is about three fold greater compared to that at suprazero temperatures. The membrane hydraulic permeability at 0 °C that was extrapolated from suprazero measurements is about five fold greater compared to that extrapolated from subzero measurements. This difference is likely due to a freezing-induced dehydration of the bound water around the phospholipid head groups. Using Fourier transform infrared spectroscopy, two distinct water transport processes, that of free and membrane bound water, can be identified during freezing with distinct activation energies. Dimethylsulfoxide, a widely used cryoprotective agent, did not prevent freezing-induced membrane dehydration but decreased the activation energy for water transport. Copyright © 2010 Elsevier B.V. All rights reserved.

HLA-DR allele reading register shifting is associated with immunity induced by SERA peptide analogues.

PubMed

Salazar, Luz Mary; Bermúdez, Adriana; Patarroyo, Manuel E

2008-07-18

SERA protein is a leading candidate molecule to be included in an antimalarial vaccine. Conserved high activity binding peptides (HABP) binding to red blood cells (RBC) have been identified in this protein. One of them (6762) localising in the 18-kDa C-terminal fragment was used to induce protective immunity with negative result. Critical RBC binding residues (assessed by glycine-analogue scanning) were replaced by others having the same mass, volume and surface but different polarity, rendering some of them immunogenic as assessed by antibody production against the parasite or its proteins and protection-inducing against challenge with a highly infectious Aotus monkey-adapted Plasmodium falciparum strain. A shift in binding to purified HLA-DR allelic molecules from the same haplotype and in their reading register was found, suggesting that modified molecules had adopted a different (1)H NMR 3D structure allowing a better fit into the MHCII-pept-TCR complex, thereby representing a new mechanism for inducing immune protection.

Antidiarrhoeal activity of Psidium guajava Linn. (Myrtaceae) leaf aqueous extract in rodents.

PubMed

Ojewole, John A O; Awe, Emmanuel O; Chiwororo, Witness D H

2008-12-01

The leaf of Psidium guajava Linn. (family: Myrtaceae) is used traditionally in African folk medicine to manage, control and/or treat a plethora of human ailments, including diarrhoea. In this study, we examined the antidiarrhoeal activity of Psidium guajava leaf aqueous extract (PGE) on experimentally-induced diarrhoea in rodents. PGE (50-400 mg/kg p.o.) produced dose-dependent and significant (P<0.05-0.01) protection of rats and mice against castor oil-induced diarrhoea, inhibited intestinal transit, and delayed gastric emptying. Like atropine (1 mg/kg, p.o.), PGE produced dose-dependent and significant (P<0.05-0.01) antimotility effect, and caused dose-related inhibition of castor oil-induced enteropooling in the animals. Like loperamide (10 mg/kg, p.o.), PGE dose-dependently and significantly (P<0.05-0.01) delayed the onset of castor oil-induced diarrhoea, decreased the frequency of defaecation, and reduced the severity of diarrhoea in the rodents. Compared with control animals, PGE dose-dependently and significantly (P<0.05-0.01) decreased the volume of castor oil-induced intestinal fluid secretion, and reduced the number, weight and wetness of faecal droppings. PGE also produced concentration-related and significant (P<0.05-0.01) inhibitions of the spontaneous, rhythmic, pendular contractions of the rabbit isolated duodenum. The findings of this study indicate that PGE possesses antidiarrhoeal activity, and thus lend pharmacological credence to the suggested folkloric use of the plant as a natural remedy for the treatment, management and/or control of diarrhoea in some rural communities of southern Africa.

Physalis angulata induces death of promastigotes and amastigotes of Leishmania (Leishmania) amazonensis via the generation of reactive oxygen species.

PubMed

Da Silva, B J M; Da Silva, R R P; Rodrigues, A P D; Farias, L H S; Do Nascimento, J L M; Silva, E O

2016-03-01

Leishmaniasis are a neglected group of emerging diseases that have been found in 98 countries and are caused by protozoa of the genus Leishmania. The therapy for leishmaniasis causes several side effects and leads to drug-resistant strains. Natural products from plants have exhibited activities against Leishmania in various experimental models. Physalis angulata is a widely used plant in popular medicine, and in the literature it has well-documented leishmanicidal activity. However, its mechanism of action is still unknown. Thus, this study aims to evaluate the mechanism driving the leishmanicidal activity of an aqueous extract of P. angulata root (AEPa). AEPa was effective against both promastigotes and intracellular amastigote forms of Leishmania amazonensis. This effect was mediated by an increase of reactive oxygen species (ROS), but not of nitric oxide (NO). The increased production of ROS induces cell death by phenotypes seems by apoptosis cell death in Leishmania, but not autophagy or necrosis. In addition, morphological analysis of macrophages showed that AEPa induced a high number of cytoplasmic projections, increased the volume of cytoplasm and number of vacuoles, caused cytoskeleton alterations and resulted in high spreading ability. AEPa also promoted superoxide anion (O2(-)) production in both uninfected macrophages and those infected with Leishmania. Therefore, these results revealed that AEPa causes cell death by phenotypes seems by apoptosis cell death in L. amazonensis and modulates macrophage activation through morphofunctional alterations and O2(-) generation to induce Leishmania death. Copyright © 2015 Elsevier Ltd. All rights reserved.

I-131 Radiation-Induced Myelosuppression in Differentiated Thyroid Cancer Therapy.

PubMed

Probst, Stephan; Abikhzer, Gad; Chaussé, Guillaume; Tamilia, Michael

2018-06-07

Radioactive iodine (RAI) treatment of differentiated thyroid cancer has been used in clinical practice for almost 60 years and is generally accepted to be a safe and efficacious treatment. Severe toxicity in the form of radiation pneumonitis, sometimes progressing to fibrosis, and bone marrow suppression are reported but remain rare. We present a case of severe myelosuppression requiring hospitalization and transfusion support in an otherwise well, young female patient who had received 175 mCi I-131 for low-volume micronodular lung disease one month prior, with a cumulative lifetime administered activity of 575 mCi. The most important risk factors for myelosuppression following RAI are the activity received, the amount of functioning thyroid tissue present, and the lifetime cumulative activity received.

Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model

PubMed Central

Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra; Toque, Haroldo A.; Cain, Michael; Wong, Abby; Howie, Nicole; Shinde, Rahul; Elsalanty, Mohammed; Yao, Lin; Chutkan, Norman; Hunter, Monty; Caldwell, Ruth B.; Isales, Carlos; Caldwell, R. William; Fulzele, Sadanand

2016-01-01

A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of L-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of L-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases. PMID:26704078

RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway

PubMed Central

Gu, Anxin; Jie, Yamin; Sun, Liang; Zhao, Shuping; E, Mingyan; You, Qingshan

2015-01-01

Radiation-induced heart disease (RIHD), which is a serious side effect of the radiotherapy applied for various tumors due to the inevitable irradiation of the heart, cannot be treated effectively using current clinical therapies. Here, we demonstrated that rhNRG-1β, an epidermal growth factor (EGF)-like protein, protects myocardium tissue against irradiation-induced damage and preserves cardiac function. rhNRG-1β effectively ameliorated irradiation-induced myocardial nuclear damage in both cultured adult rat-derived cardiomyocytes and rat myocardium tissue via NRG/ErbB2 signaling. By activating ErbB2, rhNRG-1β maintained mitochondrial integrity, ATP production, respiratory chain function and the Krebs cycle status in irradiated cardiomyocytes. Moreover, the protection of irradiated cardiomyocytes and myocardium tissue by rhNRG-1β was at least partly mediated by the activation of the ErbB2-ERK-SIRT1 signaling pathway. Long-term observations further showed that rhNRG-1β administered in the peri-irradiation period exerts continuous protective effects on cardiac pump function, the myocardial energy metabolism, cardiomyocyte volume and interstitial fibrosis in the rats receiving radiation via NRG/ErbB2 signaling. Our findings indicate that rhNRG-1β can protect the myocardium against irradiation-induced damage and preserve cardiac function via the ErbB2-ERK-SIRT1 signaling pathway. PMID:26332771

Hepatoprotective effects of the polysaccharide isolated from Tarphochlamys affinis (Acanthaceae) against CCl4-induced hepatic injury.

PubMed

Lin, Xing; Liu, Xi; Huang, Quanfang; Zhang, Shijun; Zheng, Li; Wei, Ling; He, Min; Jiao, Yang; Huang, Jianchun; Fu, Shujie; Chen, Zhaoni; Li, Yongwen; Zhuo, Lang; Huang, Renbin

2012-01-01

This study was designed to investigate the protective effects of the polysaccharide isolated from Tarphochlamys affinis (PTA) against CCl4-induced hepatotoxicity in rats. Liver injury was induced in rats by the administration of CCl4 twice a week for 2 weeks. During the experiment, the model group received CCl4 only; the treatment groups received various drugs plus CCl4, whereas the normal control group received an equal volume of saline. Compared with the CCl4 group, PTA significantly decreased the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in the serum and increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) in the liver. Moreover, the content of hepatic malondialdehyde (MDA) was reduced. Histological findings also confirmed the anti-hepatotoxic characterisation. In addition, PTA significantly inhibited the proinflammatory mediators, such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and myeloperoxidase (MPO). Further investigation showed that the inhibitory effect of PTA on the pro-inflammatory cytokines was associated with the down-regulation of nuclear factor-kappa B (NF-κB). In brief, our results show that the protective effect of PTA against CCl4-induced hepatic injury may rely on its ability to reduce oxidative stress and suppress inflammatory responses.

Orally administered lycopene attenuates diethylnitrosamine-induced hepatocarcinogenesis in rats by modulating Nrf-2/HO-1 and Akt/mTOR pathways.

PubMed

Sahin, Kazim; Orhan, Cemal; Tuzcu, Mehmet; Sahin, Nurhan; Ali, Shakir; Bahcecioglu, Ibrahim H; Guler, Osman; Ozercan, Ibrahim; Ilhan, Necip; Kucuk, Omer

2014-01-01

Hepatocarcinogenesis is one of the most prevalent and lethal cancers. We studied the mechanisms underlying the inhibition of diethylnitrosamine (DEN)-induced hepatocarcinogenesis by lycopene in rats. Hepatocarcinogenesis was induced by an intraperitoneal injection of DEN followed by promotion with phenobarbital for 24 successive wk. The rats were given lycopene (20 mg/kg body weight) 3 times a week orally for 4 wk prior to initiation, and the treatment was continued for 24 consecutive wk. Lycopene reduced incidence, number, size, and volume of hepatic nodules. Serum alanine transaminase, aspartate aminotransferase, total bilirubin, and malondialdehyde (MDA) considerably increased and hepatic antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) and glutathione decreased in DEN-treated rats when compared with the control group. Lycopene significantly reversed these biochemical changes and increased the expression of NF-E-2-related factor-2)/heme oxygenase-1, and it decreased NF-κB/cyclooxygenase-2, inhibiting the inflammatory cascade and activating antioxidant signaling (P < 0.05). Lycopene also decreased DEN-induced increases in phosphorylated mammalian target of rapamycin (p-mTOR), phosphorylated p70 ribosomal protein S6 kinase 1, phosphorylated 4E-binding protein 1, and protein kinase B (P < 0.05). Lycopene is an active chemopreventive agent that offers protection against DEN-induced hepatocarcinogenesis by inhibiting NF-κB and mTOR pathways.

Herpes zoster chronification to postherpetic neuralgia induces brain activity and grey matter volume change

PubMed Central

Cao, Song; Qin, Bangyong; Zhang, Yi; Yuan, Jie; Fu, Bao; Xie, Peng; Song, Ganjun; Li, Ying; Yu, Tian

2018-01-01

Objective: Herpes zoster (HZ) can develop into postherpetic neuralgia (PHN), which is a chronic neuropathic pain (NP). Whether the chronification from HZ to PHN induced brain functional or structural change is unknown and no study compared the changes of the same brains of patients who transited from HZ to PHN. We minimized individual differences and observed whether the chronification of HZ to PHN induces functional and pain duration dependent grey matter volume (GMV) change in HZ-PHN patients. Methods: To minimize individual differences induced error, we enrolled 12 patients with a transition from HZ to PHN. The functional and structural changes of their brains between the two states were identified with resting-state functional MRI (rs-fMRI) technique (i.e., the regional homogeneity (ReHo) and fractional aptitude of low-frequency fluctuation (fALFF) method) and the voxel based morphometry (VBM) technology respectively. The correlations between MRI parameters (i.e., ΔReHo, ΔfALFF and ΔVBM) and Δpain duration were analyzed too. Results: Compared with HZ brains, PHN brains exhibited abnormal ReHo, fALFF and VBM values in pain matrix (the frontal lobe, parietal lobe, thalamus, limbic lobe and cerebellum) as well as the occipital lobe and temporal lobe. Nevertheless, the activity of vast area of cerebellum and frontal lobe significantly increased while that of occipital lobe and limbic lobe showed apparent decrease when HZ developed to PHN. In addition, PHN brain showed decreased GMV in the frontal lobe, the parietal lobe and the occipital lobe but increased in the cerebellum and the temporal lobe. Correlation analyses showed that some of the ReHo, fALFF and VBM differential areas (such as the cerebellum posterior lobe, the thalamus extra-nuclear and the middle temporal gyrus) correlated well with Δpain duration. Conclusions: HZ chronification induced functional and structural change in cerebellum, occipital lobe, temporal lobe, parietal lobe and limbic lobe. These changes may be correlated with HZ-PHN chronification. In addition, these changes could be reasons of refractory chronic pain of PHN. PMID:29423004

Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway.

PubMed

Li, Hongzhong; Huang, Jing; Yang, Bing; Xiang, Tingxiu; Yin, Xuedong; Peng, Weiyan; Cheng, Wei; Wan, Jingyuan; Luo, Fuling; Li, Hongyuan; Ren, Guosheng

2013-10-01

Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelial-mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of β-catenin pathway. Subsequent experiments showed that inhibiting β-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active β-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

Induced seismicity provides insight into why earthquake ruptures stop.

PubMed

Galis, Martin; Ampuero, Jean Paul; Mai, P Martin; Cappa, Frédéric

2017-12-01

Injection-induced earthquakes pose a serious seismic hazard but also offer an opportunity to gain insight into earthquake physics. Currently used models relating the maximum magnitude of injection-induced earthquakes to injection parameters do not incorporate rupture physics. We develop theoretical estimates, validated by simulations, of the size of ruptures induced by localized pore-pressure perturbations and propagating on prestressed faults. Our model accounts for ruptures growing beyond the perturbed area and distinguishes self-arrested from runaway ruptures. We develop a theoretical scaling relation between the largest magnitude of self-arrested earthquakes and the injected volume and find it consistent with observed maximum magnitudes of injection-induced earthquakes over a broad range of injected volumes, suggesting that, although runaway ruptures are possible, most injection-induced events so far have been self-arrested ruptures.

Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Chen-Ming; Wang, Shih-Wei; Lee, Tzong-Huei

2013-10-15

Chondrosarcoma is the second most common primary bone tumor, and it responds poorly to both chemotherapy and radiation treatment. Nalanthamala psidii was described originally as Myxosporium in 1926. This is the first study to investigate the anti-tumor activity of trichodermin (trichothec-9-en-4-ol, 12,13-epoxy-, acetate), an endophytic fungal metabolite from N. psidii against human chondrosarcoma cells. We demonstrated that trichodermin induced cell apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 cells) instead of primary chondrocytes. In addition, trichodermin triggered endoplasmic reticulum (ER) stress protein levels of IRE1, p-PERK, GRP78, and GRP94, which were characterized by changes in cytosolic calcium levels. Furthermore,more » trichodermin induced the upregulation of Bax and Bid, the downregulation of Bcl-2, and the dysfunction of mitochondria, which released cytochrome c and activated caspase-3 in human chondrosarcoma. In addition, animal experiments illustrated reduced tumor volume, which led to an increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and an increased level of cleaved PARP protein following trichodermin treatment. Together, this study demonstrates that trichodermin is a novel anti-tumor agent against human chondrosarcoma cells both in vitro and in vivo via mitochondrial dysfunction and ER stress. - Highlights: • Trichodermin induces chondrosarcoma apoptosis. • ER stress is involved in trichodermin-induced cell death. • Trichodermin induces chondrosarcoma death in vivo.« less

Real-time detection of antibiotic activity by measuring nanometer-scale bacterial deformation.

PubMed

Iriya, Rafael; Syal, Karan; Jing, Wenwen; Mo, Manni; Yu, Hui; Haydel, Shelley E; Wang, Shaopeng; Tao, Nongjian

2017-12-01

Diagnosing antibiotic-resistant bacteria currently requires sensitive detection of phenotypic changes associated with antibiotic action on bacteria. Here, we present an optical imaging-based approach to quantify bacterial membrane deformation as a phenotypic feature in real-time with a nanometer scale (∼9  nm) detection limit. Using this approach, we found two types of antibiotic-induced membrane deformations in different bacterial strains: polymyxin B induced relatively uniform spatial deformation of Escherichia coli O157:H7 cells leading to change in cellular volume and ampicillin-induced localized spatial deformation leading to the formation of bulges or protrusions on uropathogenic E. coli CFT073 cells. We anticipate that the approach will contribute to understanding of antibiotic phenotypic effects on bacteria with a potential for applications in rapid antibiotic susceptibility testing. (2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

PubMed

Su, Chen-Ming; Chen, Chien-Yu; Lu, Tingting; Sun, Yi; Li, Weimin; Huang, Yuan-Li; Tsai, Chun-Hao; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-12-13

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo.

Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells

PubMed Central

SHI, WEI; DENG, JIAGANG; TONG, RONGSHENG; YANG, YONG; HE, XIA; LV, JIANZHEN; WANG, HAILIAN; DENG, SHAOPING; QI, PING; ZHANG, DINGDING; WANG, YI

2016-01-01

Mangiferin, which is a C-glucosylxanthone (1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside) purified from plant sources, has recently gained attention due to its various biological activities. The present study aimed to determine the apoptotic effects of mangiferin on A549 human lung adenocarcinoma cells. In vitro studies demonstrated that mangiferin exerted growth-inhibitory and apoptosis-inducing effects against A549 cells. In addition, mangiferin exhibited anti-tumor properties in A549 xenograft mice in vivo. Mangiferin triggered G2/M phase cell cycle arrest via down-regulating the cyclin-dependent kinase 1-cyclin B1 signaling pathway, and induced apoptotic cell death by inhibiting the protein kinase C-nuclear factor-κB pathway. In addition, mangiferin was able to enhance the antiproliferative effects of cisplatin on A549 cells, thus indicating the potential for a combined therapy. Notably, mangiferin exerted anticancer effects in vivo, where it was able to markedly decrease the volume and weight of subcutaneous tumor mass, and expand the lifespan of xenograft mice. The present study clarified the molecular mechanisms underlying mangiferin-induced antitumor activities, and suggested that mangiferin may be considered a potential antineoplastic drug for the future treatment of cancer. PMID:26935347

The leaves of Diospyros kaki exert beneficial effects on a benzalkonium chloride-induced murine dry eye model.

PubMed

Kim, Kyung-A; Hyun, Lee Chung; Jung, Sang Hoon; Yang, Sung Jae

2016-01-01

In this study, the beneficial effects of the oral administration of ethanol extract of Diospyros kaki (EEDK) were tested on a mouse dry eye model induced by benzalkonium chloride (BAC). A solution of 0.2% BAC was administered topically to mouse eyes for 14 days, twice daily, to induce dry eye. Various concentrations of EEDK were administrated daily by oral gavage for 14 days after BAC treatment. Preservative-free eye drops were instilled in the positive-control group. The tear secretion volume (Schirmer's test), tear break-up time (BUT), and fluorescein score were measured on the ocular surface. BAC-induced corneal damage was tested with hematoxylin-eosin staining. Moreover, apoptotic cell death in the corneal epithelial layer was investigated with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The protein expression level of interleukin-1alpha (IL-1α), IL-1β, IL-6, tumor necrosis factor- alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1) was determined with western blot analysis. Furthermore, squamous metaplasia in the corneal epithelial layer was detected with immunofluorescent staining for cytokeratine-10. The cellular proliferation in the cornea was examined with immunohistochemical staining for Ki-67. EEDK treatment resulted in prolonged BUT, decreased fluorescein score, increased tear volume, and smoother epithelial cells compared with BAC treatment alone in the cornea. Moreover, EEDK treatment inhibited the inflammatory response and corneal epithelial cell death in a BAC-induced murine dry eye model, and changes in squamous cells were inhibited. Proliferative activity in the corneal epithelium cells was improved with EEDK. EEDK could be a potential therapeutic agent in the clinical treatment of dry eye.

Therapeutic effects of topical doxycycline in a benzalkonium chloride-induced mouse dry eye model.

PubMed

Zhang, Zhen; Yang, Wen-Zhao; Zhu, Zhen-Zhen; Hu, Qian-Qian; Chen, Yan-Feng; He, Hui; Chen, Yong-Xiong; Liu, Zu-Guo

2014-05-06

We investigated the therapeutic effects and underlying mechanisms of topical doxycycline in a benzalkonium chloride (BAC)-induced mouse dry eye model. Eye drops containing 0.025%, 0.1% doxycycline or solvent were administered to a BAC-induced dry eye model four times daily. The clinical evaluations, including tear break-up time (BUT), fluorescein staining, inflammatory index, and tear volume, were performed on days 0, 1, 4, 7, and 10. Global specimens were collected on day 10 and processed for immunofluorescent staining, TUNEL, and periodic acid-Schiff assay. The levels of inflammatory mediators in the corneas were determined by real-time PCR. The total and phosphorylated nuclear factor-κB (NF-κB) were detected by Western blot. Both 0.025% and 0.1% doxycycline treatments resulted in increased BUT, lower fluorescein staining scores, and inflammatory index on days 4, 7, and 10, while no significant change in tear volume was observed. The 0.1% doxycycline-treated group showed more improvements in decreasing fluorescein staining scores, increasing Ki-67-positive cells, and decreasing TUNEL- and keratin-10-positive cells than other groups. The mucin-filled goblet cells in conjunctivas were increased, and the expression of CD11b and levels of matrix metalloproteinase-9, IL-1β, IL-6, TNF-α, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant in corneas were decreased in both doxycycline-treated groups. In addition, doxycycline significantly reduced the phosphorylation of NF-κB activated in the BAC-treated corneas. Topical doxycycline showed clinical improvements and alleviated ocular surface inflammation on BAC-induced mouse dry eye, suggesting a potential as an anti-inflammatory agent in the clinical treatment of dry eye.

How will induced seismicity in Oklahoma respond to decreased saltwater injection rates?

PubMed Central

Langenbruch, Cornelius; Zoback, Mark D.

2016-01-01

In response to the marked number of injection-induced earthquakes in north-central Oklahoma, regulators recently called for a 40% reduction in the volume of saltwater being injected in the seismically active areas. We present a calibrated statistical model that predicts that widely felt M ≥ 3 earthquakes in the affected areas, as well as the probability of potentially damaging larger events, should significantly decrease by the end of 2016 and approach historic levels within a few years. Aftershock sequences associated with relatively large magnitude earthquakes that occurred in the Fairview, Cherokee, and Pawnee areas in north-central Oklahoma in late 2015 and 2016 will delay the rate of seismicity decrease in those areas. PMID:28138533

Using resting-state fMRI to assess the effect of aerobic exercise on functional connectivity of the DLPFC in older overweight adults.

PubMed

Prehn, Kristin; Lesemann, Anne; Krey, Georgia; Witte, A Veronica; Köbe, Theresa; Grittner, Ulrike; Flöel, Agnes

2017-08-23

Cardiovascular fitness is thought to exert beneficial effects on brain function and might delay the onset of cognitive decline. Empirical evidence of exercise-induced cognitive enhancement, however, has not been conclusive, possibly due to short intervention times in clinical trials. Resting-state functional connectivity (RSFC) has been proposed asan early indicator for intervention-induced changes. Here, we conducted a study in which healthy older overweight subjects took either part in a moderate aerobic exercise program over 6months (AE group; n=11) or control condition of non-aerobic stretching and toning (NAE group; n=18). While cognitive and gray matter volume changes were rather small (i.e., appeared only in certain sub-scores without Bonferroni correction for multiple comparisons or using small volume correction), we found significantly increased RSFC after training between dorsolateral prefrontal cortex and superior parietal gyrus/precuneus in the AE compared to the NAE group. This intervention study demonstrates an exercise-induced modulation of RSFC between key structures of the executive control and default mode networks, which might mediate an interaction between task-positive and task-negative brain activation required for task switching. Results further emphasize the value of RSFC asa sensitive biomarker for detecting early intervention-related cognitive improvements in clinical trials. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Myrtus communis Linn. berries (common myrtle) in experimental ulcer models in rats.

PubMed

Sumbul, Sabiha; Ahmad, Mohd Aftab; Asif, Mohd; Saud, Ibne; Akhtar, Mohd

2010-11-01

The present study was conducted to investigate the protective effect of the dried berries of Myrtus communis L. in gastric ulcer against ethanol, indomethacin and pyloric ligation induced models in Wistar rats. Two doses of aqueous extracts of M. communis (AE( 1) and AE(2)) at the dose 105 and 175 mg/kg, respectively, and methanolic extracts (ME(1) and ME(2)) at the dose of 93 and 154 mg/kg, respectively, were administered orally to animals prior to the exposure of ulcerogens. The parameters taken to assess anti-ulcer activity were ulcer index, gastric juice volume, gastric pH, total acidity, gastric wall mucus and histopathological studies. Oral administration of AE(1) and AE(2) significantly reduced the ulcer index in all models of ulcers. Low dose of aqueous extract and high dose of methanolic extract of M. communis exhibited more significant effect in comparison to omeprazole (standard drug) in ethanol-induced ulcer model. Both the doses of aqueous and methanolic extracts also reduced the gastric juice volume, total acidity and increased the gastric pH and gastric wall mucus content in all the models of ulcers used in the present study. Histopathological examinations of gastric tissues of rats treated with the aqueous and methanolic extracts in indomethacin-induced ulcer exhibited significant ulcer-protective effect at both the dose levels.

Doxorubicin-induced co-assembling nanomedicines with temperature-sensitive acidic polymer and their in-situ-forming hydrogels for intratumoral administration.

PubMed

Wan, Jiangshan; Geng, Shinan; Zhao, Hao; Peng, Xiaole; Zhou, Qing; Li, Han; He, Ming; Zhao, Yanbing; Yang, Xiangliang; Xu, Huibi

2016-08-10

Doxorubicin (DOX)-induced co-assembling nanomedicines (D-PNAx) with temperature-sensitive PNAx triblock polymers have been developed for regional chemotherapy against liver cancer via intratumoral administration in the present work. Owing to the formation of insoluble DOX carboxylate, D-PNAx nanomedicines showed high drug-loading and entrapment efficacy via a simple mixing of doxorubicin hydrochloride and PNAx polymers. The sustained releasing profile of D-PNA100 nanomedicines indicated that only 9.4% of DOX was released within 1day, and 60% was released during 10days. Based on DOX-induced co-assembling behavior and their temperature sensitive in-situ-forming hydrogels, D-PNA100 nanomedicines showed excellent antitumor activity against H22 tumor using intratumoral administration. In contrast to that by free DOX solution (1.13±0.04 times at 9days) and blank PNA100 (2.11±0.34 times), the tumor volume treated by D-PNA100 had been falling to only 0.77±0.13 times of original tumor volume throughout the experimental period. In vivo biodistribution of DOX indicated that D-PNA100 nanomedicines exhibited much stronger DOX retention in tumor tissues than free DOX solution via intratumoral injection. D-PNA100 nanomedicines were hopeful to be developed as new temperature sensitive in-situ-forming hydrogels via i.t. injection for regional chemotherapy. Copyright © 2016. Published by Elsevier B.V.

In vitro and in vivo anti-cancer activity of silymarin on oral cancer.

PubMed

Won, Dong-Hoon; Kim, Lee-Han; Jang, Boonsil; Yang, In-Hyoung; Kwon, Hye-Jeong; Jin, Bohwan; Oh, Seung Hyun; Kang, Ju-Hee; Hong, Seong-Doo; Shin, Ji-Ae; Cho, Sung-Dae

2018-05-01

Silymarin, a standardized extract from milk thistle fruits has been found to exhibit anti-cancer effects against various cancers. Here, we explored the anti-cancer activity of silymarin and its molecular target in human oral cancer in vitro and in vivo. Silymarin dose-dependently inhibited the proliferation of HSC-4 oral cancer cells and promoted caspase-dependent apoptosis. A human apoptosis protein array kit showed that death receptor 5 may be involved in silymarin-induced apoptosis, which was also shown through western blotting, immunocytochemistry, and reverse transcription-polymerase chain reaction. Silymarin increased cleaved caspase-8 and truncated Bid, leading to accumulation of cytochrome c. In addition, silymarin activated death receptor 5/caspase-8 to induce apoptotic cell death in two other oral cancer cell lines (YD15 and Ca9.22). Silymarin also suppressed tumor growth and volume without any hepatic or renal toxicity in vivo. Taken together, these results provide in vitro and in vivo evidence supporting the anti-cancer effect of silymarin and death receptor 5, and caspase-8 may be essential players in silymarin-mediated apoptosis in oral cancer.

Anti-arthritic activity of cell wall content of Lactobacillus plantarum in freund's adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers.

PubMed

Gohil, Priyanshee; Patel, Vimal; Deshpande, Shrikalp; Chorawala, Mehul; Shah, Gaurang

2018-02-01

Alteration of microbiota is related with rheumatoid arthritis (RA) and administration of certain probiotics showed an improvement in RA. The present study was designed to find out the anti-arthritic activity of cell wall content of Lactobacillus plantarum in complete Freund's adjuvant (CFA)-induced arthritis in rats. Freund's adjuvant was injected into the left footpad in female rats on day 0 and dexamethasone (1 mg kg -1 , s.c.) & cell wall content of L. plantarum (10 5 , 10 7 , and 10 9  cfu/animal, s.c.) treatment were given from day 7 to 21. The change in body weight, paw volume and arthritic index, joint stiffness, gait test, mobility test, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, serum rheumatoid factor (RF), and serum TNF-α was measured on day 21. Cell wall content of L. plantarum treated animals showed improvement in all the parameters as compared to that in CFA-treated animals and exert anti-arthritic activity.

Freezing-induced cellular and membrane dehydration in the presence of cryoprotective agents.

PubMed

Akhoondi, Maryam; Oldenhof, Harriëtte; Sieme, Harald; Wolkers, Willem F

2012-09-01

FTIR and cryomicroscopy have been used to study mouse embryonic fibroblast cells (3T3) during freezing in the absence and presence of DMSO and glycerol. The results show that cell volume changes as observed by cryomicroscopy typically end at temperatures above -15°C, whereas membrane phase changes may continue until temperatures as low as -30°C. This implies that cellular dehydration precedes dehydration of the bound water surrounding the phospholipid head groups. Both DMSO and glycerol increase the membrane hydraulic permeability at subzero temperature and reduce the activation energy for water transport. Cryoprotective agents facilitate dehydration to continue at low subzero temperatures thereby decreasing the incidence of intracellular ice formation. The increased subzero membrane hydraulic permeability likely plays an important role in the cryoprotective action of DMSO and glycerol. In the presence of DMSO water permeability was found to be greater compared to that in the presence of glycerol. Two temperature regimes were identified in an Arrhenius plot of the membrane hydraulic permeability. The activation energy for water transport at temperature ranging from 0 to -10°C was found to be greater than that below -10°C. The non-linear Arrhenius behavior of Lp has been implemented in the water transport model to simulate cell volume changes during freezing. At a cooling rate of 1°C min(-1), ∼5% of the initial osmotically active water volume is trapped inside the cells at -30°C.

A Systematic Review of Strategies to Prevent Cisplatin‐Induced Nephrotoxicity

PubMed Central

Crona, Daniel J.; Faso, Aimee; Nishijima, Tomohiro F.; McGraw, Kathleen A.; Galsky, Matthew D.

2017-01-01

Abstract Introduction. Cisplatin, a platinum‐based antineoplastic agent, is the cornerstone for the treatment of many malignancies. Nephrotoxicity is the primary dose‐limiting toxicity, and various hydration regimens and supplementation strategies are used to prevent cisplatin‐induced kidney injury. However, evidence‐based recommendations on specific hydration regimens are limited. A systematic review was performed to evaluate clinical studies that have examined hydration and supplementation strategies to prevent cisplatin‐induced nephrotoxicity. Materials and Methods. PubMed and Excerpta Medica databases were searched from 1966 through October 2015 for clinical trials and other studies focused on hydration regimens to prevent nephrotoxicity in cancer patients treated with cisplatin. The University of Oxford Centre for Evidence‐Based Medicine criteria were used to grade level of evidence. Results. Among the 1,407 identified studies, 24 were included in this systematic review. All studies differed on type, volume, and duration of hydration. Among the 24 studies, 5 evaluated short‐duration hydration, 4 evaluated low‐volume hydration, 4 investigated magnesium supplementation, and 7 reviewed forced diuresis with hydration. Short‐duration and lower‐volume hydration regimens are effective in preventing cisplatin‐induced nephrotoxicity. Magnesium supplementation may have a role as a nephroprotectant, and forced diuresis may be appropriate in some patients receiving cisplatin. Conclusion. Hydration is essential for all patients to prevent cisplatin‐induced nephrotoxicity. Specifically, short‐duration, low‐volume, outpatient hydration with magnesium supplementation and mannitol forced diuresis (in select patients) represent best practice principles for the safe use of cisplatin. The Oncologist 2017;22:609–619 Implications for Practice. The findings contained within this systematic review show that (a) hydration is essential for all patients to prevent cisplatin‐induced nephrotoxicity, (b) short‐duration, low‐volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate‐ to high‐dose cisplatin, (c) magnesium supplementation (8–16 milliequivalents) may limit cisplatin‐induced nephrotoxicity, and (d) mannitol may be considered for high‐dose cisplatin and/or patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin‐induced nephrotoxicity. PMID:28438887

High-pressure studies of aggregation of recombinant human interleukin-1 receptor antagonist: Thermodynamics, kinetics, and application to accelerated formulation studies

PubMed Central

Seefeldt, Matthew B.; Kim, Yong-Sung; Tolley, Kevin P.; Seely, Jim; Carpenter, John F.; Randolph, Theodore W.

2005-01-01

Recombinant human interleukin-1 receptor antagonist (IL-1ra) in aqueous solutions unfolds and aggregates when subjected to hydrostatic pressures greater than about 180 MPa. This study examined the mechanism and thermodynamics of pressure-induced unfolding and aggregation of IL-1ra. The activation free energy for growth of aggregates (ΔG∓aggregation) was found to be 37 ± 3 kJ/mol, whereas the activation volume (ΔV∓aggregation) was −120 ± 20 mL/mol. These values compare closely with equilibrium values for denaturation: The free energy for denaturation, ΔGdenaturation, was 20 ± 5 kJ/mol, whereas the partial specific volume change for denaturation, ΔVdenaturation, was −110 ± 30 mL/mol. When IL-1ra begins to denature at pressures near 140 MPa, cysteines that are normally buried in the native state become exposed. Under oxidizing conditions, this results in the formation of covalently cross-linked aggregates containing nonnative, intermolecular disulfide bonds. The apparent activation free energy for nucleation of aggregates, ΔG∓nuc, was 42 ± 4 kJ/mol, and the activation volume for nucleation, ΔV∓nuc,was −175 ± 37 mL/mol, suggesting that a highly solvent-exposed conformation is needed for nucleation. We hypothesize that the large specific volume of IL-1ra, 0.752 ± 0.004 mL/g, coupled with its relatively low conformational stability, leads to its susceptibility to denaturation at relatively low pressures. The positive partial specific adiabatic compressibility of IL-1ra, 4.5 ± 0.7 ± 10−12 cm2/dyn, suggests that a significant component of the ΔVdenaturation is attributable to the elimination of solvent-free cavities. Lastly, we propose that hydrostatic pressure is a useful variable to conduct accelerated formulation studies of therapeutic proteins. PMID:16081653

Neural and vascular variability and the fMRI-BOLD response in normal aging

PubMed Central

Kannurpatti, Sridhar S.; Motes, Michael A.; Rypma, Bart; Biswal, Bharat B.

2010-01-01

Neural, vascular and structural variables contributing to the BOLD signal response variability were investigated in younger and older humans. Twelve younger healthy human subjects (6M and 6F; mean age: 24 years; range: 19–27 years) and twelve older healthy subjects (5M and 7F; mean age: 58 years; range: 55–71 years) with no history of head trauma and neurological disease were scanned. FMRI measurements using the BOLD contrast were made when participants performed a motor, cognitive or a breath hold task. Activation volume and the BOLD response amplitude were estimated for the younger and older at both group and subject levels. Mean activation volume was reduced by 45, 40 and 38% in the elderly group during the motor, cognitive and breath hold tasks respectively compared to the younger. Reduction in activation volume was substantially higher compared to the reduction in the gray matter volume of 14% in the older compared to the younger. A significantly larger variability in the inter-subject BOLD signal change occurred during the motor task, compared to the cognitive task. BH-induced BOLD signal change between subjects was significantly less-variable in the motor task-activated areas in the younger compared to older whereas such a difference between age groups was not observed during the cognitive task. Hemodynamic scaling using the BH signal substantially reduced the BOLD signal variability during the motor task compared to the cognitive task. The results indicate that the origin of the BOLD signal variability between subjects was predominantly vascular during the motor task while being principally a consequence of neural variability during the cognitive task. Thus, in addition to gray matter differences, the type of task performed can have different vascular variability weighting that can influence age-related differences in brain functional response. PMID:20117893

Neural and vascular variability and the fMRI-BOLD response in normal aging.

PubMed

Kannurpatti, Sridhar S; Motes, Michael A; Rypma, Bart; Biswal, Bharat B

2010-05-01

Neural, vascular and structural variables contributing to the blood oxygen level-dependent (BOLD) signal response variability were investigated in younger and older humans. Twelve younger healthy human subjects (six male and six female; mean age: 24 years; range: 19-27 years) and 12 older healthy subjects (five male and seven female; mean age: 58 years; range: 55-71 years) with no history of head trauma and neurological disease were scanned. Functional magnetic resonance imaging measurements using the BOLD contrast were made when participants performed a motor, cognitive or a breath hold (BH) task. Activation volume and the BOLD response amplitude were estimated for the younger and older at both group and subject levels. Mean activation volume was reduced by 45%, 40% and 38% in the elderly group during the motor, cognitive and BH tasks, respectively, compared to the younger. Reduction in activation volume was substantially higher compared to the reduction in the gray matter volume of 14% in the older compared to the younger. A significantly larger variability in the intersubject BOLD signal change occurred during the motor task, compared to the cognitive task. BH-induced BOLD signal change between subjects was significantly less-variable in the motor task-activated areas in the younger compared to older whereas such a difference between age groups was not observed during the cognitive task. Hemodynamic scaling using the BH signal substantially reduced the BOLD signal variability during the motor task compared to the cognitive task. The results indicate that the origin of the BOLD signal variability between subjects was predominantly vascular during the motor task while being principally a consequence of neural variability during the cognitive task. Thus, in addition to gray matter differences, the type of task performed can have different vascular variability weighting that can influence age-related differences in brain functional response. 2010 Elsevier Inc. All rights reserved.

Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention.

PubMed

Vercauteren, Magali; Trensz, Frederic; Pasquali, Anne; Cattaneo, Christophe; Strasser, Daniel S; Hess, Patrick; Iglarz, Marc; Clozel, Martine

2017-05-01

Endothelin (ET) receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ET B receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ET A -selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ET A -selective antagonists and bosentan and macitentan as dual antagonists were used as representatives of each class, respectively. ET A -selective antagonism caused a dose-dependent hematocrit/hemoglobin decrease that was prevented by ET B -selective receptor antagonism. ET A -selective antagonism led to a significant blood pressure reduction, plasma volume expansion, and a greater increase in vascular permeability than dual antagonism. Isolated vessel experiments showed that ET A -selective antagonism increased vascular permeability via ET B receptor overstimulation. Acutely, ET A -selective but not dual antagonism activated sympathetic activity and increased plasma arginine vasopressin and aldosterone concentrations. The hematocrit/hemoglobin decrease induced by ET A -selective antagonism was reduced in Brattleboro rats and in Wistar rats treated with an arginine vasopressin receptor antagonist. Finally, the decrease in hematocrit/hemoglobin was larger in the venous than in the arterial side, suggesting fluid redistribution. In conclusion, by activating ET B receptors, endothelin receptor antagonists (particularly ET A -selective antagonists) favor edema formation by causing: 1) fluid retention resulting from arginine vasopressin and aldosterone activation secondary to vasodilation, and 2) increased vascular permeability. Plasma volume redistribution may explain the clinical observation of a hematocrit/hemoglobin decrease even in the absence of signs of fluid retention. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Contributions of the Na+/K+-ATPase, NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses

PubMed Central

Larsen, Brian Roland; Assentoft, Mette; Cotrina, Maria L.; Hua, Susan Z.; Nedergaard, Maiken; Kaila, Kai; Voipio, Juha; MacAulay, Nanna

2015-01-01

Bursts of network activity in the brain are associated with a transient increase in extracellular K+ concentration. The excess K+ is removed from the extracellular space by mechanisms proposed to involve Kir4.1-mediated spatial buffering, the Na+/K+/2Cl− cotransporter (NKCC1), and/or Na+/K+-ATPase activity. Their individual contribution to [K+]o management has been of extended controversy. The present study aimed, by several complementary approaches, to delineate the transport characteristics of Kir4.1, NKCC1, and Na+/K+-ATPase and to resolve their involvement in clearance of extracellular K+ transients. Primary cultures of rat astrocytes displayed robust NKCC1 activity with [K+]o increases above basal levels. Increased [K+]o produced NKCC1-mediated swelling of cultured astrocytes and NKCC1 could thereby potentially act as a mechanism of K+ clearance while concomitantly mediate the associated shrinkage of the extracellular space. In rat hippocampal slices, inhibition of NKCC1 failed to affect the rate of K+ removal from the extracellular space while Kir4.1 enacted its spatial buffering only during a local [K+]o increase. In contrast, inhibition of the different isoforms of Na+/K+-ATPase reduced post-stimulusclearance of K+ transients. The glia-specific α2/β2 subunit composition of Na+/K+-ATPase, when expressed in Xenopus oocytes, displayed a K+ affinity and voltage-sensitivity that would render this astrocyte-specific subunit composition specifically geared for controlling [K+]o during neuronal activity. In rat hippocampal slices, simultaneous measurements of the extracellular space volume revealed that neither Kir4.1, NKCC1, nor Na+/K+-ATPase accounted for the stimulus-induced shrinkage of the extracellular space. Thus, NKCC1 plays no role in activity-induced extracellular K+ recovery in native hippocampal tissue while Kir4.1 and Na+/K+-ATPase serve temporally distinct roles. PMID:24482245

Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Hongzhong; Huang, Jing; Yang, Bing

Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelial–mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of β-catenin pathway. Subsequent experiments showed thatmore » inhibiting β-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active β-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. - Highlights: • Mangiferin inhibits growth and metastatic potential in breast cancer cells. • Mangiferin down-regulates MMP-7 and -9 in breast cancer cells. • Mangiferin induces the reversal of EMT in metastatic breast cancer cells. • Mangiferin inhibits the activation of β-catenin pathway in breast cancer cells. • Inhibiting β-catenin is responsible for the antitumor activity of mangiferin.« less

Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways.

PubMed

Wang, Tao; Liu, Qian; Zhou, Lin; Yuan, Jin Bo; Lin, Xixi; Zeng, Rong; Liang, Xiaonan; Zhao, Jinmin; Xu, Jiake

2015-11-17

Osteoporosis is a debilitating skeletal disorder with an increased risk of low-energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP), a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro-protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX) mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT). Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-κB and NFATc1 were evaluated using a luciferase reporter assay, and the IκBα protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk), TRACP (Acp5), and NFATc1, as well as the transcriptional activities of NF-κB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-κB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis.

Dependence of palmar sweating response and central nervous system activity on the frequency of whole-body vibration.

PubMed

Ando, Hideo; Noguchi, Ryo

2003-06-01

This study was carried out to determine the effects of the frequency of whole-body vibration on palmar sweating response and the activity of the central sympathetic nervous system. Palmar sweating volume was measured on the right palm of six healthy men before and during 3 minutes of exposure to sinusoidal whole-body vibration at three different frequencies (16, 31.5, and 63 Hz). The whole-body vibration had a frequency-weighted, root mean square (rms) acceleration magnitude of 2.0 m/s2. As the index of the activated central sympathetic nervous system, saliva level of 3-methoxy-4-hydroxyphenylglycol (MHPG) was analyzed before and immediately after each vibration exposure. Each vibration frequency induced a palmar sweating response, that of 31.5 Hz being the largest. However, no significant difference was found between the three vibration conditions. Saliva MHPG increased in all the vibration exposures, and the largest change was observed at 31.5 Hz, the difference being significant. Acute exposure to whole-body vibration induced a palmar sweating response and activated the central sympathetic nervous system. The effects on the central nervous system were found to be dependent on the frequency of the vibration.

Optogenetically induced spatiotemporal gamma oscillations and neuronal spiking activity in primate motor cortex.

PubMed

Lu, Yao; Truccolo, Wilson; Wagner, Fabien B; Vargas-Irwin, Carlos E; Ozden, Ilker; Zimmermann, Jonas B; May, Travis; Agha, Naubahar S; Wang, Jing; Nurmikko, Arto V

2015-06-01

Transient gamma-band (40-80 Hz) spatiotemporal patterns are hypothesized to play important roles in cortical function. Here we report the direct observation of gamma oscillations as spatiotemporal waves induced by targeted optogenetic stimulation, recorded by intracortical multichannel extracellular techniques in macaque monkeys during their awake resting states. Microelectrode arrays integrating an optical fiber at their center were chronically implanted in primary motor (M1) and ventral premotor (PMv) cortices of two subjects. Targeted brain tissue was transduced with the red-shifted opsin C1V1(T/T). Constant (1-s square pulses) and ramp stimulation induced narrowband gamma oscillations during awake resting states. Recordings across 95 microelectrodes (4 × 4-mm array) enabled us to track the transient gamma spatiotemporal patterns manifested, e.g., as concentric expanding and spiral waves. Gamma oscillations were induced well beyond the light stimulation volume, via network interactions at distal electrode sites, depending on optical power. Despite stimulation-related modulation in spiking rates, neuronal spiking remained highly asynchronous during induced gamma oscillations. In one subject we examined stimulation effects during preparation and execution of a motor task and observed that movement execution largely attenuated optically induced gamma oscillations. Our findings demonstrate that, beyond previously reported induced gamma activity under periodic drive, a prolonged constant stimulus above a certain threshold may carry primate motor cortex network dynamics into gamma oscillations, likely via a Hopf bifurcation. More broadly, the experimental capability in combining microelectrode array recordings and optogenetic stimulation provides an important approach for probing spatiotemporal dynamics in primate cortical networks during various physiological and behavioral conditions.

Optogenetically induced spatiotemporal gamma oscillations and neuronal spiking activity in primate motor cortex

PubMed Central

Lu, Yao; Truccolo, Wilson; Wagner, Fabien B.; Vargas-Irwin, Carlos E.; Ozden, Ilker; Zimmermann, Jonas B.; May, Travis; Agha, Naubahar S.; Wang, Jing

2015-01-01

Transient gamma-band (40–80 Hz) spatiotemporal patterns are hypothesized to play important roles in cortical function. Here we report the direct observation of gamma oscillations as spatiotemporal waves induced by targeted optogenetic stimulation, recorded by intracortical multichannel extracellular techniques in macaque monkeys during their awake resting states. Microelectrode arrays integrating an optical fiber at their center were chronically implanted in primary motor (M1) and ventral premotor (PMv) cortices of two subjects. Targeted brain tissue was transduced with the red-shifted opsin C1V1(T/T). Constant (1-s square pulses) and ramp stimulation induced narrowband gamma oscillations during awake resting states. Recordings across 95 microelectrodes (4 × 4-mm array) enabled us to track the transient gamma spatiotemporal patterns manifested, e.g., as concentric expanding and spiral waves. Gamma oscillations were induced well beyond the light stimulation volume, via network interactions at distal electrode sites, depending on optical power. Despite stimulation-related modulation in spiking rates, neuronal spiking remained highly asynchronous during induced gamma oscillations. In one subject we examined stimulation effects during preparation and execution of a motor task and observed that movement execution largely attenuated optically induced gamma oscillations. Our findings demonstrate that, beyond previously reported induced gamma activity under periodic drive, a prolonged constant stimulus above a certain threshold may carry primate motor cortex network dynamics into gamma oscillations, likely via a Hopf bifurcation. More broadly, the experimental capability in combining microelectrode array recordings and optogenetic stimulation provides an important approach for probing spatiotemporal dynamics in primate cortical networks during various physiological and behavioral conditions. PMID:25761956

Clinical Aspects of the Control of Plasma Volume at Microgravity and During Return to One Gravity

NASA Technical Reports Server (NTRS)

Convertino, Victor A.

1995-01-01

Plasma volume is reduced by 10%-20% within 24 to 48 h of exposure to simulated or actual microgravity. The clinical importance of microgravity-induced hypovolemia is manifested by its relationship with orthostatic intolerance and reduced VO2max after return to one gravity (1G). Since there is no evidence to suggest plasma volume reduction during microgravity is associated with thirst or renal dysfunctions, a diuresis induced by an immediate blood volume shift to the central circulation appears responsible for microgravity-induced hypovolemia. Since most astronauts choose to restrict their fluid intake before a space mission, absence of increased urine output during actual spaceflight may be explained by low central venous pressure (CVP) which accompanies dehydration. Compelling evidence suggests that prolonged reduction in CVP during exposure to microgravity reflects a 'resetting' to a lower operating point which acts to limit plasma volume expansion during attempts to increase fluid intake. In groudbase and spaceflight experiments, successful restoration and maintenance of plasma volume prior to returning to an upright posture may depend upon development of treatments that can return CVP to its baseline 10 operating point. Fluid-loading and LBNP have not proved completely effective in restoring plasma volume, suggesting that they may not provide the stimulus to elevate the CVP operating point. On the other, exercise, which can chronically increase CVP, has been effective in expanding plasma volume when combined with adequate dietary intake of fluid and electrolytes. The success of designing experiments to understand the physiological mechanisms of and development of effective countermeasures for the control of plasma volume in microgravity and during return to one gravity will depend upon testing that can be conducted under standardized controlled baseline condi

A New CT Reconstruction Technique Using Adaptive Deformation Recovery and Intensity Correction (ADRIC)

PubMed Central

Zhang, You; Ma, Jianhua; Iyengar, Puneeth; Zhong, Yuncheng; Wang, Jing

2017-01-01

Purpose Sequential same-patient CT images may involve deformation-induced and non-deformation-induced voxel intensity changes. An adaptive deformation recovery and intensity correction (ADRIC) technique was developed to improve the CT reconstruction accuracy, and to separate deformation from non-deformation-induced voxel intensity changes between sequential CT images. Materials and Methods ADRIC views the new CT volume as a deformation of a prior high-quality CT volume, but with additional non-deformation-induced voxel intensity changes. ADRIC first applies the 2D-3D deformation technique to recover the deformation field between the prior CT volume and the new, to-be-reconstructed CT volume. Using the deformation-recovered new CT volume, ADRIC further corrects the non-deformation-induced voxel intensity changes with an updated algebraic reconstruction technique (‘ART-dTV’). The resulting intensity-corrected new CT volume is subsequently fed back into the 2D-3D deformation process to further correct the residual deformation errors, which forms an iterative loop. By ADRIC, the deformation field and the non-deformation voxel intensity corrections are optimized separately and alternately to reconstruct the final CT. CT myocardial perfusion imaging scenarios were employed to evaluate the efficacy of ADRIC, using both simulated data of the extended-cardiac-torso (XCAT) digital phantom and experimentally acquired porcine data. The reconstruction accuracy of the ADRIC technique was compared to the technique using ART-dTV alone, and to the technique using 2D-3D deformation alone. The relative error metric and the universal quality index metric are calculated between the images for quantitative analysis. The relative error is defined as the square root of the sum of squared voxel intensity differences between the reconstructed volume and the ‘ground-truth’ volume, normalized by the square root of the sum of squared ‘ground-truth’ voxel intensities. In addition to the XCAT and porcine studies, a physical lung phantom measurement study was also conducted. Water-filled balloons with various shapes/volumes and concentrations of iodinated contrasts were put inside the phantom to simulate both deformations and non-deformation-induced intensity changes for ADRIC reconstruction. The ADRIC-solved deformations and intensity changes from limited-view projections were compared to those of the ‘gold-standard’ volumes reconstructed from fully-sampled projections. Results For the XCAT simulation study, the relative errors of the reconstructed CT volume by the 2D-3D deformation technique, the ART-dTV technique and the ADRIC technique were 14.64%, 19.21% and 11.90% respectively, by using 20 projections for reconstruction. Using 60 projections for reconstruction reduced the relative errors to 12.33%, 11.04% and 7.92% for the three techniques, respectively. For the porcine study, the corresponding results were 13.61%, 8.78%, 6.80% by using 20 projections; and 12.14%, 6.91% and 5.29% by using 60 projections. The ADRIC technique also demonstrated robustness to varying projection exposure levels. For the physical phantom study, the average DICE coefficient between the initial prior balloon volume and the new ‘gold-standard’ balloon volumes was 0.460. ADRIC reconstruction by 21 projections increased the average DICE coefficient to 0.954. Conclusion The ADRIC technique outperformed both the 2D-3D deformation technique and the ART-dTV technique in reconstruction accuracy. The alternately solved deformation field and non-deformation voxel intensity corrections can benefit multiple clinical applications, including tumor tracking, radiotherapy dose accumulation and treatment outcome analysis. PMID:28380247

[Does nodal irradiation (clavicular and internal mammary chains) increase the toxicity of adjuvant breast radiotherapy?].

PubMed

Riou, O; Bourgier, C; Fenoglietto, P; Azria, D

2015-06-01

Treatment volume is a major risk factor of radiation-induced toxicity. As nodal irradiation increases treatment volume, radiation toxicity should be greater. Nevertheless, scientific randomised data do not support this fact. However, a radiation-induced toxicity is possible outside tangential fields in the nodal volumes not related to breast-only treatment. Treatment should not be adapted only to the disease but personalized to the individual risk of toxicity for each patient. Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Interactions between surface discharges induced by volume discharges in a dielectric barrier discharge system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Yenan; Dong, Lifang, E-mail: donglfhbu@163.com; Zhao, Longhu

2014-10-15

The interaction between micro-discharges involved in surface discharges (SDs) is studied in dielectric barrier discharge system. Instantaneous images taken by high speed cameras show that the SDs are induced by volume discharges (VDs). They cannot cross the midperpendicular of two neighbouring volume charges at low voltage while they stretch along it at high voltage, indicating that there is interaction between SDs. The differences of plasma parameters between SD and VD are studied by optical emission spectroscopy. The simulation of the electric fields of the wall charges accumulated by VD further confirms the existence of the interaction.

In Vivo Anti-Inflammatory, Anti-Bacterial and Anti-Diarrhoeal Activity of Ziziphus Jujuba Fruit Extract.

PubMed

Mesaik, Ahmed M; Poh, Hiap Wei; Bin, Ooi Yan; Elawad, Izzaddinn; Alsayed, Badr

2018-05-20

Ziziphus jujuba belongs to family Rhamnaceae widely distributed in subtropical and tropical countries. It is used traditionally for several pharmacological purposes including anti-inflammation, antidiarrhoeal and antibacterial, as well as tonic and sometimes as hypnotic (sedative). To determine the in vivo antidiarrhoeal, antibacterial and anti-inflammatory activities of Z. jujuba fruit ethanolic extract. The fruit was macerated and extracted by 95% (v/v) ethanol. The antidiarrhoeal activity was evaluated using castor oil and Escherichia coli induced diarrhoea mouse model. The antidiarrhoeal and antibacterial activity was investigated at graded doses (400-1200 mg/kg). The anti-inflammatory effects were tested using the carrageenan-induced paw oedema in female Wistar rats. Rat's treatment groups received tragacanth, 100 mg/kg diclofenac sodium, 800 mg/kg, 1200 mg/kg or 1600 mg/kg of an ethanolic extract of Z. jujuba (EEZJ). All treatment groups were fed with the compounds one hour before carrageenan injection at of rat's paw. Also, the EEZJ was further analysed by HPLC-PDA system for identification of the presence of betulinic acid and quercetin. EEZJ different doses did not show inhibitory activity against castor oil induced diarrhoea except for the higher (1200 mg/kg) dose. However, the frequency of defecation of stools and watery stool were reduced significantly when compared to control group (P ≤ 0.05 and P ≤ 0.01 respectively), resulted in overall 67% inhibition of diarrhoea. Our anti-inflammatory results demonstrated that EEZJ was able to inhibit the carrageenan-induced paw oedema in rats to a significant degree (p ≤ 0.05) and the paw volume and thickness of both left and right paw were affected compared to the negative control group. EEZJ possesses antidiarrhoeal and antibacterial activity in a dose depending manner and may provide a pharmacological basis for its clinical use in diarrheal diseases. The activity may partially be due to the presence of betulinic acid and quercetin.

Non-invasive method and apparatus for monitoring intracranial pressure and pressure volume index in humans

NASA Technical Reports Server (NTRS)

Cantrell, John H. (Inventor); Yost, William T. (Inventor)

1994-01-01

Non-invasive measuring devices responsive to changes in a patient's intracranial pressure (ICP) can be accurately calibrated for monitoring purposes by providing known changes in ICP by non-invasive methods, such as placing the patient on a tilting bed and calculating a change in ICP from the tilt angle and the length of the patient's cerebrospinal column, or by placing a pressurized skull cap on the patient and measuring the inflation pressure. Absolute values for the patient's pressure-volume index (PVI) and the steady state ICP can then be determined by inducing two known changes in the volume of cerebrospinal fluid while recording the corresponding changes in ICP by means of the calibrated measuring device. The two pairs of data for pressure change and volume change are entered into an equation developed from an equation describing the relationship between ICP and cerebrospinal fluid volume. PVI and steady state ICP are then determined by solving the equation. Methods for inducing known changes in cerebrospinal fluid volume are described.

Non-invasive method and apparatus for monitoring intracranial pressure and pressure volume index in humans

NASA Technical Reports Server (NTRS)

Yost, William T. (Inventor); Cantrell, Jr., John H. (Inventor)

1997-01-01

Non-invasive measuring devices responsive to changes in a patient's intracranial pressure (ICP) can be accurately calibrated for monitoring purposes by providing known changes in ICP by non-invasive methods, such as placing the patient on a tilting bed and calculating a change in ICP from the tilt angle and the length of the patient's cerebrospinal column, or by placing a pressurized skull cap on the patient and measuring the inflation pressure. Absolute values for the patient's pressure-volume index (PVI) and the steady state ICP can then be determined by inducing two known changes in the volume of cerebrospinal fluid while recording the corresponding changes in ICP by means of the calibrated measuring device. The two pairs of data for pressure change and volume change are entered into an equation developed from an equation describing the relationship between ICP and cerebrospinal fluid volume. PVI and steady state ICP are then determined by solving the equation. Methods for inducing known changes in cerebrospinal fluid volume are described.

Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

PubMed Central

Magariños, A.M.; Li, C.J.; Toth, J. Gal; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S.

2010-01-01

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. PMID:20095008

Finite volume analysis of temperature effects induced by active MRI implants: 2. Defects on active MRI implants causing hot spots.

PubMed

Busch, Martin H J; Vollmann, Wolfgang; Grönemeyer, Dietrich H W

2006-05-26

Active magnetic resonance imaging implants, for example stents, stent grafts or vena cava filters, are constructed as wireless inductively coupled transmit and receive coils. They are built as a resonator tuned to the Larmor frequency of a magnetic resonance system. The resonator can be added to or incorporated within the implant. This technology can counteract the shielding caused by eddy currents inside the metallic implant structure. This may allow getting diagnostic information of the implant lumen (in stent stenosis or thrombosis for example). The electro magnetic rf-pulses during magnetic resonance imaging induce a current in the circuit path of the resonator. A by material fatigue provoked partial rupture of the circuit path or a broken wire with touching surfaces can set up a relatively high resistance on a very short distance, which may behave as a point-like power source, a hot spot, inside the body part the resonator is implanted to. This local power loss inside a small volume can reach (1/4) of the total power loss of the intact resonating circuit, which itself is proportional to the product of the resonator volume and the quality factor and depends as well from the orientation of the resonator with respect to the main magnetic field and the imaging sequence the resonator is exposed to. First an analytical solution of a hot spot for thermal equilibrium is described. This analytical solution with a definite hot spot power loss represents the worst case scenario for thermal equilibrium inside a homogeneous medium without cooling effects. Starting with this worst case assumptions additional conditions are considered in a numerical simulation, which are more realistic and may make the results less critical. The analytical solution as well as the numerical simulations use the experimental experience of the maximum hot spot power loss of implanted resonators with a definite volume during magnetic resonance imaging investigations. The finite volume analysis calculates the time developing temperature maps for the model of a broken linear metallic wire embedded in tissue. Half of the total hot spot power loss is assumed to diffuse into both wire parts at the location of a defect. The energy is distributed from there by heat conduction. Additionally the effect of blood perfusion and blood flow is respected in some simulations because the simultaneous appearance of all worst case conditions, especially the absence of blood perfusion and blood flow near the hot spot, is very unlikely for vessel implants. The analytical solution as worst case scenario as well as the finite volume analysis for near worst case situations show not negligible volumes with critical temperature increases for part of the modeled hot spot situations. MR investigations with a high rf-pulse density lasting below a minute can establish volumes of several cubic millimeters with temperature increases high enough to start cell destruction. Longer exposure times can involve volumes larger than 100 mm3. Even temperature increases in the range of thermal ablation are reached for substantial volumes. MR sequence exposure time and hot spot power loss are the primary factors influencing the volume with critical temperature increases. Wire radius, wire material as well as the physiological parameters blood perfusion and blood flow inside larger vessels reduce the volume with critical temperature increases, but do not exclude a volume with critical tissue heating for resonators with a large product of resonator volume and quality factor. The worst case scenario assumes thermal equilibrium for a hot spot embedded in homogeneous tissue without any cooling due to blood perfusion or flow. The finite volume analysis can calculate the results for near and not close to worst case conditions. For both cases a substantial volume can reach a critical temperature increase in a short time. The analytical solution, as absolute worst case, points out that resonators with a small product of inductance volume and quality factor (Q V(ind) < 2 cm3) are definitely save. Stents for coronary vessels or resonators used as tracking devices for interventional procedures therefore have no risk of high temperature increases. The finite volume analysis shows for sure that also conditions not close to the worst case reach physiologically critical temperature increases for implants with a large product of inductance volume and quality factor (Q V(ind) > 10 cm3). Such resonators exclude patients from exactly the MRI investigation these devices are made for.

Finite volume analysis of temperature effects induced by active MRI implants: 2. Defects on active MRI implants causing hot spots

PubMed Central

Busch, Martin HJ; Vollmann, Wolfgang; Grönemeyer, Dietrich HW

2006-01-01

Background Active magnetic resonance imaging implants, for example stents, stent grafts or vena cava filters, are constructed as wireless inductively coupled transmit and receive coils. They are built as a resonator tuned to the Larmor frequency of a magnetic resonance system. The resonator can be added to or incorporated within the implant. This technology can counteract the shielding caused by eddy currents inside the metallic implant structure. This may allow getting diagnostic information of the implant lumen (in stent stenosis or thrombosis for example). The electro magnetic rf-pulses during magnetic resonance imaging induce a current in the circuit path of the resonator. A by material fatigue provoked partial rupture of the circuit path or a broken wire with touching surfaces can set up a relatively high resistance on a very short distance, which may behave as a point-like power source, a hot spot, inside the body part the resonator is implanted to. This local power loss inside a small volume can reach ¼ of the total power loss of the intact resonating circuit, which itself is proportional to the product of the resonator volume and the quality factor and depends as well from the orientation of the resonator with respect to the main magnetic field and the imaging sequence the resonator is exposed to. Methods First an analytical solution of a hot spot for thermal equilibrium is described. This analytical solution with a definite hot spot power loss represents the worst case scenario for thermal equilibrium inside a homogeneous medium without cooling effects. Starting with this worst case assumptions additional conditions are considered in a numerical simulation, which are more realistic and may make the results less critical. The analytical solution as well as the numerical simulations use the experimental experience of the maximum hot spot power loss of implanted resonators with a definite volume during magnetic resonance imaging investigations. The finite volume analysis calculates the time developing temperature maps for the model of a broken linear metallic wire embedded in tissue. Half of the total hot spot power loss is assumed to diffuse into both wire parts at the location of a defect. The energy is distributed from there by heat conduction. Additionally the effect of blood perfusion and blood flow is respected in some simulations because the simultaneous appearance of all worst case conditions, especially the absence of blood perfusion and blood flow near the hot spot, is very unlikely for vessel implants. Results The analytical solution as worst case scenario as well as the finite volume analysis for near worst case situations show not negligible volumes with critical temperature increases for part of the modeled hot spot situations. MR investigations with a high rf-pulse density lasting below a minute can establish volumes of several cubic millimeters with temperature increases high enough to start cell destruction. Longer exposure times can involve volumes larger than 100 mm3. Even temperature increases in the range of thermal ablation are reached for substantial volumes. MR sequence exposure time and hot spot power loss are the primary factors influencing the volume with critical temperature increases. Wire radius, wire material as well as the physiological parameters blood perfusion and blood flow inside larger vessels reduce the volume with critical temperature increases, but do not exclude a volume with critical tissue heating for resonators with a large product of resonator volume and quality factor. Conclusion The worst case scenario assumes thermal equilibrium for a hot spot embedded in homogeneous tissue without any cooling due to blood perfusion or flow. The finite volume analysis can calculate the results for near and not close to worst case conditions. For both cases a substantial volume can reach a critical temperature increase in a short time. The analytical solution, as absolute worst case, points out that resonators with a small product of inductance volume and quality factor (Q Vind < 2 cm3) are definitely save. Stents for coronary vessels or resonators used as tracking devices for interventional procedures therefore have no risk of high temperature increases. The finite volume analysis shows for sure that also conditions not close to the worst case reach physiologically critical temperature increases for implants with a large product of inductance volume and quality factor (Q Vind > 10 cm3). Such resonators exclude patients from exactly the MRI investigation these devices are made for. PMID:16729878

Effects of nifedipine and captopril on vascular capacitance of ganglion-blocked anesthetized dogs.

PubMed

Ogilvie, R I; Zborowska-Sluis, D

1990-03-01

The hemodynamic effects of nifedipine and captopril at doses producing similar reductions in arterial pressure were studied in pentobarbital-anesthetized ventilated dogs after splenectomy during ganglion blockade with hexamethonium. Mean circulatory filling pressure (Pmcf) was determined during transient circulatory arrest induced by acetylcholine at baseline circulating blood volumes and after increases of 5 and 10 mL/kg. Central blood volumes (pulmonary artery to aortic root) were determined from transit times, and separately determined cardiac outputs (right atrium to pulmonary artery) were estimated by thermodilution. Nifedipine (n = 5) increased Pmcf at all circulating blood volumes and reduced total vascular capacitance without a change in total vascular compliance. Central blood volume, right atrial pressure, and cardiac output were increased with induced increases in circulating blood volume. In contrast, captopril (n = 5) did not alter total vascular capacitance, central blood volume, right atrial pressure, or cardiac output at baseline or with increased circulating volume. Thus, at doses producing similar reductions in arterial pressure, nifedipine but not captopril increased venous return and cardiac output in ganglion-blocked dogs.

Regulation of cell volume by glycosaminoglycans.

PubMed

Joerges, Jelena; Schulz, Tobias; Wegner, Jeannine; Schumacher, Udo; Prehm, Peter

2012-01-01

Cell volume is regulated by a delicate balance between ion distribution across the plasma membrane and the osmotic properties of intra- and extracellular components. Using a fluorescent calcein indicator, we analysed the effects of glycosaminoglycans on the cell volume of hyaluronan producing fibroblasts and hyaluronan deficient HEK cells over a time period of 30 h. Exogenous glycosaminoglycans induced cell blebbing after 2 min and swelling of fibroblasts to about 110% of untreated cell volume at low concentrations which decreased at higher concentrations. HEK cells did not show cell blebbing and responded by shrinking to 65% of untreated cell volume. Heparin induced swelling of both fibroblasts and HEK cells. Hyaluronidase treatment or inhibition of hyaluronan export led to cell shrinkage indicating that the hyaluronan coat maintained fibroblasts in a swollen state. These observations were explained by the combined action of the Donnan effect and molecular crowding. Copyright © 2011 Wiley Periodicals, Inc.

Protective effects of black cumin (Nigella sativa) oil on TNBS-induced experimental colitis in rats.

PubMed

Isik, F; Tunali Akbay, Tugba; Yarat, A; Genc, Z; Pisiriciler, R; Caliskan-Ak, E; Cetinel, S; Altıntas, A; Sener, G

2011-03-01

The pathogenesis and treatment of ulcerative colitis remain poorly understood. The aim of the present study is to investigate the effects of black cumin (Nigella sativa) oil on rats with colitis. Experimental colitis was induced with 1 mL trinitrobenzene sulfonic acid (TNBS) in 40% ethanol by intracolonic administration with 8-cm-long cannula under ether anesthesia to rats in colitis group and colitis + black cumin oil group. Rats in the control group were given saline at the same volume by intracolonic administration. Black cumin oil (BCO, Origo "100% natural Black Cumin Seed Oil," Turkey) was given to colitis + black cumin oil group by oral administration during 3 days, 5 min after colitis induction. Saline was given to control and colitis groups at the same volume by oral administration. At the end of the experiment, macroscopic lesions were scored and the degree of oxidant damage was evaluated by colonic total protein, sialic acid, malondialdehyde, and glutathione levels, collagen content, and tissue factor, superoxide dismutase, and myeloperoxidase activities. Tissues were also examined by histological and cytological analysis. Proinflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6], lactate dehydrogenase activity, and triglyceride and cholesterol levels were analyzed in blood samples. We found that black cumin oil decreased the proinflammatory cytokines, lactate dehydrogenase, triglyceride, and cholesterol, which were increased in colitis. BCO, by preventing inflammatory status in the blood, partly protected colonic tissue against experimental ulcerative colitis.

Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology.

PubMed

Tsuboi, Alice; Ohsawa, Shizue; Umetsu, Daiki; Sando, Yukari; Kuranaga, Erina; Igaki, Tatsushi; Fujimoto, Koichi

2018-06-11

During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Induced seismicity provides insight into why earthquake ruptures stop

PubMed Central

Galis, Martin; Ampuero, Jean Paul; Mai, P. Martin; Cappa, Frédéric

2017-01-01

Injection-induced earthquakes pose a serious seismic hazard but also offer an opportunity to gain insight into earthquake physics. Currently used models relating the maximum magnitude of injection-induced earthquakes to injection parameters do not incorporate rupture physics. We develop theoretical estimates, validated by simulations, of the size of ruptures induced by localized pore-pressure perturbations and propagating on prestressed faults. Our model accounts for ruptures growing beyond the perturbed area and distinguishes self-arrested from runaway ruptures. We develop a theoretical scaling relation between the largest magnitude of self-arrested earthquakes and the injected volume and find it consistent with observed maximum magnitudes of injection-induced earthquakes over a broad range of injected volumes, suggesting that, although runaway ruptures are possible, most injection-induced events so far have been self-arrested ruptures. PMID:29291250

A numerically optimized active shield for improved TMS targeting

PubMed Central

Hernandez-Garcia, Luis; Hall, Timothy; Gomez, Luis; Michielssen, Eric

2010-01-01

Transcranial magnetic stimulation (TMS) devices suffer of poor targeting and penetration depth. A new approach to designing TMS coils is introduced in order to improve the focus of the stimulation region through the use of actively shielded probes. Iterative optimization techniques were used to design different active shielding coils for TMS probes. The new approach aims to increase the amount of energy deposited in a thin cylindrical region below the probe relative to the energy deposited elsewhere in the region (“sharpness”), while simultaneously increase the induced electric field deep in the target region relative to the surface (“penetration”). After convergence, the resulting designs showed that there is a clear tradeoff between sharpness and penetration that can be controlled by the choice of a tuning parameter. The resulting designs were tested on a realistic human head conductivity model, taking the contribution from surface charges into account. The design of choice reduced penetration depths by 16.7%. The activated surface area was reduced by 24.1 % and the volume of the activation was reduced from 42.6% by the shield. Restoring the lost penetration could be achieved by increasing the total power to the coil by 16.3%, but in that case, the stimulated volume reduction was only 13.1% and there was a slight increase in the stimulated surface area (2.9 %) PMID:20965451

A numerically optimized active shield for improved transcranial magnetic stimulation targeting.

PubMed

Hernandez-Garcia, Luis; Hall, Timothy; Gomez, Luis; Michielssen, Eric

2010-10-01

Transcranial magnetic stimulation (TMS) devices suffer of poor targeting and penetration depth. A new approach to designing TMS coils is introduced in order to improve the focus of the stimulation region through the use of actively shielded probes. Iterative optimization techniques were used to design different active shielding coils for TMS probes. The new approach aims to increase the amount of energy deposited in a thin cylindrical region below the probe relative to the energy deposited elsewhere in the region ("sharpness"), whereas, simultaneously increase the induced electric field deep in the target region relative to the surface ("penetration"). After convergence, the resulting designs showed that there is a clear tradeoff between sharpness and penetration that can be controlled by the choice of a tuning parameter. The resulting designs were tested on a realistic human head conductivity model, taking the contribution from surface charges into account. The design of choice reduced penetration depths by 16.7%. The activated surface area was reduced by 24.1% and the volume of the activation was reduced from 42.6% by the shield. Restoring the lost penetration could be achieved by increasing the total power to the coil by 16.3%, but in that case, the stimulated volume reduction was only 13.1% and there was a slight increase in the stimulated surface area (2.9%). Copyright © 2010 Elsevier Inc. All rights reserved.

[Effects of combined use of total alkaloids of Uncaria rhynchophylla and Coryadlis ambailis migo on cerebral ischemia-reperfusion injury in rats].

PubMed

Hu, Xue-yong; Sun, An-sheng; Sui, Yu-xia

2007-11-01

To study the effects of combined use of total alkaloids (TA) of Uncaria rhynchophylla (UR) and Coryadlis ambailis migo (CAM) on cerebral ischemia/reperfusion injury in rats. Rat model of middle cerebral artery ischemia/reperfusion was established, the changes of neurological state was scored before and after treatment with the two kinds of TA, single or combined, and the changes of cerebral infarcted volume, cerebral water content, activities of NOS and SOD and content of MDA in rats' brain were estimated as well. After being treated with the combination of both TA, the average neurological score, cerebral infracted volume, cerebral water content, activity of NOS and content of MDA in the model rats significantly decreased, and the activity of SOD was significantly increased (all P < 0.05). The effect of combined use of the two TA was higher than that of use TA of UR or CAM alone (P <0.05). Moreover, the central nervous system inhibitory effect induced by combined TA was significantly weaker than that of UR. Combined use of TA of UR and CAM may facilitate the protection against cerebral ischemia/reperfusion damage, the action mechanism might be relevant to reducing the lipid peroxidation injury of brain cells through inhibiting the NOS activity and increasing the SOD activity.

Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game.

PubMed

Kühn, S; Gleich, T; Lorenz, R C; Lindenberger, U; Gallinat, J

2014-02-01

Video gaming is a highly pervasive activity, providing a multitude of complex cognitive and motor demands. Gaming can be seen as an intense training of several skills. Associated cerebral structural plasticity induced has not been investigated so far. Comparing a control with a video gaming training group that was trained for 2 months for at least 30 min per day with a platformer game, we found significant gray matter (GM) increase in right hippocampal formation (HC), right dorsolateral prefrontal cortex (DLPFC) and bilateral cerebellum in the training group. The HC increase correlated with changes from egocentric to allocentric navigation strategy. GM increases in HC and DLPFC correlated with participants' desire for video gaming, evidence suggesting a predictive role of desire in volume change. Video game training augments GM in brain areas crucial for spatial navigation, strategic planning, working memory and motor performance going along with evidence for behavioral changes of navigation strategy. The presented video game training could therefore be used to counteract known risk factors for mental disease such as smaller hippocampus and prefrontal cortex volume in, for example, post-traumatic stress disorder, schizophrenia and neurodegenerative disease.

Performance-related increases in hippocampal N-acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val homozygotes.

PubMed

Lövdén, Martin; Schaefer, Sabine; Noack, Hannes; Kanowski, Martin; Kaufmann, Jörn; Tempelmann, Claus; Bodammer, Nils Christian; Kühn, Simone; Heinze, Hans-Jochen; Lindenberger, Ulman; Düzel, Emrah; Bäckman, Lars

2011-06-01

Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

Altered baroreflex control of forearm vascular resistance during simulated microgravity

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Doerr, D. F.; Vernikos, J.

1994-01-01

Reflex peripheral vasoconstriction induced by activation of cardiopulmonary baroreceptors in response to reduced central venous pressure (CVP) is a basic mechanism for elevating systemic vascular resistance and defending arterial blood pressure during orthostatically-induced reductions in cardiac filling and output. The sensitivity of the cardiopulmonary baroreflex response [defined as the slope of the relationship between changes in forearm vascular resistance (FVR) and CVP] and the resultant vasoconstriction are closely and inversely associated with the amount of circulating blood volume. Thus, a high-gain FVR response will be elicited by a hypovolemic state. Exposure to microgravity during spaceflight results in reduced plasma volume. It is therefore reasonable to expect that the FVR response to cardiopulmonary baroreceptor unloading would be accentuated following adaptation to microgravity. Such data could provide better insight about the physiological mechanisms underlying alterations in blood pressure control following spaceflight. We therefore exposed eleven men to 6 degrees head-down bedrest for 7 days and measured specific hemodynamic responses to low levels of the lower body negative pressure to determine if there are alterations in cardiopulmonary baroreceptor stimulus-FVR reflex response relationship during prolonged exposure to an analog of microgravity.

Near infrared photoimmunotherapy for lung metastases

PubMed Central

Sato, Kazuhide; Nagaya, Tadanobu; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka

2015-01-01

Lung metastases are a leading cause of cancer related deaths; nonetheless current treatments are limited. Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies that target tumors with the toxicity induced by photosensitizers activated by NIR-light. Herein, we demonstrate the efficacy of NIR-PIT in a mouse model of lung metastases. Experiments were conducted with a HER2, luciferase and GFP expressing cell line (3T3/HER2-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. With 3D culture, repeated NIR-PIT could eradicate entire spheroids. In vivo anti-tumor effects of NIR-PIT included significant reductions in both tumor volume (p = 0.0141 vs. APC) and bioluminescence image (BLI) (p = 0.0086 vs. APC) in the flank model, and prolonged survival (p < 0.0001). BLI demonstrated a significant reduction in lung metastases volume (p = 0.0117 vs. APC). Multiple NIR-PIT doses significantly prolonged survival in the lung metastases model (p < 0.0001). These results suggested that NIR-PIT is a potential new therapy for the local control of lung metastases. PMID:26021765

A century of oilfield operations and earthquakes in the greater Los Angeles Basin, southern California

USGS Publications Warehouse

Hauksson, Egill; Goebel, Thomas; Ampuero, Jean-Paul; Cochran, Elizabeth S.

2015-01-01

Most of the seismicity in the Los Angeles Basin (LA Basin) occurs at depth below the sediments and is caused by transpressional tectonics related to the big bend in the San Andreas fault. However, some of the seismicity could be associated with fluid extraction or injection in oil fields that have been in production for almost a century and cover ∼ 17% of the basin. In a recent study, first the influence of industry operations was evaluated by analyzing seismicity characteristics, including normalized seismicity rates, focal depths, and b-values, but no significant difference was found in seismicity characteristics inside and outside the oil fields. In addition, to identify possible temporal correlations, the seismicity and available monthly fluid extraction and injection volumes since 1977 were analyzed. Second, the production and deformation history of the Wilmington oil field were used to evaluate whether other oil fields are likely to experience similar surface deformation in the future. Third, the maximum earthquake magnitudes of events within the perimeters of the oil fields were analyzed to see whether they correlate with total net injected volumes, as suggested by previous studies. Similarly, maximum magnitudes were examined to see whether they exhibit an increase with net extraction volume. Overall, no obvious previously unidentified induced earthquakes were found, and the management of balanced production and injection of fluids appears to reduce the risk of induced-earthquake activity in the oil fields.

Acute ethanol treatment increases level of progesterone in ovariectomized rats.

PubMed

Budec, Mirela; Koko, Vesna; Milovanović, Tatjana; Balint-Perić, Ljiljana; Petković, Aleksandra

2002-04-01

To determine whether an increased level of progesterone in adult female rats after acute ethanol treatment, described previously in our study, is the result of activation of adrenal glands, we analyzed adrenal cortex morphologically and measured serum levels of corticosterone and progesterone in ovariectomized rats. In addition, a possible involvement of the opioid system in an observed phenomenon was tested. Adult female Wistar rats were ovariectomized, and 3 weeks after surgery they were treated intraperitoneally with (a) ethanol (4 g/kg), (b) naltrexone (5 mg/kg), followed by ethanol (4 g/kg) 45 min later, and (c) naltrexone (5 mg/kg), followed by saline 45 min later. Untreated and saline-injected rats were used as controls. The animals were killed 0.5 h after ethanol administration. Morphometric analysis was carried out on paraffin sections of adrenal glands, stained with hematoxylin-eosin, and the following parameters were determined: absolute volume of the zona glomerulosa, the zona fasciculata, and the zona reticularis; numerical density, volume, and the mean diameter of adrenocortical cells and of their nuclei; and mean diameter and length of capillaries. The results showed that acute ethanol treatment significantly increased absolute volume of the zona fasciculata and length of its capillaries but did not alter other stereological parameters. Also, serum levels of corticosterone and progesterone were enhanced. Pretreatment with naltrexone had no effect on ethanol-induced changes. These findings are consistent with our previous hypothesis that an ethanol-induced increase of the progesterone level in adult female rats originates from the adrenal cortex.

Production of laccase by Pynoporus sanguineus using 2,5 - Xylidine and ethanol

PubMed Central

Valeriano, Viviane S.; Silva, Anna Maria F.; Santiago, Mariângela F.; Bara, Maria T. F.; Garcia, Telma A.

2009-01-01

Enzyme application in biotechnological and environmental processes has had increasing interest due to its efficiency, selectivity and mainly for being environmentally healthful, but these applications require a great volume of enzymes. In this work the effect of different concentrations of ethanol and 2,5-xylidine on growth and production of laccase by Pycnoporus sanguineus was investigated. In a medium containing 200 mg.L-1 of 2,5-xylidine or 50 g.L-1 of ethanol, the maximum activity of laccase was 2019 U.L-1 and 1035 U.L-1, respectively. No direct correlation between biomass and activity of laccase was observed for any of the inducers used during the tests. Ethanol concentrations, larger than or equal to 20 g.L-1, inhibited the radial growth of P. sanguineus. This study showed that ethanol, which has less toxicity and cost than the majority of the studied inducers, presents promising perspectives for laccase production by P. sanguineus. PMID:24031426

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF.

PubMed

Puerta, Elena; Hervias, Isabel; Barros-Miñones, Lucía; Jordan, Joaquin; Ricobaraza, Ana; Cuadrado-Tejedor, Mar; García-Osta, Ana; Aguirre, Norberto

2010-05-01

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD. Copyright 2010 Elsevier Inc. All rights reserved.

Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

PubMed Central

Nonomura, Keiko; Woo, Seung-Hyun; Chang, Rui B.; Gillich, Astrid; Qiu, Zhaozhu; Francisco, Allain G.; Ranade, Sanjeev S.; Liberles, Stephen D.; Patapoutian, Ardem

2017-01-01

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2+ vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering–Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults. PMID:28002412

Current-Induced Transistor Sensorics with Electrogenic Cells

PubMed Central

Fromherz, Peter

2016-01-01

The concepts of transistor recording of electroactive cells are considered, when the response is determined by a current-induced voltage in the electrolyte due to cellular activity. The relationship to traditional transistor recording, with an interface-induced response due to interactions with the open gate oxide, is addressed. For the geometry of a cell-substrate junction, the theory of a planar core-coat conductor is described with a one-compartment approximation. The fast electrical relaxation of the junction and the slow change of ion concentrations are pointed out. On that basis, various recording situations are considered and documented by experiments. For voltage-gated ion channels under voltage clamp, the effects of a changing extracellular ion concentration and the enhancement/depletion of ion conductances in the adherent membrane are addressed. Inhomogeneous ion conductances are crucial for transistor recording of neuronal action potentials. For a propagating action potential, the effects of an axon-substrate junction and the surrounding volume conductor are distinguished. Finally, a receptor-transistor-sensor is described, where the inhomogeneity of a ligand–activated ion conductance is achieved by diffusion of the agonist and inactivation of the conductance. Problems with regard to a development of reliable biosensors are mentioned. PMID:27120627

Tumor promoter-induced sulfiredoxin is required for mouse skin tumorigenesis.

PubMed

Wu, Lisha; Jiang, Hong; Chawsheen, Hedy A; Mishra, Murli; Young, Matthew R; Gerard, Matthieu; Toledano, Michel B; Colburn, Nancy H; Wei, Qiou

2014-05-01

Sulfiredoxin (Srx), the exclusive enzyme that reduces the hyperoxidized inactive form of peroxiredoxins (Prxs), has been found highly expressed in several types of human skin cancer. To determine whether Srx contributed to skin tumorigenesis in vivo, Srx null mice were generated on an FVB background. Mouse skin tumorigenesis was induced by a 7,12-dimethylbenz[α]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) protocol. We found that the number, volume and size of papillomas in Srx(-/-) mice were significantly fewer compared with either wild-type (Wt) or heterozygous (Het) siblings. Histopathological analysis revealed more apoptotic cells in tumors from Srx(-/-) mice. Mechanistic studies in cell culture revealed that Srx was stimulated by TPA in a redox-independent manner. This effect was mediated transcriptionally through the activation of mitogen-activated protein kinase and Jun-N-terminal kinase. We also demonstrated that Srx was capable of reducing hyperoxidized Prxs to facilitate cell survival under oxidative stress conditions. These findings suggested that loss of Srx protected mice, at least partially, from DMBA/TPA-induced skin tumorigenesis. Therefore, Srx has an oncogenic role in skin tumorigenesis and targeting Srx may provide novel strategies for skin cancer prevention or treatment.

Effect of Hygrophila spinosa in ethylene glycol induced nephrolithiasis in rats.

PubMed

Ingale, Kundan G; Thakurdesai, Prasad A; Vyawahare, Neeraj S

2012-01-01

Hygrophila spinosa (Acanthaceae) is traditionally used to treat urinary calculi. The present study aimed to evaluate the antiurolithiatic activity of methanolic extract of Hygrophila spinosa (Acanthaceae) in ethylene glycol induced nephrolithiasic rats. Methanolic extract of Hygrophila spinosa (HSME) (250 and 500 mg/ kg body weight) was administered orally to male Wistar albino rats. Ethylene glycol (EG) was used to induce nephrolithiasis. The parameters studied included water intake, urinary volume, urinary pH, urinary and kidney oxalate and calcium, urinary magnesium and serum uric acid. Ethylene glycol feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and serum uric acid along with decreased excretion of urinary magnesium. Treatment with HSME significantly reduced the elevated urinary oxalate, urinary calcium and serum uric acid with increase in reduced urinary magnesium. Ethylene glycol feeding also resulted in increased levels of calcium and oxalate in kidney which was decreased after the treatment with HSME. The increased deposition of stone forming constituents in the kidneys of ethylene glycol treated rats was significantly lowered by treatment with HSME. The results indicate that the aerial parts of Hygrophila spinosa are endowed with antiurolithiatic activity, thereby justifying its traditional claim.

Antitumor Activities of Rauwolfia vomitoria Extract and Potentiation of Carboplatin Effects Against Ovarian Cancer.

PubMed

Yu, Jun; Ma, Yan; Drisko, Jeanne; Chen, Qi

2013-12-01

Tumor resistance to platinum-based drugs has been an obstacle to the treatment of ovarian cancer. Extract of the plant Rauwolfia vomitoria has long been used by cancer patients. However, there have not been systematic studies of its anticancer activity. In an effort to enhance the effectiveness of platinum-based drugs, we investigated the anticancer effect of a Rauwolfia vomitoria extract (Rau), both alone and in combination with carboplatin (Cp). In vitro cytotoxicity and colony formation were evaluated in several ovarian cancer cell lines. In vivo effects were evaluated in an intraperitoneal ovarian cancer mouse model. The combination of Rau and Cp was assessed using Chou-Talalay's constant ratio design and median effect analysis based on the isobologram principle to determine the combination index values. Rau decreased cell growth in all 3 tested ovarian cancer cell lines dose dependently and completely inhibited formation of colonies in soft agar. Apoptosis was induced in a time- and dose-dependent manner and was the predominant form of Rau-induced cell death. Synergy of Rau with Cp was detected, with combination index values <1 and dose reduction index values for Cp ranging from 1.7- to 7-fold. Tumor growth in mice was significantly suppressed by 36% or 66% with Rau treatment alone at a low (20 mg/kg) or a high dose (50 mg/kg), respectively, an effect comparable to that of Cp alone. The volume of ascitic fluid and the number of nonblood cells in ascites were also significantly decreased. Combining Rau with Cp remarkably enhanced the effect of Cp and reduced tumor burden by 87% to 90% and ascites volume by 89% to 97%. Rau has potent antitumor activity and in combination significantly enhances the effect of Cp against ovarian cancer.

fMRI brain mapping during motion capture and FES induced motor tasks: signal to noise ratio assessment.

PubMed

Gandolla, Marta; Ferrante, Simona; Casellato, Claudia; Ferrigno, Giancarlo; Molteni, Franco; Martegani, Alberto; Frattini, Tiziano; Pedrocchi, Alessandra

2011-10-01

Functional Electrical Stimulation (FES) is a well known clinical rehabilitation procedure, however the neural mechanisms that underlie this treatment at Central Nervous System (CNS) level are still not completely understood. Functional magnetic resonance imaging (fMRI) is a suitable tool to investigate effects of rehabilitative treatments on brain plasticity. Moreover, monitoring the effective executed movement is needed to correctly interpret activation maps, most of all in neurological patients where required motor tasks could be only partially accomplished. The proposed experimental set-up includes a 1.5 T fMRI scanner, a motion capture system to acquire kinematic data, and an electro-stimulation device. The introduction of metallic devices and of stimulation current in the MRI room could affect fMRI acquisitions so as to prevent a reliable activation maps analysis. What we are interested in is that the Blood Oxygenation Level Dependent (BOLD) signal, marker of neural activity, could be detected within a given experimental condition and set-up. In this paper we assess temporal Signal to Noise Ratio (SNR) as image quality index. BOLD signal change is about 1-2% as revealed by a 1.5 T scanner. This work demonstrates that, with this innovative set-up, in the main cortical sensorimotor regions 1% BOLD signal change can be detected at least in the 93% of the sub-volumes, and almost 100% of the sub-volumes are suitable for 2% signal change detection. The integrated experimental set-up will therefore allows to detect FES induced movements fMRI maps simultaneously with kinematic acquisitions so as to investigate FES-based rehabilitation treatments contribution at CNS level. Copyright © 2011 IPEM. Published by Elsevier Ltd. All rights reserved.

Acute post-exercise myofibrillar protein synthesis is not correlated with resistance training-induced muscle hypertrophy in young men.

PubMed

Mitchell, Cameron J; Churchward-Venne, Tyler A; Parise, Gianni; Bellamy, Leeann; Baker, Steven K; Smith, Kenneth; Atherton, Philip J; Phillips, Stuart M

2014-01-01

Muscle hypertrophy following resistance training (RT) involves activation of myofibrillar protein synthesis (MPS) to expand the myofibrillar protein pool. The degree of hypertrophy following RT is, however, highly variable and thus we sought to determine the relationship between the acute activation of MPS and RT-induced hypertrophy. We measured MPS and signalling protein activation after the first session of resistance exercise (RE) in untrained men (n = 23) and then examined the relation between MPS with magnetic resonance image determined hypertrophy. To measure MPS, young men (24±1 yr; body mass index  = 26.4±0.9 kg•m²) underwent a primed constant infusion of L-[ring-¹³C₆] phenylalanine to measure MPS at rest, and acutely following their first bout of RE prior to 16 wk of RT. Rates of MPS were increased 235±38% (P<0.001) above rest 60-180 min post-exercise and 184±28% (P = 0.037) 180-360 min post exercise. Quadriceps volume increased 7.9±1.6% (-1.9-24.7%) (P<0.001) after training. There was no correlation between changes in quadriceps muscle volume and acute rates of MPS measured over 1-3 h (r = 0.02), 3-6 h (r = 0.16) or the aggregate 1-6 h post-exercise period (r = 0.10). Hypertrophy after chronic RT was correlated (r = 0.42, P = 0.05) with phosphorylation of 4E-BP1(Thr37/46) at 1 hour post RE. We conclude that acute measures of MPS following an initial exposure to RE in novices are not correlated with muscle hypertrophy following chronic RT.

Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes.

PubMed

Alvin, Zikiar V; Laurence, Graham G; Coleman, Bernell R; Zhao, Aiqiu; Hajj-Moussa, Majd; Haddad, Georges E

2011-07-01

Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes. Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively. Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes. Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia.

PubMed

Cerullo, Pierpaolo; Brancaccio, Paola; Anzilotti, Serenella; Vinciguerra, Antonio; Cuomo, Ornella; Fiorino, Ferdinando; Severino, Beatrice; Di Vaio, Paola; Di Renzo, Gianfranco; Annunziato, Lucio; Pignataro, Giuseppe

2018-06-01

Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O 2 . Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period. Copyright © 2018 Elsevier Ltd. All rights reserved.

Gas volume contents within a container, smart volume instrument

NASA Technical Reports Server (NTRS)

Van Buskirk, Paul D. (Inventor); Kelley, Anthony R. (Inventor)

2008-01-01

A method for determining the volume of an incompressible gas in a system including incompressible substances in a zero-gravity environment. The method includes inducing a volumetric displacement within a container and measuring the resulting pressure change. From this data, the liquid level can be determined.

Antinociceptive and anti-inflammatory activity of the ethanolic extract of Cymbidium aloifolium (L.).

PubMed

Howlader, Md Amran; Alam, Mahmudul; Ahmed, Kh Tanvir; Khatun, Farjana; Apu, Apurba Sarker

2011-10-01

The ethanol leaf extract of Cymbidium aloifolium (L.) was evaluated for its analgesic and antiinflammatory activities. The extract, at the dose of 200 and 400 mg kg(-1) body weight, exerted the analgesic activity by observing the number of abdominal contractions and anti-inflammatory activity against Carrageenin induced paw edema in mice by measuring the paw volume. The ethanolic extract of Cymbidium aloifolium (L.) showed statistically significant (p < 0.05) reduction of percentage of writhing of 33.57 and 61.31% at 200 and 400 mg kg(-1) oral dose, respectively, when compared to negative control. The Ethanolic plant extract also showed significant (p < 0.05) dose dependent reduction of mean increase of formation of paw edema. The results of the experiment and its statistical analysis showed that the ethanolic plant extract had shown significant (p < 0.05) dose dependent analgesic and anti-inflammatory activities when compared to the control.

Crude venom from nematocysts of Pelagia noctiluca (Cnidaria: Scyphozoa) elicits a sodium conductance in the plasma membrane of mammalian cells

NASA Astrophysics Data System (ADS)

Morabito, Rossana; Costa, Roberta; Rizzo, Valentina; Remigante, Alessia; Nofziger, Charity; La Spada, Giuseppa; Marino, Angela; Paulmichl, Markus; Dossena, Silvia

2017-01-01

Cnidarians may negatively impact human activities and public health but concomitantly their venom represents a rich source of bioactive substances. Pelagia noctiluca is the most venomous and abundant jellyfish of the Mediterranean Sea and possesses a venom with hemolytic and cytolytic activity for which the mechanism is largely unknown. Here we show that exposure of mammalian cells to crude venom from the nematocysts of P. noctiluca profoundly alters the ion conductance of the plasma membrane, therefore affecting homeostatic functions such as the regulation and maintenance of cellular volume. Venom-treated cells exhibited a large, inwardly rectifying current mainly due to permeation of Na+ and Cl-, sensitive to amiloride and completely abrogated following harsh thermal treatment of crude venom extract. Curiously, the plasma membrane conductance of Ca2+ and K+ was not affected. Current-inducing activity was also observed following delivery of venom to the cytosolic side of the plasma membrane, consistent with a pore-forming mechanism. Venom-induced NaCl influx followed by water and consequent cell swelling most likely underlie the hemolytic and cytolytic activity of P. noctiluca venom. The present study underscores unique properties of P. noctiluca venom and provides essential information for a possible use of its active compounds and treatment of envenomation.

An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death.

PubMed

Garcia-Belinchón, Mercè; Sánchez-Osuna, María; Martínez-Escardó, Laura; Granados-Colomina, Carla; Pascual-Guiral, Sònia; Iglesias-Guimarais, Victoria; Casanelles, Elisenda; Ribas, Judit; Yuste, Victor J

2015-08-21

Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as "apoptosis-necrosis continuum." To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like cell death. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death*

PubMed Central

Garcia-Belinchón, Mercè; Sánchez-Osuna, María; Martínez-Escardó, Laura; Granados-Colomina, Carla; Pascual-Guiral, Sònia; Iglesias-Guimarais, Victoria; Casanelles, Elisenda; Ribas, Judit; Yuste, Victor J.

2015-01-01

Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as “apoptosis-necrosis continuum.” To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like cell death. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death. PMID:26124276

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Cun; Ren, Yang; Cui, Lishan

Under high pressure, materials usually shrink during compression as described by an equation of state. Here, we present the anomalous volume expansion behavior of a one-dimensional Nb nanowire embedded in a NiTi transforming matrix, while the matrix undergoes a pressure-induced martensitic transformation. The Nb volume expansion depends on the NiTi transition pressure range from the matrix, which is controlled by the shear strain induced by different pressure transmitting media. The transformation-induced interfacial stresses between Nb and NiTi may play a major role in this anomaly. In conclusion, our discovery sheds new light on the nano-interfacial effect on mechanical anomalies inmore » heterogeneous systems during a pressure-induced phase transition.« less

Jak2 and Ca2+/calmodulin are key intermediates for bradykinin B2 receptor-mediated activation of Na+/H+ exchange in KNRK and CHO cells.

PubMed

Lefler, David; Mukhin, Yurii V; Pettus, Tobiah; Leeb-Lundberg, L M Fredrik; Garnovskaya, Maria N; Raymond, John R

2003-04-01

Na(+)/H(+) exchangers are ubiquitous in mammalian cells, carrying out key functions, such as cell volume defense, acid-base homeostasis, and regulation of the cytoskeleton. We used two screening technologies (FLIPR and microphysiometry) to characterize the signal transduction pathway used by the bradykinin B(2) receptor to activate Na(+)/H(+) exchange in two cell lines, KNRK and CHO. In both cell types, B(2) receptor activation resulted in rapid increases in the rate of proton extrusion that were sodium-dependent and could be blocked by the Na(+)/H(+) exchange inhibitors EIPA and MIA or by replacing extracellular sodium with TMA. Activation of Na(+)/H(+) exchange by bradykinin was concentration-dependent and could be blocked by the selective B(2) receptor antagonist HOE140, but not by the B(1) receptor antagonist des-Arg10-HOE140. Inhibitors of Jak2 tyrosine kinase (genistein and AG490) and of CAM (W-7 and calmidazolium) attenuated bradykinin-induced activation of Na(+)/H(+) exchange. Bradykinin induced formation of a complex between CAM and Jak2, supporting a regulatory role for Jak2 and CAM in the activation of Na(+)/H(+) exchange in KNRK and CHO cells. We propose that this pathway (B(2) receptor --> Jak2 --> CAM --> Na(+)/H(+) exchanger) is a fundamental regulator of Na(+)/H(+) exchange activity.

Semipurified Ethyl Acetate Partition of Methanolic Extract of Melastoma malabathricum Leaves Exerts Gastroprotective Activity Partly via Its Antioxidant-Antisecretory-Anti-Inflammatory Action and Synergistic Action of Several Flavonoid-Based Compounds

PubMed Central

Ismail Suhaimy, Noor Wahida; Noor Azmi, Ahmad Khusairi; Mohtarrudin, Norhafizah; Cheema, Manraj Singh

2017-01-01

Recent study has demonstrated the gastroprotective activity of crude methanolic extract of M. malabathricum leaves. The present study evaluated the gastroprotective potential of semipurified extracts (partitions): petroleum ether, ethyl acetate (EAMM), and aqueous obtained from the methanolic extract followed by the elucidation of the gastroprotective mechanisms of the most effective partition. Using the ethanol-induced gastric ulcer assay, all partitions exerted significant gastroprotection, with EAMM being the most effective partition. EAMM significantly (i) reduced the volume and acidity (free and total) while increasing the pH of gastric juice and enhanced the gastric wall mucus secretion when assessed using the pylorus ligation assay, (ii) increased the enzymatic and nonenzymatic antioxidant activity of the stomach tissue, (iii) lost its gastroprotective activity following pretreatment with N-omega-nitro-L-arginine methyl ester (L-NAME; NO blocker) or carbenoxolone (CBXN; NP-SH blocker), (iv) exerted antioxidant activity against various in vitro oxidation assays, and (v) showed moderate in vitro anti-inflammatory activity via the LOX-modulated pathway. In conclusion, EAMM exerts a remarkable NO/NP-SH-dependent gastroprotective effect that is attributed to its antisecretory and antioxidant activities, ability to stimulate the gastric mucus production and endogenous antioxidant system, and synergistic action of several gastroprotective-induced flavonoids. PMID:28168011

Reversing song behavior phenotype: testosterone driven induction of singing and measures of song quality in adult male and female canaries (Serinus canaria)

PubMed Central

Madison, Farrah N.; Rouse, Melvin L.; Balthazart, Jacques; Ball, Gregory F

2014-01-01

In songbirds, such as canaries (Serinus canaria), the song control circuit has been shown to undergo a remarkable change in morphology in response to exogenous testosterone (T). It is also well established that HVC, a telencephalic nucleus involved in song production, is significantly larger in males than in females. T regulates seasonal changes in HVC volume in males and exposure to exogenous T in adult females increases HVC volume and singing activity such that their song becomes more male-like in frequency and structure. However, whether there are sex differences in the ability of T to modulate changes in the song system and song behavior has not been investigated in canaries. In this study, we compared the effects of increasing doses of T on singing and song control nuclei volumes in adult male and female American Singer canaries exposed to identical environmental conditions. Males were castrated and all birds were placed on short days (8L:16D) for 8 weeks. Males and females were implanted either with a 2, 6 or 12 mm long Silastic™ implant filled with crystalline T or an empty 12 mm implant as control. Birds were then housed individually in sound attenuated chambers. Brains were collected from six birds from each group after 1 week or 3 weeks of treatment. Testosterone was not equally effective in increasing singing activity in both males and females. Changes in song quality and occurrence rate took place after a shorter latency in males than in females however, females did undergo marked changes in a number of measures of song behavior if given sufficient time. Males responded with an increase in HVC volume at all three doses. In females, T-induced changes in HVC volume only had limited amplitude and these volumes never reached male-typical levels a suggesting that there are sex differences in the neural substrate that responds to T. PMID:25260250

InSAR MSBAS Time-Series Analysis of Induced Seismicity in Colorado and Oklahoma

NASA Astrophysics Data System (ADS)

Barba, M.; Tiampo, K. F.; Samsonov, S. V.

2016-12-01

Since 2009, the number of earthquakes in the central and eastern United States has dramatically increased from an average of 24 M ≥ 3 earthquakes a year (1973-2008) to an average of 193 M ≥ 3 earthquakes a year (2009-2014) (Ellsworth, 2013). Wastewater injection, the deep disposal of fluids, is considered to be the primary reason for this increase in seismicity rate (Weingarten et al., 2015). We use Interferometric Synthetic Aperture Radar (InSAR) to study four potential regions with injection induced seismicity: Greely, CO, Platteville, CO, Edmond, OK, and Jones, OK. Currently, Platteville is not seismically active; however, it serves as a baseline since its high-volume injection wells have the potential to induce future earthquakes. InSAR data complements seismic data by providing insight into the surface deformation potentially correlated with earthquake activity. To study the ground deformation associated with the induced seismicity and injection well activity, we develop full-resolution interferograms using raw radar data from Radarsat-1/2, ERS-1/2, Envisat, ALOS, and Sentinel-1. We pair the SAR images using the small perpendicular baseline approach (Berardino et al., 2002) to minimize spatial decorrelation. The paired SAR images are processed into interferograms using the JPL ISCE software (Gurrola et al., 2010). Using the MSBAS algorithm (Samsonov et al., 2013, Samsonov and d'Oreye, 2012) and the JPL GIAnT software (Agram et al., 2013), we construct a time-series of the cumulative surface displacement, integrating all interferograms for the region. To correlate the relationship between surface deformation and wastewater injection, we compare the well locations, depths, and injection rates with the spatial and temporal signature of the surface deformation before and after induced earthquakes, filling in the spatiotemporal gap lacking from seismicity. By monitoring the surface deformation for wells associated with past and current induced seismicity, we can implement measures to mitigate induced seismicity and its social and economic impact.

Stretch-Induced Hypertrophy Activates NFkB-Mediated VEGF Secretion in Adult Cardiomyocytes

PubMed Central

Leychenko, Anna; Konorev, Eugene; Jijiwa, Mayumi; Matter, Michelle L.

2011-01-01

Hypertension and myocardial infarction are associated with the onset of hypertrophy. Hypertrophy is a compensatory response mechanism to increases in mechanical load due to pressure or volume overload. It is characterized by extracellular matrix remodeling and hypertrophic growth of adult cardiomyocytes. Production of Vascular Endothelial Growth Factor (VEGF), which acts as an angiogenic factor and a modulator of cardiomyocyte function, is regulated by mechanical stretch. Mechanical stretch promotes VEGF secretion in neonatal cardiomyocytes. Whether this effect is retained in adult cells and the molecular mechanism mediating stretch-induced VEGF secretion has not been elucidated. Our objective was to investigate whether cyclic mechanical stretch induces VEGF secretion in adult cardiomyocytes and to identify the molecular mechanism mediating VEGF secretion in these cells. Isolated primary adult rat cardiomyocytes (ARCMs) were subjected to cyclic mechanical stretch at an extension level of 10% at 30 cycles/min that induces hypertrophic responses. Cyclic mechanical stretch induced a 3-fold increase in VEGF secretion in ARCMs compared to non-stretch controls. This increase in stretch-induced VEGF secretion correlated with NFkB activation. Cyclic mechanical stretch-mediated VEGF secretion was blocked by an NFkB peptide inhibitor and expression of a dominant negative mutant IkBα, but not by inhibitors of the MAPK/ERK1/2 or PI3K pathways. Chromatin immunoprecipitation assays demonstrated an interaction of NFkB with the VEGF promoter in stretched primary cardiomyocytes. Moreover, VEGF secretion is increased in the stretched myocardium during pressure overload-induced hypertrophy. These findings are the first to demonstrate that NFkB activation plays a role in mediating VEGF secretion upon cyclic mechanical stretch in adult cardiomyocytes. Signaling by NFkB initiated in response to cyclic mechanical stretch may therefore coordinate the hypertrophic response in adult cardiomyocytes. Elucidation of this novel mechanism may provide a target for developing future pharmacotherapy to treat hypertension and heart disease. PMID:22174951

Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Yuanxue; Xu, Xiaojun; Chang, Sai

The natural product totarol, a phenolic diterpenoid and a major constituent isolated from the sap of Podocarpus totara, has been reported to have a potent antimicrobial activity. In this study, we determined whether totarol possessed an additional neuroprotective activity in vitro and in vivo. We found that totarol prevented glutamate- and oxygen and glucose deprivation-induced neuronal death in primary rat cerebellar granule neuronal cells and cerebral cortical neurons. Totarol increased Akt and GSK-3β phosphorylation, Nrf2 and heme oxygenase-1 (HO-1) protein expressions and suppressed oxidative stress by increasing GSH and SOD activities. The PI3K/Akt inhibitor LY294002 prevented totarol neuroprotective effect bymore » suppressing the totarol-induced changes in HO-1 expression and the activities of GSH and SOD. The HO-1 inhibitor ZnPPIX also prevented totarol-increased GSH and SOD activities. In a model of acute cerebral ischemic injury in Sprague–Dawley rats, produced by occlusion of the middle cerebral artery for 2 h followed by 22 h or 46 h of reperfusion, totarol significantly reduced infarct volume and improved the neurological deficit. In this model, totarol increased HO-1 expression and the activities of GSH and SOD. These observations suggest that totarol may be a novel activator of the Akt/HO-1 pathway protecting against ischemic stroke through reduction of oxidative stress. - Graphical abstract: It is unknown whether the natural product totarol has neuroprotective effects in vitro and in vivo. This study underscores that totarol prevents neuronal injury in vitro, not only by activating PI3K/Akt pathway, but also via induction of Nrf2, HO-1, GSH and SOD expressions. Totarol also ameliorated acute cerebral ischemic injury in a rat ischemic stroke model. The findings highlight that totarol may be exploited for protecting against ischemic stroke through Akt/HO-1 pathway. - Highlights: • Totarol protects glutamate- and OGD-induced neuronal injury in vitro. • Totarol activates PI3K/Akt pathway in neurons. • Totarol induces HO-1, GSH and SOD expression in vitro and in vivo. • Totarol exhibits neuroprotective effects in rat brain ischemic stroke model.« less

Anthropogenic seismicity rates and operational parameters at the Salton Sea Geothermal Field.

PubMed

Brodsky, Emily E; Lajoie, Lia J

2013-08-02

Geothermal power is a growing energy source; however, efforts to increase production are tempered by concern over induced earthquakes. Although increased seismicity commonly accompanies geothermal production, induced earthquake rate cannot currently be forecast on the basis of fluid injection volumes or any other operational parameters. We show that at the Salton Sea Geothermal Field, the total volume of fluid extracted or injected tracks the long-term evolution of seismicity. After correcting for the aftershock rate, the net fluid volume (extracted-injected) provides the best correlation with seismicity in recent years. We model the background earthquake rate with a linear combination of injection and net production rates that allows us to track the secular development of the field as the number of earthquakes per fluid volume injected decreases over time.

Experimental study on beryllium-7 production via sequential reactions in lithium-containing compounds irradiated by 14 MeV neutrons

NASA Astrophysics Data System (ADS)

Maekawa, F.; Verzilov, Y. M.; Smith, D. L.; Ikeda, Y.

2000-12-01

Except for 3H and 14C, no radioactive nuclide is produced by neutron-induced reactions with lithium in lithium-containing materials such as Li 2O and Li 2CO 3. However, when the lithium-containing materials are irradiated by 14 MeV neutrons, radioactive 7Be is produced by sequential charged particle reactions (SCPR). In this study, we measured effective 7Be production cross-sections in several lithium-containing samples at 14 MeV: the cross-sections are in the order of μb. Estimation of the effective cross-sections is attempted, and the estimated values agreed well with the experimental data. It was shown that the 7Be activity in a unit volume of lithium-containing materials in D-T fusion reactors can exceed total activity of the same unit volume of the SiC structural material in a certain cooling time. Consequently, a careful consideration of the 7Be production by SCPR is required to assess radioactive inventories in lithium-containing D-T fusion blanket materials.

Changes in the size and synthetic activity of nuclear populations in chronically stimulated rabbit skeletal muscle.

PubMed Central

Joplin, R E; Franchi, L L; Salmons, S

1987-01-01

The adaptive response of mammalian fast-twitch skeletal muscle to long-term low-frequency stimulation involves coordinated changes in the expression of a large number of genes and an increase in the synthesis of proteins and nucleic acids. Morphological correlates of these changes were sought in a qualitative and quantitative study of nuclear populations that included autoradiography at both light and electron microscopic levels. Stimulation-induced changes in biosynthetic activity were found to be supported by increases in the numbers of both non-muscle and muscle nuclei, and myonuclear counts were significantly increased in relation to sarcoplasmic volume. Moreover, the chronically stimulated muscle fibres showed ultrastructural signs consistent with mobilisation of transcriptional and translational activity. Images Fig. 2 Fig. 4 (cont.) Fig. 4 Fig. 5 PMID:3503051

Photoacoustic imaging to detect rat brain activation after cocaine hydrochloride injection

NASA Astrophysics Data System (ADS)

Jo, Janggun; Yang, Xinmai

2011-03-01

Photoacoustic imaging (PAI) was employed to detect small animal brain activation after the administration of cocaine hydrochloride. Sprague Dawley rats were injected with different concentrations (2.5, 3.0, and 5.0 mg per kg body) of cocaine hydrochloride in saline solution through tail veins. The brain functional response to the injection was monitored by photoacoustic tomography (PAT) system with horizontal scanning of cerebral cortex of rat brain. Photoacoustic microscopy (PAM) was also used for coronal view images. The modified PAT system used multiple ultrasonic detectors to reduce the scanning time and maintain a good signal-to-noise ratio (SNR). The measured photoacoustic signal changes confirmed that cocaine hydrochloride injection excited high blood volume in brain. This result shows PAI can be used to monitor drug abuse-induced brain activation.

Comparison of surgical conditions in 2 different anesthesia techniques of esmolol-induced controlled hypotension in breast reduction surgery

PubMed Central

Besir, Ahmet; Cekic, Bahanur; Kutanis, Dilek; Akdogan, Ali; Livaoglu, Murat

2017-01-01

Abstract Background: Breast reduction surgery is a common cosmetic surgery with a high incidence of blood loss and transfusion. In this surgery, the reduction of blood loss related to surgical manipulation and the volume of resected tissue is a target. In the present study, we compared the effects of esmolol-induced controlled hypotension on surgical visibility, surgical bleeding, and the duration of surgery in patients anesthetized with propofol/remifentanil (PR) or sevoflurane/remifentanil (SR). Methods: Patients in the American Society of Anesthesiologists I/II risk group undergoing breast reduction surgery were prospectively randomized into PR (n = 25) and SR (n = 25) groups. Controlled hypotension was induced with esmolol in both groups. During the intraoperative period, the heart rate (HR), mean arterial pressure (MAP), operation duration, volume of intraoperative blood loss, volume of blood received through postoperative drains, volume of resected tissues, and surgical area bleeding score were recorded. Results: The duration of operation in the incisional period was shorter in group PR compared to group SR (P = 0.04). The change in HR was lower in incision and hemostasis periods in the group PR compared to the group SR (P < 0.001). Total intraoperative intraoperative bleeding volume and volume of blood received through drains on postoperative postoperative day 1, day 2, and in total were found to be significantly lower in group PR compared to group SR. Surgical visibility scoring was more effective in group PR compared to SR. Conclusion: In the breast reduction surgery performed under esmolol-induced controlled hypotension, the effect of propofol + remifentanil anesthesia on the duration of incisional surgery, surgical visibility, and volume of surgical blood loss was more reliable and effective compared to that of sevoflurane + remifentanil, which seems to be an advantage. PMID:28272228

Prevention of contrast-induced acute kidney injury: is simple oral hydration similar to intravenous? A systematic review of the evidence.

PubMed

Hiremath, Swapnil; Akbari, Ayub; Shabana, Wael; Fergusson, Dean A; Knoll, Greg A

2013-01-01

Pre-procedural intravenous fluid administration is an effective prophylaxis measure for contrast-induced acute kidney injury. For logistical ease, the oral route is an alternative to the intravenous. The objective of this study was to compare the efficacy of the oral to the intravenous route in prevention of contrast-induced acute kidney injury. A systematic review and meta-analysis of randomised trials with a stratified analysis and metaregression. Databases included MEDLINE (1950 to November 23 2011), EMBASE (1947 to week 47 2011), Cochrane CENTRAL (3(rd) quarter 2011). Two reviewers identified relevant trials and abstracted data. SETTINGS AND POPULATION: Trials including patients undergoing a contrast enhanced procedure. Randomised controlled trial; adult (>18 years) population; comparison of oral versus intravenous volume expansion. Oral route of volume expansion compared to the intravenous route. Any measure of acute kidney injury, need for renal replacement therapy, hospitalization and death. Six trials including 513 patients met inclusion criteria. The summary odds ratio was 1.19 (95% CI 0.46, 3.10, p = 0.73) suggesting no difference between the two routes of volume expansion. There was significant heterogeneity (Cochran's Q = 11.65, p = 0.04; I(2) = 57). In the stratified analysis, inclusion of the five studies with a prespecified oral volume expansion protocol resulted in a shift towards oral volume expansion (OR 0.75, 95% CI 0.37, 1.50, p = 0.42) and also resolved the heterogeneity (Q = 3.19, P = 0.53; I(2) = 0). Small number of studies identified; lack of hard clinical outcomes. The oral route may be as effective as the intravenous route for volume expansion for contrast-induced acute kidney injury prevention. Adequately powered trials with hard endpoints should be done given the potential advantages of oral (e.g. reduced patient burden and cost) over intravenous volume expansion.

Memantine attenuates cell apoptosis by suppressing the calpain-caspase-3 pathway in an experimental model of ischemic stroke.

PubMed

Chen, Bin; Wang, Guoxiang; Li, Weiwei; Liu, Weilin; Lin, Ruhui; Tao, Jing; Jiang, Min; Chen, Lidian; Wang, Yun

2017-02-15

Ischemic stroke, the second leading cause of death worldwide, leads to excessive glutamate release, over-activation of N-methyl-D-aspartate receptor (NMDAR), and massive influx of calcium (Ca 2+ ), which may activate calpain and caspase-3, resulting in cellular damage and death. Memantine is an uncompetitive NMDAR antagonist with low-affinity/fast off-rate. We investigated the potential mechanisms through which memantine protects against ischemic stroke in vitro and in vivo. Middle cerebral artery occlusion-reperfusion (MCAO) was performed to establish an experimental model of ischemic stroke. The neuroprotective effects of memantine on ischemic rats were evaluated by neurological deficit scores and infarct volumes. The activities of calpain and caspase-3, and expression levels of microtubule-associated protein-2 (MAP2) and postsynaptic density-95 (PSD95) were determined by Western blotting. Additionally, Nissl staining and immunostaining were performed to examine brain damage, cell apoptosis, and neuronal loss induced by ischemia. Our results show that memantine could significantly prevent ischemic stroke-induced neurological deficits and brain infarct, and reduce ATP depletion-induced neuronal death. Moreover, memantine markedly suppressed the activation of the calpain-caspase-3 pathway and cell apoptosis, and consequently, attenuated brain damage and neuronal loss in MCAO rats. These results provide a molecular basis for the role of memantine in reducing neuronal apoptosis and preventing neuronal damage, suggesting that memantine may be a promising therapy for stroke patients. Copyright © 2017 Elsevier Inc. All rights reserved.

PPAR{gamma} agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Seong-Ryong; Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu; Kim, Hahn-Young

2009-02-27

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation withmore » pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.« less

Measurement of myeloid maturation by flow cytochemistry in HL-60 leukemia: esterase is inducible, myeloperoxidase is not.

PubMed

Ross, D W

1986-05-01

The phenomenon of leukemic cell maturation requires a measurement of myeloid maturation to understand the process and to exploit it as a means of therapy for leukemia. The HL-60 leukemic cell line was used as a model of induced leukemic cell maturation in order to develop a method of quantitating granulocytic and monocytic maturation in response to drug therapy. An automated flow cytochemistry system (Hemalog-D) was employed to measure mean cell volume, myeloperoxidase (MPO), and nonspecific esterase (NSE). For granulocytic maturation induced by vitamin A or DMSO, MPO and cell volume decreased by 50%, maintaining a constant mean cellular MPO concentration throughout maturation from promyelocyte to neutrophil-like forms. For monocytic maturation induced by low-dose ARA-c, the mean NSE increased substantially, while cell volume remained constant. Unlike MPO concentration, NSE was truly inducible and thus a useful quantitative measure of maturation caused by low-dose ARA-c. Flow cytochemistry and cytofluorometry may be developed to allow for quantitative monitoring of therapeutic trials of induced maturation in human leukemias. However, this will require adapting these techniques to the complexity of human leukemias in vivo, and the necessity of handling heterogeneous populations encountered in bone marrow samples.

Non-verbal emotion communication training induces specific changes in brain function and structure

PubMed Central

Kreifelts, Benjamin; Jacob, Heike; Brück, Carolin; Erb, Michael; Ethofer, Thomas; Wildgruber, Dirk

2013-01-01

The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure. PMID:24146641

Non-verbal emotion communication training induces specific changes in brain function and structure.

PubMed

Kreifelts, Benjamin; Jacob, Heike; Brück, Carolin; Erb, Michael; Ethofer, Thomas; Wildgruber, Dirk

2013-01-01

The perception of emotional cues from voice and face is essential for social interaction. However, this process is altered in various psychiatric conditions along with impaired social functioning. Emotion communication trainings have been demonstrated to improve social interaction in healthy individuals and to reduce emotional communication deficits in psychiatric patients. Here, we investigated the impact of a non-verbal emotion communication training (NECT) on cerebral activation and brain structure in a controlled and combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry study. NECT-specific reductions in brain activity occurred in a distributed set of brain regions including face and voice processing regions as well as emotion processing- and motor-related regions presumably reflecting training-induced familiarization with the evaluation of face/voice stimuli. Training-induced changes in non-verbal emotion sensitivity at the behavioral level and the respective cerebral activation patterns were correlated in the face-selective cortical areas in the posterior superior temporal sulcus and fusiform gyrus for valence ratings and in the temporal pole, lateral prefrontal cortex and midbrain/thalamus for the response times. A NECT-induced increase in gray matter (GM) volume was observed in the fusiform face area. Thus, NECT induces both functional and structural plasticity in the face processing system as well as functional plasticity in the emotion perception and evaluation system. We propose that functional alterations are presumably related to changes in sensory tuning in the decoding of emotional expressions. Taken together, these findings highlight that the present experimental design may serve as a valuable tool to investigate the altered behavioral and neuronal processing of emotional cues in psychiatric disorders as well as the impact of therapeutic interventions on brain function and structure.

Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation.

PubMed

Glynos, Constantinos; Toumpanakis, Dimitris; Loverdos, Konstantinos; Karavana, Vassiliki; Zhou, Zongmin; Magkou, Christina; Dettoraki, Maria; Perlikos, Fotis; Pavlidou, Athanasia; Kotsikoris, Vasilis; Topouzis, Stavros; Theocharis, Stamatios E; Brouckaert, Peter; Giannis, Athanassios; Papapetropoulos, Andreas; Vassilakopoulos, Theodoros

2015-06-01

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.