In JoVE (1)

Other Publications (160)

Articles by Pei Zhong in JoVE

Other articles by Pei Zhong on PubMed

In Vivo Assessment of Free Radical Activity During Shock Wave Lithotripsy Using a Microdialysis System: the Renoprotective Action of Allopurinol

The Journal of Urology. Jan, 2002  |  Pubmed ID: 11743351

Shock wave lithotripsy is believed to cause renal damage directly through cellular injury from high energy shock waves and indirectly through vascular injury and resultant ischemia, which gives rise to oxygen free radical compounds. The transient and volatile nature of free radicals and derived products makes their detection difficult. Moreover, certain medications may provide a protective effect against shock wave lithotripsy induced renal parenchymal injury. We introduced an innovative microdialysis system for in vivo sampling of interstitial fluids that can be analyzed for free radical mediated lipid peroxidation products after shock wave lithotripsy treatment in the swine model. In addition, this system was used to test the antioxidant or renoprotective action of allopurinol.

Pre-treatment with Melatonin Reduces Volume of Cerebral Infarction in a Permanent Middle Cerebral Artery Occlusion Stroke Model in the Rat

Neuroscience Letters. Feb, 2002  |  Pubmed ID: 11803119

We investigated whether pre-treatment with melatonin, a potent free radical scavenger and antioxidant, would protect against permanent focal cerebral ischemia without reperfusion in a rat middle cerebral artery occlusion (MCAO) model. A single dose of melatonin at 5, 15, or 50 mg/kg or the vehicle alone was given via an intraperitoneal injection at 0.5 h before permanent MCAO. Relative infarction volumes on day 3 were significantly reduced in the groups treated with melatonin at 5 (mean+/-SEM, 17.0+/-6.5%), 15 (18.1+/-5.8%), or 50 (20.6+/-5.0%) mg/kg when compared with the vehicle-treated group (37.1+/-2.8%) and so melatonin treatment achieved a relative reduction in infarct volume by 54.2, 51.2 and 44.5%, respectively. Melatonin did not affect the hemodynamic parameters. Thus, pre-treatment with melatonin at a dose between 5 and 50 mg/kg protects against focal cerebral ischemia without reperfusion.

Pretreatment with Melatonin Reduces Volume of Cerebral Infarction in a Rat Middle Cerebral Artery Occlusion Stroke Model

Journal of Pineal Research. Apr, 2002  |  Pubmed ID: 12074100

Melatonin is a potent scavenger of free radicals and an indirect antioxidant. Recent studies have shown that melatonin possesses beneficial effects in experimental models of brain trauma and global cerebral ischemia. The effects of pretreatment with melatonin on volume of cerebral infarction were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hr. A single dose of melatonin (1.5, 5, 15, or 50 mg/kg in 1 mL normal saline) or its vehicle was given via an intraperitoneal injection at 0.5 hr before MCAO. Relative infarction volumes on day 3 after MCAO were significantly reduced in the groups treated with melatonin at 5 (mean +/- S.E.M., 15.7 +/- 2.5%) or 15 (21.4 +/- 3.1 %) mg/kg but not at 1.5 (30.6 +/- 3.5%) or 50 (26.7 +/- 2.8%) mg/ kg when compared with the vehicle group (33.9 +/- 3.5%). There was no significant difference in the arterial blood pressure (BP), heart rate (HR) and relative cerebral blood flow among the experimental groups. These results indicate that pretreatment with melatonin at a dose between 5 and 15 mg/kg protects against focal cerebral ischemia.

The Role of Stress Waves and Cavitation in Stone Comminution in Shock Wave Lithotripsy

Ultrasound in Medicine & Biology. May, 2002  |  Pubmed ID: 12079703

Using an experimental system that mimics stone fragmentation in the renal pelvis, we have investigated the role of stress waves and cavitation in stone comminution in shock-wave lithotripsy (SWL). Spherical plaster-of-Paris stone phantoms (D = 10 mm) were exposed to 25, 50, 100, 200, 300 and 500 shocks at the beam focus of a Dornier HM-3 lithotripter operated at 20 kV and a pulse repetition rate of 1 Hz. The stone phantoms were immersed either in degassed water or in castor oil to delineate the contribution of stress waves and cavitation to stone comminution. It was found that, while in degassed water there is a progressive disintegration of the stone phantoms into small pieces, the fragments produced in castor oil are fairly sizable. From 25 to 500 shocks, clinically passable fragments (< 2 mm) produced in degassed water increases from 3% to 66%, whereas, in castor oil, the corresponding values are from 2% to 11%. Similar observations were confirmed using kidney stones with a primary composition of calcium oxalate monohydrate. After 200 shocks, 89% of the fragments of the kidney stones treated in degassed water became passable, but only 22% of the fragments of the kidney stones treated in castor oil were less than 2 mm in size. This apparent size limitation of the stone fragments produced primarily by stress waves (in castor oil) is likely caused by the destructive superposition of the stress waves reverberating inside the fragments, when their sizes are less than half of the compressive wavelength in the stone material. On the other hand, if a stone is only exposed to cavitation bubbles induced in SWL, the resultant fragmentation is much less effective than that produced by the combination of stress waves and cavitation. It is concluded that, although stress wave-induced fracture is important for the initial disintegration of kidney stones, cavitation is necessary to produce fine passable fragments, which are most critical for the success of clinical SWL. Stress waves and cavitation work synergistically, rather than independently, to produce effective and successful disintegration of renal calculi in SWL

In Vitro Comparison of Standard Ultrasound and Pneumatic Lithotrites with a New Combination Intracorporeal Lithotripsy Device

Urology. Jul, 2002  |  Pubmed ID: 12100916

A new combination intracorporeal lithotripter (Lithoclast Ultra) has been developed that incorporates the beneficial effects of pneumatic lithotripsy (rapid stone fragmentation) and ultrasound lithotripsy (rapid fragment removal). An in vitro study was performed to assess the efficiency of stone fragmentation and clearance of this new combination intracorporeal lithotripter compared with currently available ultrasound and pneumatic units.

Cyclooxygenase-1 Gene Knockout Does Not Alter Middle Cerebral Artery Occlusion in a Mouse Stroke Model

Neuroscience Letters. Sep, 2002  |  Pubmed ID: 12213634

Cyclooxygenase (COX) is crucial in inflammation; COX-1 is constitutional, and COX-2 is inducible. In this study, neurological function and infarct volume were evaluated at 24 h after permanent endovascular middle cerebral artery occlusion (MCAO) in both COX-1-gene knockout (homozygous or heterozygous) and wide-type mice. Similar infarct volumes and neurological deficits were seen among mice of different genotypes. There was no difference among the groups in arterial blood pressure and regional cerebral blood flow during the first 30 min of ischemia. Our results failed to confirm the harmful effect of losing COX-1 activity due to gene knockout in a permanent endovascular MCAO mouse stroke model.

BegoStone--a New Stone Phantom for Shock Wave Lithotripsy Research

The Journal of the Acoustical Society of America. Oct, 2002  |  Pubmed ID: 12398432

Suppression of Large Intraluminal Bubble Expansion in Shock Wave Lithotripsy Without Compromising Stone Comminution: Refinement of Reflector Geometry

The Journal of the Acoustical Society of America. Jan, 2003  |  Pubmed ID: 12558294

Using the Hamilton model [Hamilton, J. Acoust. Soc. Am. 93, 1256-1266 (1993)], the effects of reflector geometry on the pulse profile and sequence of the shock waves produced by the original and upgraded reflector of an HM-3 lithotripter were evaluated qualitatively. Guided by this analysis, we have refined the geometry of the upgraded reflector to enhance its suppressive effect on intraluminal bubble expansion without compromising stone comminution in shock wave lithotripsy. Using the original HM-3 reflector at 20 kV, rupture of a standard vessel phantom made of cellulose hollow fiber (i.d. = 0.2 mm), in which degassed water seeded with ultrasound contrast agents was circulated, was produced at the lithotripter focus after about 30 shocks. In contrast, using the upgraded reflector at 24 kV no rupture of the vessel phantom could be produced within a 20-mm diameter around the lithotripter focus even after 200 shocks. On the other hand, stone comminution was comparable between the two reflector configurations, although slightly larger fragments were produced by the upgraded reflector. After 2000 shocks, stone comminution efficiency produced by the original HM-3 reflector at 20 kV is 97.15 +/- 1.92% (mean +/- SD), compared to 90.35 +/- 1.96% produced by the upgraded reflector at 24 kV (p<0.02). All together, it was found that the upgraded reflector could significantly reduce the propensity for vessel rupture in shock wave lithotripsy while maintaining satisfactory stone comminution.

Melatonin Protects SHSY5Y Neuronal Cells but Not Cultured Astrocytes from Ischemia Due to Oxygen and Glucose Deprivation

Journal of Pineal Research. Apr, 2003  |  Pubmed ID: 12614479

As a potent free radical scavenger and antioxidant, melatonin protects brain tissue against ischemia-reperfusion injury, partly via suppression of ischemia-induced production of nitric oxide, when given before ischemia-reperfusion or within 2 hr of onset of ischemia. In this study, we examined the neuroprotective effect of melatonin in an in vitro model of ischemia. Primary cultured astrocytes were subjected to 4 or 8 hr of oxygen-glucose deprivation (OGD), and cultured SHSY5Y human neuronal cells were exposed to 1 hr of OGD. Melatonin was added to the medium at the commencement of OGD to achieve different final concentrations, and cell death was quantified using the measurement of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) at 24 hr after reversion of OGD. Treatment with melatonin did not affect the astrocytic cell death following 4 or 8 hr of OGD. The relative MTT values of the neuronal cells were (as mean +/- S.E.M.) 59.1 +/- 2.4% in the vehicle-treated OGD group and 80.1 +/- 2.7%, 82.5 +/- 2.9%, 74.1 +/- 2.3%, 64.2 +/- 2.3%, 62.7 +/- 2.8%, and 61.0 +/- 3.9% in the OGD groups treated with melatonin at 10(-3), 10(-4), 10(-5), 10(-6), 10(-7), and 10(-8) m, respectively. Reduction in cell death was significant following treatment with melatonin at 10(-3), 10(-4), or 10(-5) m. Reverse transcription-polymerase chain reaction showed that human mt1 and MT2 membrane receptors were not expressed in the cultured neuronal cells. Our results show that melatonin co-treatment protects cultured neuronal cells but not astrocytes against OGD-induced cell death in a dose-dependent manner and that the neuroprotection is independent of its known membrane receptors.

Administration of Melatonin After Onset of Ischemia Reduces the Volume of Cerebral Infarction in a Rat Middle Cerebral Artery Occlusion Stroke Model

Stroke. Mar, 2003  |  Pubmed ID: 12624306

In both permanent and transient 3-hour middle cerebral artery occlusion rat stroke models, a single intraperitoneal injection of melatonin at 5 or 15 mg/kg given before ischemia was shown to reduce infarct volume at 72 hours. The present study was conducted to examine the treatment time window when melatonin was commenced after onset of ischemia.

Clinical Efficacy of a Combination Pneumatic and Ultrasonic Lithotrite

The Journal of Urology. Apr, 2003  |  Pubmed ID: 12629336

A new combination pneumatic/ultrasonic intracorporeal lithotriptor has been developed for percutaneous applications. It combines the stone clearing efficiency of an ultrasonic device with the fragmentation strength of a pneumatic probe into a single handpiece. We present our early clinical experience with this device in a prospective, randomized comparison a combination pneumatic/ultrasound lithotrite and standard ultrasonic lithotripsy.

Shock Wave Lithotripsy Causes Ipsilateral Renal Injury Remote from the Focal Point: the Role of Regional Vasoconstriction

The Journal of Urology. Apr, 2003  |  Pubmed ID: 12629408

Shock wave lithotripsy induced renal damage can occur as a result of multiple mechanisms, including small vessel injury and free radical production. Previous studies have demonstrated that shock wave lithotripsy exerts a regional change in renal hemodynamics, resulting in a global reduction in the glomerular filtration rate and renal plasma blood flow. We determined if biochemical evidence of cellular damage could be identified in ipsilateral locations remote from the shock wave site or in the contralateral kidney, suggesting regional or systemic alterations in renal function.

In Vitro Analysis of Stone Fragmentation Ability of the FREDDY Laser

Journal of Endourology. Apr, 2003  |  Pubmed ID: 12803991

The Frequency-Doubled Double-Pulse Nd:Yag) (FREDDY) laser (World of Medicine, Berlin Germany) is a short-pulsed, double-frequency solid-state laser with wavelengths of 532 and 1064 nm. This low-power, low-cost laser was developed for intracorporeal lithotripsy. We designed an experimental set-up to test its fragmentation efficiency at different energy and frequency settings.

COX-2-deficient Mice Are Less Prone to MPTP-neurotoxicity Than Wild-type Mice

Neuroreport. Oct, 2003  |  Pubmed ID: 14561922

The primary lesion in Parkinson's disease is the death of dopaminergic neurons in the substantia nigra. The role of cyclooxygenase (COX)-2 in the etiology of Parkinson's disease was explored using COX-2 gene knockout mice. Mortality after injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP, a chemical known to cause parkinsonism in humans) in heterozygous COX-2-deficient mice was lower than that in wild-type mice. The number of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta of MPTP-treated wild-type mice declined to a greater extent than in heterozygous mice. Inhibition of COX-2 protein expression decreased the lesion caused by MPTP and protected the dopaminergic neurons in substantia nigra pars compacta. This result suggested that inhibition of COX-2 has potential therapeutic implications.

Evaluation of Synchronous Twin Pulse Technique for Shock Wave Lithotripsy: Determination of Optimal Parameters for in Vitro Stone Fragmentation

The Journal of Urology. Dec, 2003  |  Pubmed ID: 14634376

The Twinheads extracorporeal shock wave lithotriptor (THSWL) is composed of 2 identical shock wave generators and reflectors. One reflector is under the table and the other is over the table with a variable angle between the axes of the 2 reflectors. The 2 reflectors share a common second focal point, making it possible to deliver an almost synchronous twin pulse to the targeted stone. We studied the optimal parameters for in vitro stone fragmentation.

Reduction of Tissue Injury in Shock-wave Lithotripsy by Using an Acoustic Diode

Ultrasound in Medicine & Biology. May, 2004  |  Pubmed ID: 15183234

An acoustic diode (AD) was constructed of two acoustic transparent membranes with good initial contact to allow the transmission of the positive pressure of lithotripter shock wave at an almost unaltered level, yet attenuate significantly its negative pressure, was fabricated. It was evaluated systematically on a Dornier HM-3 lithotripter to assess its application potential to reduce vascular injury without compromising stone fragmentation efficiency during shock-wave lithotripsy. By inserting the AD, the maximum compressive pressure, maximum tensile pressure and tensile duration of the lithotripter shock wave were formed to drop from 49.7 to 47.8 MPa, -7.5 to -7.0 MPa and 6.0 to 5.1 micros, respectively. Damage of a 0.2-mm inner diameter vessel phantom (cellulose hollow fiber) was reduced from rupture after 31 +/- 11 shocks to no rupture after 100 shocks. Maximum bubble size in free-field, maximum dilation of the vessel phantom wall and bubble collapse time became smaller with the use of the AD. However, stone fragmentation showed similar results without a statistically significant difference between the case with and without the AD. All these evidences suggest that the use of an acoustic diode may be a feasible approach to reduce tissue injury without compromising stone comminution in shock-wave lithotripsy.

The Effect of Treatment Strategy on Stone Comminution Efficiency in Shock Wave Lithotripsy

The Journal of Urology. Jul, 2004  |  Pubmed ID: 15201809

The comminution of kidney stones in shock wave lithotripsy (SWL) is a dose dependent process caused primarily by the combination of 2 fundamental mechanisms, namely stress waves and cavitation. The effect of treatment strategy with emphasis on enhancing the effect of stress waves or cavitation on stone comminution in SWL was investigated. Because vascular injury in SWL is also dose dependent, optimization of the treatment strategy may produce improved stone comminution with decreased tissue injury in SWL.

Pretreatment with Melatonin Exerts Anti-inflammatory Effects Against Ischemia/reperfusion Injury in a Rat Middle Cerebral Artery Occlusion Stroke Model

Journal of Pineal Research. Sep, 2004  |  Pubmed ID: 15298666

Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague-Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response.

In Vitro Comparison of Fragmentation Efficiency of Flexible Pneumatic Lithotripsy Using 2 Flexible Ureteroscopes

The Journal of Urology. Sep, 2004  |  Pubmed ID: 15311011

Pneumatic lithotripsy has been shown to be an effective and safe intracorporeal lithotripsy modality for renal and ureteral calculi, capable of fragmenting stones of all compositions. We determined the in vitro stone fragmentation abilities of the 0.5 mm flexible pneumatic lithotripsy probe when inserted through the working channel of 2, 7.5Fr flexible ureteroscope designs (straight working channel and offset working channel at approximately 30 degrees from the long axis of the endoscope). The velocity and displacement of the pneumatic probe tip were also evaluated with the probe inserted through each endoscope.

The Effect of Surface Agitation on Ultrasound-mediated Gene Transfer in Vitro

The Journal of the Acoustical Society of America. Oct, 2004  |  Pubmed ID: 15534963

This article reports the effect of surface agitation of culture medium on ultrasound-mediated gene transfection in vitro and its possible mechanisms. The possibility of active induction of bubbles without using contrast microbubbles for effective gene transfer was also demonstrated. Cultured HeLa cells mixed with green fluorescent protein plasmid were exposed to 1.0 MHz ultrasound in 24-well culture plates. Up to 26% transfection efficiency in the survival cell population was achieved in samples exposed to 0.44 MPa ultrasound pulses with the presence of surface agitation. Inertial cavitation and bubble generation were observed throughout the ultrasound exposure. When surface agitation was suppressed by covering the medium surface with a thin membrane, bubble generation and gene transfection were significantly suppressed. Interestingly, transfection efficiency could be partially resumed by adding a small amount of culture medium onto the covering membrane to rebuild the surface agitation and bubble generation. Pressure fluctuation and transient high-pressure loci were found in samples with surface agitation. Numerical simulations of bubble dynamics showed that transient high pressures above the inertial cavitation threshold could generate bubbles, which might be subsequently stabilized at lower pressures by rectified diffusion, and exert strong shear forces that might create transient pores on cell membranes to facilitate gene transfer.

Innovations in Shock Wave Lithotripsy Technology: Updates in Experimental Studies

The Journal of Urology. Nov, 2004  |  Pubmed ID: 15540748

We developed innovations in shock wave lithotripsy (SWL) technology.

Aggregated Alpha-synuclein Activates Microglia: a Process Leading to Disease Progression in Parkinson's Disease

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Apr, 2005  |  Pubmed ID: 15791003

A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.

Microglial NADPH Oxidase is a Novel Target for Femtomolar Neuroprotection Against Oxidative Stress

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Apr, 2005  |  Pubmed ID: 15791005

Inflammation has been increasingly recognized to contribute to the pathogenesis of Parkinson's disease. Several compounds are neuroprotective at femtomolar concentrations through the inhibition of inflammation. However, the mechanisms mediating femtomolar-acting compounds are poorly understood. Here we show that both gly-gly-phe (GGF), a tri-peptide contained in the dynorphin opioid peptide, and naloxone are neuroprotective at femtomolar concentrations against LPS-induced dopaminergic neurotoxicity through the reduction of microglial activation. Mechanistic studies demonstrated the critical role of NADPH oxidase in the GGF and naloxone inhibition of microglial activation and associated DA neurotoxicity. Pharmacophore analysis of the neuroprotective dynorphin peptides and naloxone revealed common chemical properties (hydrogen bond acceptor, hydrogen bond donor, positive ionizable, hydrophobic) of these femtomolar-acting compounds. These results support a common high-affinity site of action for several femtomolar-acting compounds, where NADPH oxidase is the critical mechanism governing neuroprotection, suggesting a novel avenue of anti-inflammatory and neuroprotective therapy.

In Vitro Comparison of Stone Retropulsion and Fragmentation of the Frequency Doubled, Double Pulse Nd:yag Laser and the Holmium:yag Laser

The Journal of Urology. May, 2005  |  Pubmed ID: 15821590

The frequency doubled, double pulse Nd:YAG (FREDDY) laser (World of Medicine, Berlin, Germany) functions through the generation of a plasma bubble. Upon bubble collapse a mechanical shock wave is generated, causing stone fragmentation. This mechanism of action is in contrast to the holmium laser, which cause stone destruction by vaporization. Observed clinical stone retropulsion and fragmentation with the FREDDY and holmium lasers has prompted a series of in vitro experiments designed to compare laser induced retropulsion and fragmentation with those of a holmium laser and pneumatic lithotrite.

MPP+-induced COX-2 Activation and Subsequent Dopaminergic Neurodegeneration

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jul, 2005  |  Pubmed ID: 15845609

The importance of cyclooxygenase-2 (COX-2) in mediating Parkinson's disease (PD) was suggested in reports, indicating that COX-2 selective inhibitors or genetic knockout reduce 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurotoxicity in a mouse model of PD. However, cell types and mechanisms underlying the activation of COX-2 have not been clearly elucidated in these animal studies. Using primary neuron-glia cultures, we aimed to determine 1) whether microglia participate in 1-methyl-4-phenylpryridinium (MPP)-induced COX-2 activation and 2) whether the activation of COX-2 contributes to subsequent neurotoxicity. MPP, in a concentration-dependent manner, increased prostaglandin E2 (PGE2) production in mixed neuron-microglia cultures but not in enriched neuron, microglia, or astroglia cultures nor in mixed neuron-astroglia cultures. MPP-induced PGE2 increase was completely abolished by treatment with DuP697, a COX-2 selective inhibitor. DuP697 also significantly reduced MPP-induced DA neurotoxicity as determined by DA uptake assay. Immunocytochemistry and confocal microscopy studies showed enhanced COX-2 expression in both microglia and neurons after MPP treatment. However, neuronal increase in COX-2 expression was not totally dependent on the production of PGE2 from microglia, since microglia deficient in COX-2 only attenuated, but did not completely block, MPP-increased PGE2 production in mixed neuron-microglia cultures, suggesting that part of PGE2 production was originated from neurons. Together, these results indicate that MPP-induced COX-2 expression and subsequent PGE2 production depend on interactions between neurons and microglia. Microgliosis may also be responsible for the COX-2 activation in neurons, leading to the enhanced DA neurotoxicity, which, in turn, reinforces microgliosis. Thus inhibition of microgliosis and COX-2 activity may stop this vicious circle and be valuable strategies in PD therapy.

Release of Endogenous Danger Signals from HIFU-treated Tumor Cells and Their Stimulatory Effects on APCs

Biochemical and Biophysical Research Communications. Sep, 2005  |  Pubmed ID: 16055092

The effects of high-intensity focused ultrasound (HIFU) on the release of endogenous danger signals from tumor cells and subsequent activation of antigen-presenting cells (APCs) were evaluated in vitro. MC-38 mouse tumor cells were treated using a 1.1 MHz HIFU transducer under two different protocols (P-=6.7 MPa, 30% duty cycle, 5 s vs. P-=10.7 MPa, 3% duty cycle, 30 s) to produce either thermal necrosis or mechanical lysis of the tumor cells. Here, we report that HIFU treatment can cause the release of endogenous danger signals (ATP and hsp60) and exposure of dendritic cells (DCs) and macrophages to the supernatants of HIFU-treated tumor cells leads to an increased expression of co-stimulatory molecules (CD80 and CD86) with enhanced secretion of IL-12 by the DCs and elevated secretion of TNF-alpha by the macrophages. The potency in APC activation produced by mechanical lysis is much stronger than thermal necrosis of the tumor cells. These findings suggest that optimization of treatment strategy may help to enhance HIFU-elicited anti-tumor immunity.

Endoplasmic Reticulum Stress and Mitochondrial Cell Death Pathways Mediate A53T Mutant Alpha-synuclein-induced Toxicity

Human Molecular Genetics. Dec, 2005  |  Pubmed ID: 16239241

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and mutations in alpha-synuclein cause autosomal-dominant hereditary PD. Here, we generated A53T mutant alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory system. Inducing expression of A53T alpha-synuclein in differentiated PC12 cells decreased proteasome activity, increased the intracellular ROS level and caused up to approximately 40% cell death, which was accompanied by mitochondrial cytochrome C release and elevation of caspase-9 and -3 activities. Cell death was partially blocked by cyclosporine A [an inhibitor of the mitochondrial permeability transition (MPT) process], z-VAD (a pan-caspase inhibitor) and inhibitors of caspase-9 and -3 but not by a caspase-8 inhibitor. Furthermore, induction of A53T alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated caspase-12 activity. RNA interference to knock down caspase-12 levels or salubrinal (an ER stress inhibitor) partially protected against cell death and further reduced A53T toxicity after treatment with z-VAD. Our results indicate that both ER stress and mitochondrial dysfunction contribute to A53T alpha-synuclein-induced cell death. This study sheds light into the pathogenesis of alpha-synuclein cellular toxicity in PD and provides a cell model for screening PD therapeutic agents.

Twenty-five Years of Shockwave Lithotripsy: Back to the Future?

Journal of Endourology. Oct, 2005  |  Pubmed ID: 16253052

Citrate and Vitamin E Blunt the Shock Wave-induced Free Radical Surge in an in Vitro Cell Culture Model

Urological Research. Dec, 2005  |  Pubmed ID: 16317535

Free radical formation plays a major role in shock wave lithotripsy induced renal damage. Moreover, previous studies suggest that free radicals may also promote de novo calcium oxalate crystallization of previously damaged urothelium. Citrate is a known inhibitor of renal stone formation and has also been used as a free radical scavenger. Using an in vitro model with Madin-Darby canine kidney (MDCK) cells, we investigated the influence of two free radical scavengers, citrate and vitamin E, on the prevention of the shock wave-induced free radical surge. Suspensions of MDCK cells were placed in containers for shock wave exposure. Six groups of six containers each were examined: (a) no scavengers 0 shocks, (b) no scavengers 100 shocks, (c) citrate 0 shocks, (d) citrate 100 shocks, (e) vitamin E 0 shocks, (f) vitamin E 100 shocks. An unmodified HM3 was used to deliver 100 shocks at 24 kV. The cell groups that were not shocked acted as the control group and were handled identically, except for the lack of shock wave exposure. After shock wave administration, the containers were emptied and cell suspensions were immediately centrifuged. The supernatant was examined for lactate dehydrogenase (LDH) and 8-isoprostane (8-IP), markers of cellular injury and free radical formation, respectively. Intracellular LDH uniformly increased in all groups exposed to shock wave energy. Similarly, 8-IP increased in all shocked groups. However, the 8-IP increase was significantly reduced when the free radical scavengers were employed. As citrate is a well-known inhibitor of calcium nephrolithiasis, its mechanism of action may be further enhanced, based on its ability to reduce free radical formation, by a protective effect on the urothelium. These data further support the use of citrate based medications during the peri-operative period of shock wave lithotripsy, not only to inhibit stone formation and facilitate fragment passage, but also to reduce the incidence of shock wave induced renal damage. Further studies are warranted to clinically test this hypothesis.

High Intensity Focused Ultrasound-induced Gene Activation in Sublethally Injured Tumor Cells in Vitro

The Journal of the Acoustical Society of America. Nov, 2005  |  Pubmed ID: 16334906

Cultured human cervical cancer (HeLa) and rat mammary carcinoma (R3230Ac) cells were transfected with vectors encoding green fluorescent protein (GFP) under the control of hsp70B promoter. Aliquots of 10-microl transfected cells (5 x 10(7) cells/ml) were placed in 0.2-ml thin-wall polymerase chain reaction tubes and exposed to 1.1-MHz high intensity focused ultrasound (HIFU) at a peak negative pressure P- = 2.68 MPa. By adjusting the duty cycle of the HIFU transducer, the cell suspensions were heated to a peak temperature from 50 to 70 degrees C in 1-10 s. Exposure dependent cell viability and gene activation were evaluated. For a 5-s HIFU exposure, cell viability dropped from 95% at 50 degrees C to 13% at 70 degrees C. Concomitantly, gene activation in sublethally injured tumor cells increased from 4% at 50 degrees C to 41% at 70 degrees C. A similar trend was observed at 60 degrees C peak temperature as the exposure time increased from 1 to 5 s. Further increase of exposure duration to 10 s led to significantly reduced cell viability and lower overall gene activation in exposed cells. Altogether, maximum HIFU-induced gene activation was achieved at 60 degrees C in 5 s. Under these experimental conditions, HIFU-induced gene activation was found to be produced primarily by thermal rather than mechanical stresses.

Leucine-rich Repeat Kinase 2 (LRRK2) Interacts with Parkin, and Mutant LRRK2 Induces Neuronal Degeneration

Proceedings of the National Academy of Sciences of the United States of America. Dec, 2005  |  Pubmed ID: 16352719

Parkinson's disease (PD) is a disorder of movement, cognition, and emotion, and it is characterized pathologically by neuronal degeneration with Lewy bodies, which are cytoplasmic inclusion bodies containing deposits of aggregated proteins. Most PD cases appear to be sporadic, but genetic forms of the disease, caused by mutations in alpha-synuclein, parkin, and other genes, have helped elucidate pathogenesis. Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with clinical features of PD and with pleomorphic pathology including deposits of aggregated protein. To study expression and interactions of LRRK2, we synthesized cDNAs and generated expression constructs coding for human WT and mutant LRRK2 proteins. Expression of full-length LRRK2 in cells in culture suggests that the protein is predominately cytoplasmic, as is endogenous protein by subcellular fractionation. Using coimmunoprecipitation, we find that LRRK2, expressed in cells in culture, interacts with parkin but not with alpha-synuclein, DJ-1, or tau. A small proportion of the cells overexpressing LRRK2 contain protein aggregates, and this proportion is greatly increased by coexpression of parkin. In addition, parkin increases ubiquitination of aggregated protein. Also, mutant LRRK2 causes neuronal degeneration in both SH-SY5Y cells and primary neurons. This cell model may be useful for studies of PD cellular pathogenesis and therapeutics. These findings suggest a gain-of-function mechanism in the pathogenesis of LRRK2-linked PD and suggest that LRRK2 may be involved in a pathogenic pathway with other PD-related proteins such as parkin, which may help illuminate both familial and sporadic PD.

Reactive Microgliosis Participates in MPP+-induced Dopaminergic Neurodegeneration: Role of 67 KDa Laminin Receptor

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. May, 2006  |  Pubmed ID: 16675848

It has been reported that extracellular matrix (ECM) molecules regulate monocyte activation by binding with a 67 kDa nonintegrin laminin receptor (LR). As microgliosis is a pivotal factor in propelling the progress of chronic neurodegeneration in the brain, we hypothesized that LR may regulate the microgliosis and subsequent neurotoxicity. Using 1-methyl-4-phenylpyridinium (MPP+) -treated C57 mice primary mesencephalic neuron-glia cultures as an in vitro Parkinson's disease (PD) model, we observed that MPP+ treatment increased LR expression only in the mixed neuron-glia but not in microglia-enriched or microglia-depleted cultures, indicating that MPP+-induced increase of LR expression is associated with neuron-microglia interaction. Using confocal microscopic examination, we found that LR was localized in the microglia, which were F4/80 positive. Treatment with the antibody (Ab) against LR (LR-Ab) or YIGSR, a synthetic pentapeptide inhibitor for LR, significantly attenuated the MPP+-increased F4/80 immunoreactivity (24 h) and dopaminergic (DA) neurotoxicity. LR-Ab also attenuated MPP+-increased microglial phagocytotic activity (48 h) and the superoxide production (4 days). Further study demonstrated that exogenous laminin (1-10 microg/ml) treatment induced microglial activation and DA neurotoxicity, in a dose-dependent manner, which was partially attenuated by the LR-Ab. We concluded that by regulating cell-ECM interaction, LR plays important roles in mediating microgliosis and subsequent DA neurotoxicity. Laminin is a potential ligand for activating this LR receptor. This study also suggests that laminin/LR is a potential target for developing new therapeutic drugs against neurodegenerative disorders such as PD.

Depletion of CBP is Directly Linked with Cellular Toxicity Caused by Mutant Huntingtin

Neurobiology of Disease. Sep, 2006  |  Pubmed ID: 16766198

Huntington's disease is a neurodegenerative disease caused by an expanded polyglutamine stretch within the huntingtin protein. Transfection of mutant huntingtin causes cell toxicity and depletion of CREB binding protein (CBP) or its recruitment into huntingtin aggregates. However, the role of CBP has been controversial and the relationship between polyglutamine-induced toxicity and CBP depletion has not been examined on an individual cell basis. Using a single-cell based assay, we found that, in HT22 cells or primary neurons transfected with mutant huntingtin, cell toxicity was accompanied by CBP depletion, rather than merely recruitment. Transfection with a htt exon1 construct containing uninterrupted polyglutamine or a polyglutamine region engineered to form a compact beta structure resulted in cell toxicity. CBP depletion was accompanied by histone hypo-acetylation. CBP overexpression rescued both acetylated histone levels and cell toxicity. These data suggest that CBP dysfunction and altered gene transcription contribute to mutant htt-induced neurotoxicity.

The Effect of Reflector Geometry on the Acoustic Field and Bubble Dynamics Produced by an Electrohydraulic Shock Wave Lithotripter

The Journal of the Acoustical Society of America. Jun, 2006  |  Pubmed ID: 16838506

A theoretical model for the propagation of shock wave from an axisymmetric reflector was developed by modifying the initial conditions for the conventional solution of a nonlinear parabolic wave equation (i.e., the Khokhlov-Zabolotskaya-Kuznestsov equation). The ellipsoidal reflector of an HM-3 lithotripter is modeled equivalently as a self-focusing spherically distributed pressure source. The pressure wave form generated by the spark discharge of the HM-3 electrode was measured by a fiber optic probe hydrophone and used as source conditions in the numerical calculation. The simulated pressure wave forms, accounting for the effects of diffraction, nonlinearity, and thermoviscous absorption in wave propagation and focusing, were compared with the measured results and a reasonably good agreement was found. Furthermore, the primary characteristics in the pressure wave forms produced by different reflector geometries, such as that produced by a reflector insert, can also be predicted by this model. It is interesting to note that when the interpulse delay time calculated by linear geometric model is less than about 1.5 micros, two pulses from the reflector insert and the uncovered bottom of the original HM-3 reflector will merge together. Coupling the simulated pressure wave form with the Gilmore model was carried out to evaluate the effect of reflector geometry on resultant bubble dynamics in a lithotripter field. Altogether, the equivalent reflector model was found to provide a useful tool for the prediction of pressure wave form generated in a lithotripter field. This model may be used to guide the design optimization of reflector geometries for improving the performance and safety of clinical lithotripters.

High Intensity Focused Ultrasound-induced Gene Activation in Solid Tumors

The Journal of the Acoustical Society of America. Jul, 2006  |  Pubmed ID: 16875245

In this work, the activation of heat-sensitive trans-gene by high-intensity focused ultrasound (HIFU) in a tumor model was investigated. 4T1 cancer cells (2 x 10(6)) were inoculated subcutaneously in the hind limbs of Balb/C mice. The tumors were subsequently transducted on day 10 by intratumoral injection of a heat-sensitive adenovirus vector (Adeno-hsp70B-Luc at 2 x 10(8) pfu/tumor). On day 11, the tumors were heated to a peak temperature of 55, 65, 75, or 85 degrees C within 10-30 s at multiple sites around the center of the tumor by a 1.1- or 3.3-MHz HIFU transducer. Inducible luciferase gene expression was increased from 15-fold to 120-fold of the control group following 1.1-MHz HIFU exposure. Maximum gene activation (120-fold) was produced at a peak temperature of 65-75 degrees C one day following HIFU exposure and decayed to baseline within 7 days. HIFU-induced gene activation (75 degrees C-10 s) could be further improved by using a 3.3-MHz transducer and a dense scan strategy to 170-fold. Thermal stress, rather than nonthermal mechanical stress, was identified as the primary physical mechanism for HIFU-induced gene activation in vivo. Overall, these observations open up the possibility for combining HIFU thermal ablation with heat-regulated gene therapy for cancer treatment.

Measurement of High Intensity Focused Ultrasound Fields by a Fiber Optic Probe Hydrophone

The Journal of the Acoustical Society of America. Aug, 2006  |  Pubmed ID: 16938956

The acoustic fields of a high intensity focused ultrasound (HIFU) transducer operating either at its fundamental (1.1 MHz) or third harmonic (3.3 MHz) frequency were measured by a fiber optic probe hydrophone (FOPH). At 1.1 MHz when the electric power applied to the transducer was increased from 1.6 to 125 W, the peak positive/negative pressures at the focus were measured to be p(+) = 1.7-23.3 MPa and p(-) = -1.2(-) -10.0 MPa. The corresponding spatial-peak pulse-average (I(SPPA)) and spatial-average pulse-average (I(SAPA)) intensities were I(SPPA) =77-6000 W/cm2 and I(SAPA) = 35-4365 W/cm2. Nonlinear propagation with harmonics generation was dominant at high intensities, leading to a reduced -6 dB beam size (L x W) of the compressional wave (11.5 x 1.8-8.8 1.04 mm) but an increased beam size of the rarefactional wave (12.5 x 1.6-13.2 x 2.0 mm). Enhancement ratio of absorbed power density in water increased from 1.0 to 3.0. In comparison, the HIFU transducer working at 3.3 MHz produced higher peak pressures (p(+) = 3.0-35.1 MPa and p(-) = -2.5(-) - 13.8 MPa) with smaller beam size (0.5 x 4 mm). Overall, FOPH was found to be a convenient and reliable tool for HIFU exposimetry measurement.

Kinase Activity of Mutant LRRK2 Mediates Neuronal Toxicity

Nature Neuroscience. Oct, 2006  |  Pubmed ID: 16980962

Mutations in the the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson disease and some cases of sporadic Parkinson disease. Here we found that LRRK2 kinase activity was regulated by GTP via the intrinsic GTPase Roc domain, and alterations of LRRK2 protein that reduced kinase activity of mutant LRRK2 correspondingly reduced neuronal toxicity. These data elucidate the pathogenesis of LRRK2-linked Parkinson disease, potentially illuminate mechanisms of sporadic Parkinson disease and suggest therapeutic targets.

Progressive Increase of Lithotripter Output Produces Better In-vivo Stone Comminution

Journal of Endourology. Sep, 2006  |  Pubmed ID: 16999607

Shockwave lithotripsy (SWL) has become a first-line intervention for treatment of nephrolithiasis. However, few studies have examined the effects of modifications in the method of shockwave energy administration on comminution efficiency. We propose that a gradual increase in output voltage will produce superior stone fragmentation in comparison with a constant or a decreasing output voltage by optimizing the stress wave and cavitation erosion forces on renal calculi.

Nogo-A is Involved in Secondary Axonal Degeneration of Thalamus in Hypertensive Rats with Focal Cortical Infarction

Neuroscience Letters. May, 2007  |  Pubmed ID: 17382469

We investigate whether Nogo-A is involved in the secondary axonal degeneration in the thalamus after distal middle cerebral artery occlusion (MCAO) in stroke-prone renovascular hypertensive rats (RHRSP). The expression of Nogo-A in ipsilateral ventroposterior nucleus (VPN) of the thalamus in RHRSP was observed at 1, 2 and 4 weeks after distal MCAO. In addition, intracerebroventricular infusion of NEP1-40, a Nogo-66 receptor (NgR) antagonist peptide, was administered starting 24 h after MCAO and continued for 1, 2 and 4 weeks, respectively. Axonal damage and regeneration were evaluated by analysis of the immunoreactivity (IR) of amyloid betaA4 precursor protein (APP), growth associated protein 43 (GAP-43) and microtubule associated protein 2 (MAP-2) in ipsilateral VPN of the thalamus at 1, 2 and 4 weeks after distal MCAO. Following ischemia, the expression of Nogo-A in oligodendrocytes increased persistently and its localization became redistributed around damaged axons and dendrites. Administration of NEP1-40 downregulated the expression of Nogo-A, reduced axonal injury and enhanced axonal regeneration. Our data suggest that Nogo-A is involved in secondary axonal degeneration and that inhibition of Nogo-A can reduce neuronal damage in the thalamus after distal MCAO.

The Effect of Frequency Doubled Double Pulse Nd:YAG Laser Fiber Proximity to the Target Stone on Transient Cavitation and Acoustic Emission

The Journal of Urology. Apr, 2007  |  Pubmed ID: 17382775

Scant information has been published describing the effect of laser fiber distance from the stone target on the mechanism of calculus fragmentation. Using high speed photography and acoustic emission measurements we characterized the impact of laser fiber proximity on stone comminution. We evaluated the effect of laser fiber distance from the stone target on resultant cavitation bubble formation and shock wave generation.

Investigation of HIFU-induced Anti-tumor Immunity in a Murine Tumor Model

Journal of Translational Medicine. Jul, 2007  |  Pubmed ID: 17625013

High intensity focused ultrasound (HIFU) is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment.

MAC1 Mediates LPS-induced Production of Superoxide by Microglia: the Role of Pattern Recognition Receptors in Dopaminergic Neurotoxicity

Glia. Oct, 2007  |  Pubmed ID: 17654704

Microglia-derived superoxide is critical for the inflammation-induced selective loss of dopaminergic (DA) neurons, but the underlying mechanisms of microglial activation remain poorly defined. Using neuron-glia and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1-/-), we demonstrate that lipopolysaccharide (LPS) treatment results in lower TNFalpha response, attenuated loss of DA neurons, and absence of extracellular superoxide production in MAC1-/- cultures. Microglia accumulated fluorescently labeled LPS in punctate compartments associated with the plasma membrane, intracellular vesicles, and the Golgi apparatus. Cytochalasin D (CD), an inhibitor of phagocytosis, blocked LPS internalization. However, microglia derived from Toll-like receptor 4 deficient mice and MAC1-/- mice failed to show a significant decrease in intracellular accumulation of labeled LPS, when compared with controls. Pretreatment with the scavenger receptor inhibitor, fucoidan, inhibited 79% of LPS accumulation in microglia without affecting superoxide, indicating that LPS internalization and superoxide production are mediated by separate phagocytosis receptors. Together, these data demonstrate that MAC1 is essential for LPS-induced superoxide from microglia, implicating MAC1 as a critical trigger of microglial-derived oxidative stress during inflammation-mediated neurodegeneration.

New Concepts in Shock Wave Lithotripsy

The Urologic Clinics of North America. Aug, 2007  |  Pubmed ID: 17678987

This monograph reviews the basic principles of shock wave lithotripsy. The focus is on new research on stone fragmentation and tissue injury and how this improved understanding of shock-wave technology is leading to modifications in lithotripsy that will allow this therapy to be a safer, more effective treatment for nephrolithiasis.

Delayed Decompressive Craniectomy Improves the Long-term Outcomes in Hypertensive Rats with Space-occupying Cerebral Infarction

Neurocritical Care. 2007  |  Pubmed ID: 17701109

No experimental data has been published on the long-term effects of decompressive craniotomy in hypertensive rats with space-occupying cerebral infarction. The aim of the present study was to investigate the efficacy of decompressive craniectomy in a middle cerebral artery occlusion (MCAO) model of hypertensive rats in a prolonged period.

Ebselen Attenuates Oxidative DNA Damage and Enhances Its Repair Activity in the Thalamus After Focal Cortical Infarction in Hypertensive Rats

Brain Research. Nov, 2007  |  Pubmed ID: 17920569

Oxidative DNA damage has been proposed to be a major contributor to focal cerebral ischemic injury. However, little is known about the role of oxidative DNA damage in remote damage secondary to the primary infarction. In the present study, we investigated oxidative damage within the ventroposterior nucleus (VPN) after distal middle cerebral artery occlusion (MCAO) in hypertensive rats. We also examined the possible protective effect of ebselen, one glutathione peroxidase mimic, on delayed degeneration in the VPN after distal MCAO. Neuronal damage in the ipsilateral VPN was examined by Nissl staining. Oxidative DNA damage and base repair enzyme activity were assessed by analyzing immunoreactivity of 8-hydroxy-2'-deoxyguanosine (8-ohdG) and 8-oxoguanine DNA glycosylase (OGG1), respectively. The number of intact neurons in the ipsilateral VPN decreased by 52% compared to the contralateral side in ischemia group 2 weeks after distal cerebral cortical infarction. The immunoreactivity of 8-ohdG significantly increased while OGG1 immunoreactivity significantly decreased in the ipsilateral VPN 2 weeks after distal cortical infarction (all p<0.01). Compared with vehicle treatment, ebselen significantly attenuated the neuron loss, ameliorated ischemia-induced increase in 8-ohdG level as well as decrease in OGG1 level within the ipsilateral VPN (all p<0.01). OGG1 was further demonstrated to mainly express in neurons. These findings strongly suggest that oxidative DNA damage may be involved in the delayed neuronal death in the VPN region following distal MCAO. Furthermore, ebselen protects against the delayed damage in the VPN when given at 24 h following distal MCAO.

NADPH Oxidase Inhibitor DPI is Neuroprotective at Femtomolar Concentrations Through Inhibition of Microglia Over-activation

Parkinsonism & Related Disorders. 2007  |  Pubmed ID: 18267257

In this paper we report that diphenyliodonium (DPI), a NADPH oxidase inhibitor, shows potent anti-inflammatory and neuroprotective effects at femtomolar concentrations (10(-13) to 10(-14) M) in primary midbrain cultures. Mechanistic studies revealed that DPI-elicited effects were mediated by the inhibition of LPS-induced microglial ROS production and the subsequent release of pro-inflammatory cytokine TNFa, and the production of nitric oxide. Further studies showed that 10(-14) M DPI significantly reduced LPS-induced ERK phosphorylation. Taken together, our results demonstrate that femtomolar concentrations of DPI exert potent anti-inflammatory and neuroprotective effects by inhibiting microglial activation through the inhibition of ERK-regulated PHOX activity.

Interaction of Lithotripter Shockwaves with Single Inertial Cavitation Bubbles

Journal of Fluid Mechanics. 2007  |  Pubmed ID: 19018296

The dynamic interaction of a shockwave (modelled as a pressure pulse) with an initially spherically oscillating bubble is investigated. Upon the shockwave impact, the bubble deforms non-spherically and the flow field surrounding the bubble is determined with potential flow theory using the boundary-element method (BEM). The primary advantage of this method is its computational efficiency. The simulation process is repeated until the two opposite sides of the bubble surface collide with each other (i.e. the formation of a jet along the shockwave propagation direction). The collapse time of the bubble, its shape and the velocity of the jet are calculated. Moreover, the impact pressure is estimated based on water-hammer pressure theory. The Kelvin impulse, kinetic energy and bubble displacement (all at the moment of jet impact) are also determined. Overall, the simulated results compare favourably with experimental observations of lithotripter shockwave interaction with single bubbles (using laser-induced bubbles at various oscillation stages). The simulations confirm the experimental observation that the most intense collapse, with the highest jet velocity and impact pressure, occurs for bubbles with intermediate size during the contraction phase when the collapse time of the bubble is approximately equal to the compressive pulse duration of the shock wave. Under this condition, the maximum amount of energy of the incident shockwave is transferred to the collapsing bubble. Further, the effect of the bubble contents (ideal gas with different initial pressures) and the initial conditions of the bubble (initially oscillating vs. non-oscillating) on the dynamics of the shockwave-bubble interaction are discussed.

Assessment of Shock Wave Lithotripters Via Cavitation Potential

Physics of Fluids (Woodbury, N.Y. : 1994). 2007  |  Pubmed ID: 19865493

A method to characterize shock wave lithotripters by examining the potential for cavitation associated with the lithotripter shock wave (LSW) has been developed. The method uses the maximum radius achieved by a bubble subjected to a LSW as a representation of the cavitation potential for that region in the lithotripter. It is found that the maximum radius is determined by the work done on a bubble by the LSW. The method is used to characterize two reflectors: an ellipsoidal reflector and an ellipsoidal reflector with an insert. The results show that the use of an insert reduced the -6 dB volume (with respect to peak positive pressure) from 1.6 to 0.4 cm(3), the -6 dB volume (with respect to peak negative pressure) from 14.5 to 8.3 cm(3), and reduced the volume characterized by high cavitation potential (i.e., regions characterized by bubbles with radii larger than 429 µm) from 103 to 26 cm(3). Thus, the insert is an effective way to localize the potentially damaging effects of shock wave lithotripsy, and suggests an approach to optimize the shape of the reflector.

CT and MR Findings in HIV-negative Neurosyphilis

European Journal of Radiology. Apr, 2008  |  Pubmed ID: 17628376

The purpose of this study was to describe and evaluate neuroimaging findings of patients with neurosyphilis.

Serum Uric Acid Levels of Patients with Multiple Sclerosis and Other Neurological Diseases

Multiple Sclerosis (Houndmills, Basingstoke, England). Mar, 2008  |  Pubmed ID: 17942520

The serum uric acid (UA) levels were measured in 112 patients with multiple sclerosis (MS) and 794 patients with different types of other neurological diseases (OND) or healthy control group. Serum UA levels, along with relevant clinical parameters of MS and OND, were also investigated. MS patients had significantly lower UA levels than those with transient ischemia attack (344.6 +/- 130.6 micromol/L, P = 0.000), cerebral hemorrhage (311.9 +/- 104.7 micromol/L, P = 0.000), cerebral infarction (291.3 +/- 101.6 micromol/L, P = 0.014) and the healthy control group (312.1 +/- 92.8 micromol/L, P = 0.000). MS patients had significantly higher serum UA levels than those with cryptococcus meningitis or meningoencephalitis (178.9 +/- 107.0 micromol/L, P = 0.000) and tuberculous meningitis or meningoencephalitis patients (175.7 +/- 99.9 micromol/L, P = 0.000). There were no significant differences in UA levels between patients with MS and those with facial neuritis, viral meningitis or encephalitis, pulmonary tuberculosis, polymyositis or dermatomyositis, myasthenia gravis, subarachnoid hemorrhage, migraine, Guillain-Barre syndrome and myelitis. In addition, UA levels were independently correlated with gender and duration of MS, but neither with MRI activity, disability nor subtypes of the disease in MS patients. Our data suggest that UA has two biphasic functions: neuroprotective and injurious. Our studies may help physicians to deal with conditions having abnormal UA levels.

Longitudinal Investigations on the Anterograde and Retrograde Degeneration in the Pyramidal Tract Following Pontine Infarction with Diffusion Tensor Imaging

Cerebrovascular Diseases (Basel, Switzerland). 2008  |  Pubmed ID: 18216462

Secondary degeneration following supratentorial stroke has been detected by some studies using diffusion tensor imaging (DTI), but the anterograde and retrograde degeneration in pyramidal tract after pontine infarction and its potential clinical significance are not well understood.

Exogenous Kallikrein Enhances Neurogenesis and Angiogenesis in the Subventricular Zone and the Peri-infarction Region and Improves Neurological Function After Focal Cortical Infarction in Hypertensive Rats

Brain Research. Apr, 2008  |  Pubmed ID: 18353282

Kallikrein, a serine proteinase, has been identified as an angiogenic growth factor recently. We investigated whether delayed treatment with exogenous kallikrein enhances neurogenesis and angiogenesis after focal cortical infarction in stroke-prone renovascular hypertensive rats. Human tissue kallikrein (1.6 x 10(-2) PNAU/kg) or vehicle was given through a tail vein daily for 6 consecutive days starting 24 h after distal middle cerebral artery occlusion (MCAO). Cell proliferation was examined by using 5'-bromo-2'-deoxyuridine (BrdU, 50 mg/kg). Rats were sacrificed at 3, 7, 14 or 28 d after MCAO, respectively. Treatment with kallikrein significantly increased the number of BrdU(+) cells in the subventricular zone (SVZ) and the peri-infarction region initiating 3 d after MCAO compared with the vehicle group (all p<0.05). Kallikrein significantly increased the number of BrdU(+)/DCX(+) cells and BrdU(+)/nestin(+) cells in the SVZ as well as vascular density in the peri-infarction region compared with the vehicle group (all p<0.05), which increased at 3 d, peaked at 7-14 d after MCAO, and then gradually decreased. Kallikrein markedly increased the number of BrdU(+)/NeuN(+) cells in the peri-infarction region compared with the vehicle group at 14 d and 28 d after MCAO (all p<0.05). The kallikrein group showed better functional improvement after stroke (all p<0.05). Our study demonstrates that delayed administration of kallikrein at 24 h after cortical infarction promotes the SVZ neuroblasts proliferation, migration, and selective differentiation. Moreover, kallikrein enhanced endogenous neurogenesis is associated with angiogenesis, both attributing to functional improvement after stroke. Therefore, kallikrein may have a potential therapeutic perspective on ischemic stroke.

Focusing of Shock Waves Induced by Optical Breakdown in Water

The Journal of the Acoustical Society of America. Jun, 2008  |  Pubmed ID: 18537359

The focusing of laser-generated shock waves by a truncated ellipsoidal reflector was experimentally and numerically investigated. Pressure waveform and distribution around the first (F(1)) and second foci (F(2)) of the ellipsoidal reflector were measured. A neodymium doped yttrium aluminum garnet laser of 1046 nm wavelength and 5 ns pulse duration was used to create an optical breakdown at F(1), which generates a spherically diverging shock wave with a peak pressure of 2.1-5.9 MPa at 1.1 mm stand-off distance and a pulse width at half maximum of 36-65 ns. Upon reflection, a converging shock wave is produced which, upon arriving at F(2), has a leading compressive wave with a peak pressure of 26 MPa and a zero-crossing pulse duration of 0.1 mus, followed by a trailing tensile wave of -3.3 MPa peak pressure and 0.2 mus pulse duration. The -6 dB beam size of the focused shock wave field is 1.6 x 0.2 mm(2) along and transverse to the shock wave propagation direction. Formation of elongated plasmas at high laser energy levels limits the increase in the peak pressure at F(2). General features in the waveform profile of the converging shock wave are in qualitative agreement with numerical simulations based on the Hamilton model.

Blockade of EphB2 Enhances Neurogenesis in the Subventricular Zone and Improves Neurological Function After Cerebral Cortical Infarction in Hypertensive Rats

Brain Research. Sep, 2008  |  Pubmed ID: 18639535

EphB2/ephrinBs has been recently demonstrated to regulate cell proliferation in the neurogenic subventricular zone (SVZ). However, little is known about the role of EphB2 in adult neurogenesis following cerebral infarction. In the present study, we investigated the role of EphB2 in proliferation and differentiation of precursor cells within the SVZ, as well as the neurological function recovery after permanent middle cerebral artery occlusion (MCAO) in hypertensive rats. Bromodeoxyuridine (BrdU) was given twice per day starting from 24h after MCAO for 6-consecutive days. Recombinant EphB2-Fc or IgG-Fc was preclustered by incubation with anti-human Fcgamma and then intraventricularly administrated at 24h after MCAO. The neurological function was evaluated before operation and at 7, 14 and 21 days after MCAO respectively. The infarct size and immunoreactivities of BrdU, Nestin, DCX, GFAP and NeuN were measured at 7, 14 and 21 days after MCAO respectively. Treatment with EphB2-Fc markedly improved the neurological function recovery within 3 weeks after MCAO. In parallel, EphB2-Fc significantly increased the number of BrdU-labeled cells and led to marked increases in BrdU+/DCX+ and BrdU+/Nestin+ cells within the ipsilateral SVZ for 2 weeks after MCAO respectively (all p < 0.05). The BrdU+/NeuN+ cells in the peri-infarct area and neighboring ipsilateral striatum were significantly increased following EphB2-Fc infusion within 3 weeks after MCAO (all p < 0.05). Our data suggest that administration of exogenous clustered EphB2-Fc at 24h can enhance the endogenous neurogenesis and concomitantly improve neurological recovery after cerebral infarction.

Segmented Echo Planar MR Imaging of the Brachial Plexus with Inversion Recovery Magnetization Preparation at 3.0T

Journal of Magnetic Resonance Imaging : JMRI. Aug, 2008  |  Pubmed ID: 18666178

To evaluate the image quality of segmented echo planar MRI with inversion recovery magnetization preparation (seg-IR-EPI) to depict the anatomy and pathologic changes involving the brachial plexus.

The Effect of High Intensity Focused Ultrasound Treatment on Metastases in a Murine Melanoma Model

Biochemical and Biophysical Research Communications. Oct, 2008  |  Pubmed ID: 18727919

This study aims to assess the risk of high intensity focused ultrasound (HIFU) therapy on the incidence of distant metastases and to investigate its association with HIFU-elicited anti-tumor immunity in a murine melanoma (B16-F10) model. Tumor-bearing legs were amputated immediately after or 2 days following HIFU treatment to differentiate the contribution of the elicited anti-tumor immunity. In mice undergoing amputation immediately after mechanical, thermal, or no HIFU treatment, metastasis rates were comparable (18.8%, 13.3%, and 12.5%). In contrast, with a 2-day delay in amputation, the corresponding metastasis rates were 6.7%, 11.8%, and 40%, respectively. Animal survival rate was higher and CTL activity was enhanced in the HIFU treatment groups. Altogether, our results suggest that HIFU treatment does not increase the risk of distant metastasis. Instead, HIFU treatment can elicit an anti-tumor immune response that may be harnessed to improve the overall effectiveness and quality of cancer therapy.

Excessive Blinking As an Initial Manifestation of Juvenile Huntington's Disease

Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. Sep, 2008  |  Pubmed ID: 18810605

Juvenile Huntington's disease (JHD) is mostly characterized by rigidity, myoclonus, bradykinesia, dystonia and seizure. We report a 9-year-old male JHD patient presenting excessive blinking as the initial symptom two years prior to typical JHD symptoms. Genetic analysis revealed expansion of 108 CAG repeats and magnetic resonance imaging showed caudate atrophy with lateral ventricular enlargement.

Ultrasound-mediated Drug Delivery

IEEE Engineering in Medicine and Biology Magazine : the Quarterly Magazine of the Engineering in Medicine & Biology Society. Jan-Feb, 2009  |  Pubmed ID: 19150772

New-onset Constipation at Acute Stage After First Stroke: Incidence, Risk Factors, and Impact on the Stroke Outcome

Stroke. Apr, 2009  |  Pubmed ID: 19228840

The prevalence of constipation after stroke varies from 30% to 60%. The incidence of new-onset constipation during the early stage of stroke remains uncertain. The present study was designed to investigate the prevalence of new-onset constipation, its risk factors, and its impact on stroke outcome in patients with their first stroke at acute stage.

Progression of Pathological Changes in the Middle Cerebellar Peduncle by Diffusion Tensor Imaging Correlates with Lesser Motor Gains After Pontine Infarction

Neurorehabilitation and Neural Repair. Sep, 2009  |  Pubmed ID: 19244384

Wallerian degeneration in pyramidal tract following supratentorial stroke has been detected by some studies using diffusion tensor imaging (DTI), but the Wallerian degeneration in middle cerebellar peduncle after pontine infarction and its potential clinical significance remain to be confirmed.

High Definition Laparoscopy: Objective Assessment of Performance Characteristics and Comparison with Standard Laparoscopy

Journal of Endourology. Mar, 2009  |  Pubmed ID: 19250028

High definition (HD) digital imaging represents a major advance in endoscope technology. The development of the charge-coupled device chip and its location at the distal end of the endoscope allows for image capture and digitization, as well as specific light filtration and processing. We assessed the capability of HD technology combined with digital imaging to provide improved image quality and enhanced spatial three-dimensional positioning.

Morphological Analysis in Patients with Sciatica: a Magnetic Resonance Imaging Study Using Three-dimensional High-resolution Diffusion-weighted Magnetic Resonance Neurography Techniques

Spine. Apr, 2009  |  Pubmed ID: 19333087

A prospective observational study of patients with sciatica.

A Novel Marine Compound Xyloketal B Protects Against Oxidized LDL-induced Cell Injury in Vitro

Biochemical Pharmacology. Oct, 2009  |  Pubmed ID: 19481065

Xyloketal B is a novel marine compound with unique chemical structure isolated from mangrove fungus Xylaria sp. (no. 2508). Pretreatment with xyloketal B (0.63-40 microM) significantly improved oxLDL (150 microg/ml)-induced injury in human umbilical vein endothelial cells (HUVECs) without either toxic or proliferative effects. Xyloketal B concentration-dependently attenuated oxLDL-induced ROS generation, peroxynitrite formation and decrease of Bcl-2 expression. In addition, xyloketal B significantly inhibited NADPH oxidase activity, as well as mRNA expression of gp91phox and p47phox. Furthermore, xyloketal B alone augmented the production of nitric oxide (NO). Collectively, these data indicate that xyloketal B protects against oxLDL-induced endothelial oxidative injury probably through inhibiting NADPH oxidase-derived ROS generation, promoting NO production and restoring Bcl-2 expression, making it a promising compound for further evaluation in the treatment of atherosclerosis.

Low-amplitude Ultrasound Enhances Hydrodynamic-based Gene Delivery to Rat Kidney

Biochemical and Biophysical Research Communications. Aug, 2009  |  Pubmed ID: 19523454

The synergistic combination of hydrodynamic-based gene delivery and ultrasound was investigated to achieve improved gene transfer to the kidney. Plasmids encoding firefly luciferase and Erythropoietin (EPO) gene were delivered into the left kidney of rats by single or combinative application of renal vein hydrodynamic injection and ultrasound treatment with or without the addition of ultrasound contrast agents (UCA). Ultrasound exposure was found to enhance the efficiency of hydrodynamic-based gene delivery for both luciferase and EPO expression. An ultrasound exposure intensity of 2 W/cm2 at 10% duty cycle for 15 min, produced a maximal gene expression 4.5 times higher than hydrodynamic delivery alone. Duration, location, and tissue-specificity of gene expression were not changed by ultrasound exposure. Application of UCA reduced the intensity and exposure duration of ultrasound treatment needed for optimal expression. Appropriate application of ultrasound and UCA did not alter histological structure or impair physiological function of the treated kidney.

Enhanced Angiogenesis with Dl-3n-butylphthalide Treatment After Focal Cerebral Ischemia in RHRSP

Brain Research. Sep, 2009  |  Pubmed ID: 19524555

Appropriate restoration of blood flow via angiogenesis is critical for the recovery from ischemic stroke. Previously, we reported that treatment with dl-3n-butylphthalide (NBP) increases the number of local potent cerebral microvessels. However, the underlying mechanism remained unclear. The present study was conducted to test whether NBP enhances post-ischemic cerebral angiogenesis via vascular endothelial growth factor (VEGF) and hypoxia induced factor-1 alpha (HIF-1 alpha). Stroke-prone renovascular hypertensive rats (RHRSP) were used to create middle cerebral artery occlusion (MCAO) model. NBP was given 80 mg/kg per d for 10 consecutive days, starting 12, 24, 48 and 72 h respectively after MCAO. Neurological function was assessed daily and infarct volume as well as the expressions of CD31, VEGF, HIF-1 alpha and bFGF was detected 13 days after MCAO. The administration of NBP starting within 24 h after MCAO enhanced recovery of neurobehavioral function, reduced infarct volume, increased the quantity of CD31 positive vessels, and up-regulated expressions of VEGF and HIF-1 alpha. These findings suggest that treatment with NBP within 24 h post-ischemic stroke rescues brain tissue by enhancing angiogenesis associated with up-regulation of VEGF and HIF-1 alpha expressions.

Neurogenesis and Angiogenesis Within the Ipsilateral Thalamus with Secondary Damage After Focal Cortical Infarction in Hypertensive Rats

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Sep, 2009  |  Pubmed ID: 19536072

Neurogenesis and angiogenesis in the subventricular zone and peri-infarct region have been confirmed. However, newly formed neuronal cells and blood vessels that appear in the nonischemic ipsilateral ventroposterior nucleus (VPN) of the thalamus with secondary damage after stroke has not been previously studied. Twenty-four stroke-prone renovascular hypertensive rats were subjected to distal right middle cerebral artery occlusion (MCAO) or sham operation. 5'-Bromo-2'-deoxyuridine (BrdU) was used to label cell proliferation. Rats were killed at 7 or 14 days after the operation. Neuronal nuclei (NeuN), OX-42, BrdU, nestin, laminin(+), BrdU(+)/nestin(+), BrdU(+)/NeuN(+), nestin(+)/GFAP(+)(glial fibrillary acidic protein), and BrdU(+)/laminin(+) immunoreactive cells were detected within the ipsilateral VPN. The primary infarction was confined to the right somatosensory cortex. Within the ipsilateral VPN of the ischemic rats, the number of NeuN(+) neurons decreased, the OX-42(+) microglia cells were activated, and BrdU(+) and nestin(+) cells were detected at day 7 after MCAO and increased in number at day 14. Moreover, BrdU(+)/nestin(+) cells and BrdU(+)/NeuN(+) cells were detected at day 14 after MCAO. In addition, the ischemic rats showed a significant increase in vascular density in the ipsilateral VPN compared with the sham-operated rats. These results suggest that secondary damage with neurogenesis and angiogenesis of the ipsilateral VPN of the thalamus occurs after focal cortical infarction.

DL-3-n-butylphthalide Protects Endothelial Cells Against Oxidative/nitrosative Stress, Mitochondrial Damage and Subsequent Cell Death After Oxygen Glucose Deprivation in Vitro

Brain Research. Sep, 2009  |  Pubmed ID: 19616517

DL-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Recently, we found that NBP can reduce the incidence of stroke and have protective action on cerebral microvessels, suggesting a direct action of NBP on endothelial cells. However, it is difficult to evaluate the direct action of NBP on endothelial cells in vivo because of the interactions of endothelial cells with other types of neuronal cells. Therefore, we investigated whether NBP protects against oxygen glucose deprivation (OGD)-induced cell injury in an immortalized human umbilical vein endothelial cells (HUVEC) in vitro. Cells were exposed to OGD, leading to endothelial damage. Endothelial injury was assessed by measuring MTT and the changes in chromatin morphology. Mitochondrial superoxide, mitochondrial membrane potential and mitochondrial morphology were assessed using MitoSOX Red. Rhodamine 123 and MitoTracker, respectively. Nitrosative stress was assessed by measuring the production of peroxynitrite. The activity of superoxide dismutase (SOD) is evaluated using SOD assay kit-WST. The expression of hypoxia inducible factor-1 alpha (HIF-1alpha) was assessed at the protein level by immunofluorescence and Western blotting. NBP at doses between 0.01 and 100 micromol/L dose-dependently protected against OGD-induced cell death. In addition, NBP attenuated OGD-induced mitochondria superoxide, cellular formation of peroxynitrite, and decrease in SOD activity, mitochondria fragmentation and loss of mitochondrial membrane potential. In parallel, NBP enhanced OGD-induced HIF-1alpha expression. This study demonstrates that NBP can protect HUVEC against OGD-induced oxidative/nitrosative stress, mitochondrial damage and subsequent cell death. This protective effect is, at least in part, associated with its enhancement on OGD-induced HIF-1alpha expression.

Marine Compound Xyloketal B Protects PC12 Cells Against OGD-induced Cell Damage

Brain Research. Dec, 2009  |  Pubmed ID: 19765563

Xyloketal B is a novel marine compound with unique chemical structure isolated from mangrove fungus Xylaria sp. (no. 2508). Recently, we have demonstrated that Xyloketal B is an antioxidant and can protect against oxidized low density lipoprotein (LDL)-induced cell injury. In the present study, we investigated whether Xyloketal B can protect against ischemia-induced cell injury in an in vitro oxygen glucose deprivation (OGD) model of ischemic stroke in PC12 cells. We found that Xyloketal B could directly scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and protect PC12 cells against OGD insult. Furthermore, Xyloketal B alleviated OGD-induced mitochondria superoxide, mitochondria fragmentation and GTPase dynamin-related protein 1 (Drp1) overexpression as well as reduction of mitochondrial membrane potential. All together, the present study demonstrates that Xyloketal B protects PC12 cells against OGD-induced cell injury and that the anti-oxidative property and protective action on mitochondria may account for its neuroprotective actions.

Endostatin Expression in Neurons During the Early Stage of Cerebral Ischemia is Associated with Neuronal Apoptotic Cell Death in Adult Hypertensive Rat Model of Stroke

Brain Research. Jan, 2010  |  Pubmed ID: 19941836

Endostatin (ES) has been recognized as a potent anti-angiogenic factor. We here investigated the expression of ES in ischemic brain and the consequence of cells expressing ES after stroke in adult stroke-prone renovascular hypertensive rats. A single dose of Ca-074ME, a membrane-permeable cathepsin B (CB) specific inhibitor, or vehicle was given by intraperitoneal injection immediately after distal middle cerebral artery occlusion (dMCAO), ES expression was evaluated using fluorescent immunohistochemistry staining, and CB enzyme activity was tested by measuring the free 7-amino-4-methylcoumarin (AMC) released by CB from its' specific substrate, the Z-Arg-Arg-7-amido-4-methylcoumarin. ES immunoreactivity (IR) was significantly up-regulated as early as 6 h and returned to baseline level at 3 days in peri-infarct area following dMCAO. Double-staining experiment revealed that the majority of ischemia-induced ES positive cells were neurons. Furthermore, ES was co-labeled with CB and Cleaved Caspase-3(Asp175) whereas treatment with Ca-074ME reduced up-regulation of ES expression and attenuated apoptosis in peri-infarct neurons. Collectively, our data suggest that peri-infarct neurons express ES during the early stage of cerebral ischemia and treatment with Ca-074ME attenuates ES expression and apoptosis in peri-infarct neurons.

Boosting High-intensity Focused Ultrasound-induced Anti-tumor Immunity Using a Sparse-scan Strategy That Can More Effectively Promote Dendritic Cell Maturation

Journal of Translational Medicine. Jan, 2010  |  Pubmed ID: 20105334

The conventional treatment protocol in high-intensity focused ultrasound (HIFU) therapy utilizes a dense-scan strategy to produce closely packed thermal lesions aiming at eradicating as much tumor mass as possible. However, this strategy is not most effective in terms of inducing a systemic anti-tumor immunity so that it cannot provide efficient micro-metastatic control and long-term tumor resistance. We have previously provided evidence that HIFU may enhance systemic anti-tumor immunity by in situ activation of dendritic cells (DCs) inside HIFU-treated tumor tissue. The present study was conducted to test the feasibility of a sparse-scan strategy to boost HIFU-induced anti-tumor immune response by more effectively promoting DC maturation.

Visuospatial Attention Deficit in Patients with Local Brain Lesions

Brain Research. Mar, 2010  |  Pubmed ID: 20132799

The disability of visuospatial attention can lead to poor volitional movement and functional recovery in patients with brain lesions. However, the accurate clinical method to assess visuospatial attention is limited. The frontoparietal network including the posterior parietal cortex and the frontal eye fields has been shown to involve in visuospatial attention. The Attention Network Test provided measures for three different components of visuospatial attention: alerting, orienting and executive control. This study was to probe the deficit and relationship of visuospatial attention using Attention Network Test paradigm in patients with frontoparietal network lesions. During this task, patients responded significantly slower on each cue condition and target type than controls, and showed deficits in the alerting and orienting networks. The efficiency of resolving conflict was decreased in patients with frontal lesions whereas this was increased in patients with parietal lesions. These findings suggest that the frontoparietal network is involved in the alerting and orienting attentional function and the executive function is possibly selectively associated with the frontal lobe. The Attention Network Test paradigm produces sensitive, valid and reliable subject estimates of visuospatial attention function in patients with brain lesions, and may be useful for clinical rehabilitation strategy selection for patients with the frontoparietal network lesions.

Protective Effects of Xyloketal B Against MPP+-induced Neurotoxicity in Caenorhabditis Elegans and PC12 Cells

Brain Research. May, 2010  |  Pubmed ID: 20347725

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 2% of the population over age 65years. Mitochondrial defect and oxidative stress actively participate in the dopaminergic (DA) neuron degeneration in PD. Xyloketal B is a novel marine compound with unique chemical structure isolated from mangrove fungus Xylaria sp. (no. 2508). Recently, we have demonstrated that Xyloketal B can directly scavenge DPPH free radicals and protects mitochondria against oxidative insult. In the present study, we investigate the neuroprotective action of xyloketal B against MPP+-induced neurotoxicity in Caenorhabditis elegans and PC12 cells. The viability and DA neurodegeneration was assessed in C. elegans selectively expressing green fluorescent protein (GFP) in DA neurons. PC12 cell damage was measured using MTT and nuclear morphology. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential and total GSH were assessed. Xyloketal B dose-dependently protected against MPP+-induced loss of viability and DA neurodegeneration in C. elegans. Similar neuroprotection was replicated in MPP+ PC12 cell model. In addition, xyloketal B attenuated MPP+-induced intracellular ROS accumulation, loss of mitochondrial membrane potential and restored total GSH level in PC12 cells. All together, the present study demonstrates that xyloketal B protects against MPP+-induced neurotoxicity in C. elegans and PC12 cells mainly through its antioxidant property and restoration of total GSH level.

Effect of Lithotripter Focal Width on Stone Comminution in Shock Wave Lithotripsy

The Journal of the Acoustical Society of America. Apr, 2010  |  Pubmed ID: 20370044

Using a reflector insert, the original HM-3 lithotripter field at 20 kV was altered significantly with the peak positive pressure (p(+)) in the focal plane increased from 49 to 87 MPa while the -6 dB focal width decreased concomitantly from 11 to 4 mm. Using the original reflector, p(+) of 33 MPa with a -6 dB focal width of 18 mm were measured in a pre-focal plane 15-mm proximal to the lithotripter focus. However, the acoustic pulse energy delivered to a 28-mm diameter area around the lithotripter axis was comparable ( approximately 120 mJ). For all three exposure conditions, similar stone comminution ( approximately 70%) was produced in a mesh holder of 15 mm after 250 shocks. In contrast, stone comminution produced by the modified reflector either in a 15-mm finger cot (45%) or in a 30-mm membrane holder (14%) was significantly reduced from the corresponding values (56% and 26%) produced by the original reflector (no statistically significant differences were observed between the focal and pre-focal planes). These observations suggest that a low-pressure/broad focal width lithotripter field will produce better stone comminution than its counterpart with high-pressure/narrow focal width under clinically relevant in vitro comminution conditions.

Baicalein Reduces E46K Alpha-synuclein Aggregation in Vitro and Protects Cells Against E46K Alpha-synuclein Toxicity in Cell Models of Familiar Parkinsonism

Journal of Neurochemistry. Jul, 2010  |  Pubmed ID: 20412383

The E46K is a point mutation in alpha-synuclein (alpha-syn) that causes familial Parkinsonism with Lewy body dementia. We have now generated a cell model of Parkinsonism/Parkinson's disease (PD) and demonstrated cell toxicity after expression of E46K in the differentiated PC12 cells. E46K alpha-syn inhibited proteasome activity and induced mitochondrial depolarization in the cell model. Baicalein has been reported to inhibit fibrillation of wild type alpha-syn in vitro, and to protect neurons against several chemical-induced models of PD. We now report that baicalein significantly attenuated E46K-induced mitochondrial depolarization and proteasome inhibition, and protected cells against E46K-induced toxicity in a cell model of PD. Baicalein also reduced E46K fibrilization in vitro, with a concentration-dependent decrease in beta sheet conformation, though it increased some oligomeric species, and decreased formation of E46K alpha-syn-induced aggregates and rescued toxicity in N2A cells. Taken together, these data indicate that mitochondrial dysfunction, proteasome inhibition and specific aspects of abnormal E46K aggregation accompany E46K alpha-syn-induced cell toxicity, and baicalein can protect as well as altering aggregation properties. Baicalein has potential as a tool to understand the relation between different aggregation species and toxicity, and might be a candidate compound for further validation by using in vivo alpha-syn genetic PD models.

Design and Synthesis of Novel Xyloketal Derivatives and Their Vasorelaxing Activities in Rat Thoracic Aorta and Angiogenic Activities in Zebrafish Angiogenesis Screen

Journal of Medicinal Chemistry. Jun, 2010  |  Pubmed ID: 20481602

A novel series of xyloketal derivatives (1-21) were designed and prepared. The majority of the compounds demonstrated vasorelaxation action on 60 mM KCl-induced contractions rat isolated aortic rings in a concentration-dependent manner, and the action is mediated by both endothelium-independent and endothelium-dependent mechanisms. Compounds 9, 12, 13, 14, 15, and 19 showed higher vasorelaxation activities comparing with the lead compound 3. In addition, these derivatives had potential protective action against oxLDL-induced endothelial oxidative injury and enhanced NO production in HUVECs without toxic effects. The NO release was completely inhibited by eNOS inhibitor L-NAME. Furthermore, 3 significantly promoted the angiogenesis in zebrafish in a concentration-dependent manner at 0.1, 1, and 10 muM. Compounds 9, 12, 14, 16, 20, and 21 exhibited stronger angiogenic activities than 3. Therefore, xyloketal derivatives are unique compounds with multiple pharmacological properties and may have potential implications in the treatment of cardiovascular diseases.

A Simple Method for Fabricating Artificial Kidney Stones of Different Physical Properties

Urological Research. Aug, 2010  |  Pubmed ID: 20652562

A simple method for preparing artificial kidney stones with varying physical properties is described. BegoStone was prepared with a powder-to-water ratio ranging from 15:3 to 15:6. The acoustic properties of the phantoms were characterized using an ultrasound transmission technique, from which the corresponding mechanical properties were calculated based on elastic wave theory. The measured parameters for BegoStone phantoms of different water contents are: longitudinal wave speed (3,148-4,159 m/s), transverse wave speed (1,813-2,319 m/s), density (1,563-1,995 kg/m(3)), longitudinal acoustic impedance (4.92-8.30 kg/m(2) s), transverse acoustic impedance (2.83-4.63 kg/m(2) s), Young's modulus (12.9-27.4 GPa), bulk modulus (8.6-20.2 GPa), and shear modulus (5.1-10.7 GPa), which cover the range of corresponding properties reported in natural kidney stones. In addition, diametral compression tests were carried out to determine tensile failure strength of the stone phantoms. BegoStone phantoms with varying water content at preparation have tensile failure strength from 6.9 to 16.3 MPa when tested dry and 3.2 to 7.1 MPa when tested in water-soaked condition. Overall, it is demonstrated that this new BegoStone preparation method can be used to fabricate artificial stones with physical properties matched with those of natural kidney stones of various chemical compositions.

Nonmotor Symptoms Are Independently Associated with Impaired Health-related Quality of Life in Chinese Patients with Parkinson's Disease

Movement Disorders : Official Journal of the Movement Disorder Society. Dec, 2010  |  Pubmed ID: 20945434

We performed a cross-sectional study of 82 Chinese patients with Parkinson's disease (PD) enrolled during an 18-month period using a clinical interview to assess the prevalence of nonmotor symptoms (NMS), the association with disease severity and motor status, and the impact on patients' health-related quality of life (Hr-QoL). The patients' NMS, Hr-QoL, disease severity, and motor status were assessed by the Nonmotor Symptoms Scale (NMSS), the 39-item Parkinson's Disease Questionnaire (PDQ-39), the modified Hoehn and Yahr staging scale (H&Y) and the Unified Parkinson's Disease Rating Scale part III (UPDRS III), respectively. We found that 100% of patients with PD presented with NMS. The NMSS significantly correlated with disease duration (Spearman's r(S) = 0.276, P = 0.012), H&Y (r(S) = 0.230, P = 0.038), and UPDRS III (r(S) = 0.350, P = 0.001). Similarly, the PDQ-39 SI significantly associated with the disease duration (r(S) = 0.258, P = 0.019), H&Y (r(S) = 0.340, P = 0.002), and UPDRS III (r(S) = 0.453, P < 0.001). NMS domains that influenced the PDQ-39 SI were sleep/fatigue, mood, gastrointestinal, urinary, and miscellaneous symptoms. This strongly suggested that the five domains played a key role in the manifestation of Hr-QoL. NMSS explains more of the variability in Hr-QoL than UPDRS III, when both are the model (stepwise multiple linear regression analysis R² change, 47.8% vs. 5.87%, respectively). Therefore, these findings demonstrate that NMS are independently and negatively associated with Hr-QoL in PD and that improving NMS should be viewed as an important part in the management of PD.

Hypoxic Tissues Are Associated with Microvessel Density Following Brain Ischemia-reperfusion

Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. Dec, 2010  |  Pubmed ID: 20957504

Hypoxic tissue has been observed in the surrounding areas of the ischemic core following cerebral infarction. The underlying mechanisms for this potentially reversible ischemic region remain to be determined. In this study, we generated permanent brain ischemia (PI) and reperfusion after inducing ischemia for 1.5 h (ischemia-reperfusion or IR) in a rat model of middle cerebral artery occlusion. Using immunofluorescence, we observed hypoxic tissue in ischemic brains and assessed microvessel density in and surrounding the hypoxic tissue. We found that the hypoxic tissues were observed at 1 and 3 days in PI rats and at 1, 3, 7, and 14 days in IR rats. The hypoxic tissue gradually decreased over time. The microvessel density increased in a time-dependent manner in focal brain ischemic tissue in PI and IR rats. Furthermore, IR induced a significant increase in microvessel density when compared with PI rats (P < 0.05). Microvessel density surrounding hypoxic tissue was significantly higher when compared with within the hypoxic tissue (P < 0.05). These data demonstrate that hypoxic tissue may exist for a long period (14 days) following brain IR and indicate that hypoxic tissue usually existed with low microvessel density. Furthermore, the duration of hypoxic tissue was partially dependent on the degree of microvessel proliferation.

Displacement of Particles in Microfluidics by Laser-generated Tandem Bubbles

Applied Physics Letters. Nov, 2010  |  Pubmed ID: 21124726

The dynamic interaction between laser-generated tandem bubble and individual polystyrene particles of 2 and 10 μm in diameter is studied in a microfluidic channel (25 μm height) by high-speed imaging and particle image velocimetry. The asymmetric collapse of the tandem bubble produces a pair of microjets and associated long-lasting vortices that can propel a single particle to a maximum velocity of 1.4 m∕s in 30 μs after the bubble collapse with a resultant directional displacement up to 60 μm in 150 μs. This method may be useful for high-throughput cell sorting in microfluidic devices.

Reduction of β-amyloid Deposits by γ-secretase Inhibitor is Associated with the Attenuation of Secondary Damage in the Ipsilateral Thalamus and Sensory Functional Improvement After Focal Cortical Infarction in Hypertensive Rats

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Feb, 2011  |  Pubmed ID: 20683452

Abnormal β-amyloid (Aβ) deposits in the thalamus have been reported after cerebral cortical infarction. In this study, we investigated the association of Aβ deposits, with the secondary thalamic damage after focal cortical infarction in rats. Thirty-six stroke-prone renovascular hypertensive rats were subjected to distal middle cerebral artery occlusion (MCAO) and then randomly divided into MCAO, vehicle, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) groups and 12 sham-operated rats as control. The DAPT was administered orally at 72 hours after MCAO. Seven days after MCAO, sensory function, neuron loss, and glial activation and proliferation were evaluated using adhesive removal test, Nissl staining, and immunostaining, respectively. Thalamic Aβ accumulation was evaluated using immunostaining and enzyme-linked immunosorbent assay (ELISA). Compared with vehicle group, the ipsilateral thalamic Aβ, neuronal loss, glial activation and proliferation, and the mean time to remove the stimulus from right forepaw significantly decreased in DAPT group. The mean time to remove the stimulus from the right forepaw and thalamic Aβ burden were both negatively correlated with the number of thalamic neurons. These findings suggest that Aβ deposits are associated with the secondary thalamic damage. Reduction of thalamic Aβ by γ-secretase inhibitor may attenuate the secondary damage and improve sensory function after cerebral cortical infarction.

LRRK2 R1398H Polymorphism is Associated with Decreased Risk of Parkinson's Disease in a Han Chinese Population

Parkinsonism & Related Disorders. May, 2011  |  Pubmed ID: 21159540

The Digital Flexible Ureteroscope: in Vitro Assessment of Optical Characteristics

Journal of Endourology. Mar, 2011  |  Pubmed ID: 21361823

Recent advances in endoscope design have placed the charged coupled device chip on the tip of the endoscope. The image is instantly digitalized and converted into an electrical signal for transmission. Digital technology was first introduced into flexible cystoscopes/nephroscopes and subsequently into rigid and flexible ureteroscopes. Herein, we assess the image characteristics and advantages of a new generation of digital flexible ureteroscopes.

[Significant Improvement of Motor Symptoms by Deep Brain Stimulation of Bilateral Subthalamic Nucleus in Patients with Moderate or Advanced Parkinson's Disease]

Zhonghua Yi Xue Za Zhi. Feb, 2011  |  Pubmed ID: 21419000

To study the effects of deep brain stimulation (DBS) of bilateral subthalamic nucleus (STN) on the motor and non-motor symptoms in moderate or advanced Parkinson's disease (PD) patients.

Early Detection of Secondary Damage in Ipsilateral Thalamus After Acute Infarction at Unilateral Corona Radiata by Diffusion Tensor Imaging and Magnetic Resonance Spectroscopy

BMC Neurology. May, 2011  |  Pubmed ID: 21542942

Traditional magnetic resonance (MR) imaging can identify abnormal changes in ipsilateral thalamus in patients with unilateral middle cerebral artery (MCA) infarcts. However, it is difficult to demonstrate these early changes quantitatively. Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (MRS) are potentially sensitive and quantitative methods of detection in examining changes of tissue microstructure and metabolism. In this study, We used both DTI and MRS to examine possible secondary damage of thalamus in patients with corona radiata infarction.

Early Stage Transplantation of Bone Marrow Cells Markedly Ameliorates Copper Metabolism and Restores Liver Function in a Mouse Model of Wilson Disease

BMC Gastroenterology. Jun, 2011  |  Pubmed ID: 21676234

Recent studies have demonstrated that normal bone marrow (BM) cells transplantation can correct liver injury in a mouse model of Wilson disease (WD). However, it still remains unknown when BM cells transplantation should be administered. The aim of this study was to investigate the potential impact of normal BM cells transplantation at different stages of WD to correct liver injury in toxic milk (tx) mice.

Optimization of Treatment Strategy Used During Shockwave Lithotripsy to Maximize Stone Fragmentation Efficiency

Journal of Endourology. Sep, 2011  |  Pubmed ID: 21834658

Previous studies have demonstrated that treatment strategy plays a critical role in ensuring maximum stone fragmentation during shockwave lithotripsy (SWL). We aimed to develop an optimal treatment strategy in SWL to produce maximum stone fragmentation.

Decrease of Tight Junction Integrity in the Ipsilateral Thalamus During the Acute Stage After Focal Infarction and Ablation of the Cerebral Cortex in Rats

Clinical and Experimental Pharmacology & Physiology. Nov, 2011  |  Pubmed ID: 21851377

1. Whether damage to the blood-brain barrier (BBB) occurs in remote areas after a focal cortical lesion remains unknown. The present study investigated tight junction-related proteins and tight junction microstructure in the ipsilateral thalamus during the acute stage after middle cerebral artery occlusion (MCAO) and cortical aspiration lesion (CAL) in rats. 2. Thirty-six hypertensive and normotensive rats were subjected to MCAO or CAL; another 18 rats in each group were submitted to sham operation. Zonula Occluden (ZO)-1, occludin and albumin were detected by western blotting 12 and 24 h after surgery. Tight junction microstructure was evaluated using electron microscopy, whereas albumin location in the ipsilateral thalamus was determined using double immunostaining for albumin and occludin or albumin and neuronal nuclei (NeuN) 24 h after surgery. 3. Twenty-four hours after MCAO or CAL, occludin expression was reduced to 78.4% and 81.3%, respectively, compared with control. A reduction in ZO-1 expression in the ipsilateral thalamus (to 79%) was seen only after CAL (P < 0.05). Membrane contact at the tight junction was discontinuous in the ipsilateral thalamus in both MCAO and CAL rats. Albumin levels were 23.2% and 82.5% higher in the ipsilateral thalamus after MCAO and CAL, respectively (P < 0.05). The percentage of the albumin-positive area that coincided with the occludin-positive area in the MCAO and CAL groups was 76.8% and 64.6%, respectively, indicating that albumin was mainly localized around the microvessels. 4. The results of the present study suggest that tight junction integrity decreases during the acute stage in the ipsilateral thalamus after MCAO and CAL in rats.

Dynamics of Tandem Bubble Interaction in a Microfluidic Channel

The Journal of the Acoustical Society of America. Nov, 2011  |  Pubmed ID: 22088007

The dynamics of tandem bubble interaction in a microfluidic channel (800  ×  21 μm, W × H) have been investigated using high-speed photography, with resultant fluid motion characterized by particle imaging velocimetry. A single or tandem bubble is produced reliably via laser absorption by micron-sized gold dots (6 μm in diameter with 40 μm in separation distance) coated on a glass surface of the microfluidic channel. Using two pulsed Nd:YAG lasers at λ = 1064 nm and ∼10 μJ/pulse, the dynamics of tandem bubble interaction (individual maximum bubble diameter of 50 μm with a corresponding collapse time of 5.7 μs) are examined at different phase delays. In close proximity (i.e., interbubble distance = 40 μm or γ = 0.8), the tandem bubbles interact strongly with each other, leading to asymmetric deformation of the bubble walls and jet formation, as well as the production of two pairs of vortices in the surrounding fluid rotating in opposite directions. The direction and speed of the jet (up to 95 m/s), as well as the orientation and strength of the vortices can be varied by adjusting the phase delay.

Decrease in the Production of β-amyloid by Berberine Inhibition of the Expression of β-secretase in HEK293 Cells

BMC Neuroscience. Dec, 2011  |  Pubmed ID: 22152059

Berberine (BER), the major alkaloidal component of Rhizoma coptidis, has multiple pharmacological effects including inhibition of acetylcholinesterase, reduction of cholesterol and glucose levels, anti-inflammatory, neuroprotective and neurotrophic effects. It has also been demonstrated that BER can reduce the production of beta-amyloid40/42, which plays a critical and primary role in the pathogenesis of Alzheimer's disease. However, the mechanism by which it accomplishes this remains unclear.

The Genes for Gibberellin Biosynthesis in Wheat

Functional & Integrative Genomics. Mar, 2012  |  Pubmed ID: 21853379

The gibberellin biosynthesis pathway is well defined in Arabidopsis and features seven key enzymes including ent-copalyl diphosphate synthase (CPS), ent-kaurene synthase (KS), ent-kaurene oxidase (KO), ent-kaurenoic acid oxidase (KAO), GA 20-oxidase, GA 3-oxidase, and GA 2-oxidase. The Arabidopsis genes were used to identify their counterparts in wheat and the TaCPS, TaKS, TaKO, and TaKAO genes were cloned from Chinese Spring wheat. In order to determine their chromosome locations, expression patterns and feedback regulations, three TaCPS genes, three TaKS genes, three TaKO genes, and three TaKAO genes were cloned from Chinese Spring wheat. They are mainly located on chromosomes 7A, 7B, 7D and 2A, 2B and 2D. The expression patterns of TaCPS, TaKS, TaKO, and TaKAO genes in wheat leaves, young spikes, peduncles, the third and forth internodes were investigated using quantitative PCR. The results showed that all the genes were constitutively expressed in wheat, but their relative expression levels varied in different tissues. They were mainly transcribed in stems, secondly in leaves and spikes, and the least in peduncles. Feedback regulation of the TaCPS, TaKS, TaKO, and TaKAO genes was not evident. These results indicate that all the genes and their homologs may play important roles in the developmental processes of wheat, but each of the homologs may function differently in different tissues or during different developmental stages.

Melatonin Protects Against Rotenone-induced Cell Injury Via Inhibition of Omi and Bax-mediated Autophagy in Hela Cells

Journal of Pineal Research. Jan, 2012  |  Pubmed ID: 21883444

Parkinson's disease is the second most common neurodegenerative disease, and environmental toxins such as rotenone play an important role in causing degeneration of dopaminergic neurons. Melatonin, a major secretory product of pineal, is recently reported to protect against rotenone-induced cell death in animal models. Yet, the mechanism involved in this protection needs to be elucidated. Here, we report that rotenone treatment (0-100 μM) decreased cell survival of Hela cells in a dose-dependent manner. At concentrations ranging from 0.1 to 100 μM, rotenone induced a dose-dependent increase in the expression of microtubule-associated protein 1 light chain 3 (LC3)-II, a protein associated with the autophagosomal membrane. Knockdown of Bax or Omi using shRNA inhibited 1 μM rotenone-induced autophagy. To determine whether melatonin would protect cells against rotenone-induced cell death and autophagy, we pretreated Hela cells with 250 μM melatonin for 24 hr in the presence of rotenone. Melatonin inhibited Bax expression and the release of the omi/HtrA2 into the cytoplasm induced by 1 μM rotenone. Melatonin 250 μM treatment also suppressed cell death induced by 0.1-100 μM rotenone and protected against the formation of LC3-II in cells exposed to 1 μM rotenone. This work demonstrates a novel role for melatonin as a neuroprotective agent against rotenone.

Autophagosomes Accumulation is Associated with β-amyloid Deposits and Secondary Damage in the Thalamus After Focal Cortical Infarction in Hypertensive Rats

Journal of Neurochemistry. Feb, 2012  |  Pubmed ID: 21950964

Focal cerebral cortical infarction after distal middle cerebral artery occlusion causes β-amyloid deposition and secondary neuronal degeneration in the ipsilateral ventroposterior nucleus of the thalamus. Several studies suggest that autophagy is an active pathway for β-amyloid peptide generation. This study aimed to investigate the role of autophagy in thalamic β-amyloid deposition and neuronal degeneration after cerebral cortical infarction in hypertensive rats. At 7 and 14days after middle cerebral artery occlusion, neuronal death and β-amyloid deposits were evident in the ipsilateral ventroposterior nucleus, and the activity of β-site amyloid precursor protein (APP)-cleaving enzyme 1, required for β-amyloid peptide generation, was elevated in the thalamus. In correlation, both the number of cells showing punctate microtubule-associated protein 1A light chain 3 fluorescence and levels of light chain 3-II protein, an autophagosome marker, were markedly increased. Notably, most of the cells that over-expressed β-site APP-cleaving enzyme 1 displayed punctate light chain 3 staining. Furthermore, the inhibition of autophagy with 3-methyladenine significantly reduced the thalamic neuronal damage, β-amyloid deposits, and β-site APP-cleaving enzyme 1 activity. These results suggest that autophagosomes accumulate within thalamic cells after cerebral cortical infarction, which is associated with thalamic β-amyloid deposition and secondary neuronal degeneration via elevation of β-site APP-cleaving enzyme 1 level.

Cognitive Impairment is Common in Parkinson's Disease Without Dementia in the Early and Middle Stages in a Han Chinese Cohort

Parkinsonism & Related Disorders. Feb, 2012  |  Pubmed ID: 21975261

Cognitive impairments have been reported to be common in Parkinson's disease (PD) without dementia, which occur not only in the late stages of PD, but also in the early and middle stages. Until now, no reports on the profile of cognitive impairment in Chinese non-demented PD population have been published yet. Different ethnic groups should be assessed to improve evaluation of cognitive impairment in clinical practice. The aims of this study are to estimate the frequencies and profile of cognitive impairments and to explore the risk factors of cognitive impairments in Han Chinese non-demented PD patients at early and middle stages.

Beclin 1 Knockdown Inhibits Autophagic Activation and Prevents the Secondary Neurodegenerative Damage in the Ipsilateral Thalamus Following Focal Cerebral Infarction

Autophagy. Jan, 2012  |  Pubmed ID: 22108007

Cerebral infarction can cause secondary degeneration of thalamus and delay functional recovery. However, the mechanisms underlying secondary degeneration are unclear. The present study aimed to determine the occurrence and contribution of autophagy to the thalamic degeneration after cerebral infarction. Focal cerebral infarction was induced by distal middle cerebral artery occlusion (MCAO). Autophagic activation, Beclin 1 expression and amyloid β (Aβ) deposits were determined by immunofluorescence, immunoblot and electron microscopy. Secondary damage to thalamus was assessed with Nissl staining and immunofluorescence analysis. Apoptosis was determined using TUNEL staining. The contribution of autophagy to the secondary damage was evaluated by shRNA-mediated downregulation of Beclin 1 and the autophagic inhibitor, 3-methyladenine (3-MA). The potential role of Aβ in autophagic activation was determined with N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The results showed that the conversion of LC3-II, the formation of autophagosomes, and the levels of activated cathepsin B and Beclin 1 were significantly increased in the ipsilateral thalamus at 7 and 14 days after MCAO (p < 0.05 or 0.01). Both Beclin 1 knockdown and 3-MA treatment significantly reduced LC3-II conversion and autophagosome formation, which were accompanied by obvious decreases in neuronal loss, gliosis and apoptosis in the ipsilateral thalamus (p < 0.05 or 0.01). Additionally, DAPT treatment markedly reduced Aβ deposits, which coincided with decreases in LC3-II conversion and autophagosome formation (p < 0.01). These results suggest that inhibition of autophagy by Beclin 1 knockdown can attenuate the secondary thalamic damage after focal cerebral infarction. Furthermore, Aβ deposits may be involved in the activation of autophagy.

Dl-3n-butylphthalide Promotes Angiogenesis Via the Extracellular Signal-regulated Kinase 1/2 and Phosphatidylinositol 3-kinase /Akt- Endothelial Nitric Oxide Synthase Signaling Pathways

Journal of Cardiovascular Pharmacology. Jan, 2012  |  Pubmed ID: 22286127

ABSTRACT: We have previously demonstrated that dl-3n-butylphthalide (NBP) has a potential angiogenic activity. In this study, we investigated the angiogenic effect of NBP and the molecular mechanisms underlying NBP-mediated angiogenesis. Zebrafish embryos and human umbilical vein endothelial cells (HUVEC) were treated with various doses of NBP and several signaling pathway inhibitors. NBP induced ectopic subintestinal vessel production in zebrafish embryos and induced invasion, migration and endothelial cell tube formation of HUVEC in a dose-dependent manner. These NBP-induced angiogenic effects were partially suppressed by SU5402, a fibroblast growth factor receptor 1 (FGFR-1) inhibitor; U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor; LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor; 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, an Akt inhibitor; Cavtratin, an eNOS inhibitor and completely inhibited by a combination of U0126 and LY294002. NBP enhanced phosphorylation of ERK1/2 and FGF-2 expression, which were inhibited by U0126. NBP increased phosphorylation of Akt and endothelial nitric oxide synthase at serine 1177, which were blocked by LY294002. NBP stimulated nitric oxide production, which was reduced by LY294002. Our data demonstrated that 1) NBP promoted angiogenesis and 2) the angiogenic effects of NBP were mediated by the ERK1/2 and PI3K/Akt-eNOS signaling pathways. Our findings suggest that NBP could be a novel agent for therapeutic angiogenesis in ischemic diseases.

Peroxisome Proliferator Activated Receptor (PPAR)-γ Co-activator 1-α and Hypoxia Induced Factor-1α Mediate Neuro- and Vascular Protection by Hypoxic Preconditioning in Vitro

Brain Research. Apr, 2012  |  Pubmed ID: 22342160

Preconditioning-induced cellular adaptation is a new therapeutic strategy for ischemic stroke. This research aims to examine the role of peroxisome proliferator activated receptor (PPAR)-γ co-activator 1-α (PGC-1α) and hypoxia induced factor-1α (HIF-1α) in hypoxic preconditioning-induced protection. In this study, rat artery endothelial cells and neuronal PC12 cells were preconditioned with hypoxia before oxygen-glucose deprivation (OGD) insult. Cell viability, protein expression and oxidative stress were then evaluated. PGC-1α and HIF-1α were knocked down by RNA interference. We found that hypoxic preconditioning significantly reduced cell damage, enhanced the expression of PGC-1α, HIF-1α and VEGF and attenuated oxidative stress in endothelial and PC12 cells in OGD model. The protective effects of hypoxic preconditioning were hardly detected in HIF-1α or PGC-1α deficit cells. The loss of protection was accompanied with a significant loss of VEGF expression in HIF-1α or PGC-1α deficit PC12 cells and PGC-1α deficit endothelial cells as well as a considerable decrease of anti-oxidative effects in PGC-1α knocked-down endothelial cells. The present study demonstrated that both PGC-1α and HIF-1α played crucial roles in hypoxic preconditioning in endothelial and neuronal cells.

Characteristics of the Secondary Bubble Cluster Produced by an Electrohydraulic Shock Wave Lithotripter

Ultrasound in Medicine & Biology. Apr, 2012  |  Pubmed ID: 22390990

This study investigated the characteristics of the secondary bubble cluster produced by an electrohydraulic lithotripter using high-speed imaging and passive cavitation detection techniques. The results showed that (i) the discrepancy of the collapse time between near a flat rigid boundary and in a free field of the secondary bubble cluster was not as significant as that by the primary one; (ii) the secondary bubble clusters were small but in a high bubble density and nonuniform in distribution, and they did not expand and aggregate significantly near a rigid boundary; and (iii) the corresponding bubble collapse was weaker with few microjet formation and bubble rebound. By applying a strong suction flow near the electrode tip, the production of the secondary shock wave (SW) and induced bubble cluster could be disturbed significantly, but without influence on the primary ones. Consequently, stone fragmentation efficiency was reduced from 41.2 ± 7.1% to 32.2 ± 3.5% after 250 shocks (p < 0.05). Altogether, these observations suggest that the secondary bubble cluster produced by an electrohydraulic lithotripter may contribute to its ability for effective stone fragmentation.

Abnormalities of Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging Are Correlated with Executive Dysfunction in Patients with Ischemic Leukoaraiosis

Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. May, 2012  |  Pubmed ID: 22502913

Abnormal diffusion tensor imaging (DTI) results have been observed in the periventricular white matter in patients with ischemic leukoaraiosis (ILA). However, the underlying pathological changes and their relationship to cognitive impairments are obscure. In addition, damage in the thalamus, an important structure in the executive function network, has been suggested in ILA, but is poorly understood. Twenty patients with ILA and 20 healthy volunteers with similar ages and educational histories underwent DTI, magnetic resonance spectroscopy (MRS) and a neuropsychological assessment. In patients with ILA, we observed an increased mean diffusivity (MD) and decreased levels of N-acetylaspartate (NAA)/creatine (Cr) in the anterior and posterior periventricular region and the thalamus, as well as decreased fractional anisotropy (FA) in the anterior and posterior periventricular regions. MD and NAA/Cr levels in the anterior and posterior periventricular white matter and NAA/Cr levels in the thalamus were correlated with executive function. DTI and MRS abnormalities were consistent with axonal and/or neuronal loss and dysfunction in the anterior and posterior periventricular white matter and the thalamus. This study demonstrates that DTI and MRS techniques can be used to investigate pathological changes in the anterior and posterior periventricular white matter and the thalamus; these changes may be correlated with executive functional changes in patients with ILA.

Stereoscopic High-speed Imaging Using Additive Colors

The Review of Scientific Instruments. Apr, 2012  |  Pubmed ID: 22559533

An experimental system for digital stereoscopic imaging produced by using a high-speed color camera is described. Two bright-field image projections of a three-dimensional object are captured utilizing additive-color backlighting (blue and red). The two images are simultaneously combined on a two-dimensional image sensor using a set of dichromatic mirrors, and stored for off-line separation of each projection. This method has been demonstrated in analyzing cavitation bubble dynamics near boundaries. This technique may be useful for flow visualization and in machine vision applications.

The Beta-lactam Antibiotic, Ceftriaxone, Provides Neuroprotective Potential Via Anti-excitotoxicity and Anti-inflammation Response in a Rat Model of Traumatic Brain Injury

The Journal of Trauma and Acute Care Surgery. Sep, 2012  |  Pubmed ID: 22710775

The beta-lactam antibiotic, ceftriaxone (CTX), has been reported to induce neuroprotection in animal models of diverse neurologic diseases. Currently, no data have explored the potential for CTX to provide neuroprotection in the animal models of traumatic brain injury (TBI). The aim of this study was to investigate the neuroprotective effect by CTX on TBI and to determine the underlying mechanisms.

Nogo-A is Associated with Secondary Degeneration of Substantia Nigra in Hypertensive Rats with Focal Cortical Infarction

Brain Research. Aug, 2012  |  Pubmed ID: 22771857

We investigated the association of Nogo-A protein, a myelin-associated inhibitor of axon regeneration, with secondary damage of the ipsilateral substantia nigra pars reticulata (SNr) after distal middle cerebral artery occlusion (dMCAO) in adult stroke-prone, renovascular hypertensive rats. Intracerebroventricular infusion of NEP1-40, a Nogo-66 receptor antagonist peptide, or vehicle was administered starting 24h after dMCAO and continued for 1, 2, or 4 weeks. The expression of Nogo-A in the ipsilateral SNr was assessed by immunohistochemistry. Neuron death and apoptosis were evaluated using Nissl and terminal uridine nick-end labeling (TUNEL) staining. Glial activation was monitored by immunoreactivity of glial fibrillary acidic protein and the oligodendrocyte marker RIP. Axonal damage and regeneration were determined by Bielschowsky's silver staining and immunoreactivity of growth associated protein 43 and microtubule associated protein 2. We found progressive damage in the center of the ipsilateral SNr through 4 weeks after dMCAO. The neuronal loss was topographically related to axonal degeneration that occurred indirectly from the infarcted cortex. Nogo-A protein in oligodendrocytes was persistently increased in the damaged SNr. Administration of NEP1-40 inhibited Nogo-A expression, the loss of neurons, apoptosis, and proliferation of oligodendrocytes and astrocytes. It also boosted the regenerative response of injured axons and encouraged compensatory neurite growth in the ipsilateral SNr. Our data suggest that secondary damage in the ipsilateral SNr may be due to trans-synaptic axonal degeneration that followed the cortical infarct. Further, we showed that Nogo-A is involved in axonal degeneration, and NEP1-40 reduces secondary nigral damage after focal cortical ischemia.

LRRK2 A419V is Not Associated with Parkinson's Disease in Different Chinese Populations

PloS One. 2012  |  Pubmed ID: 22807999

It has been suggested that a common LRRK2 polymorphic variant (A419V (rs34594498 C >T)) may be a risk factor among Asians (especially in Taiwan). In this study, we examined this variant in a larger and independent Taiwan cohort. We found the frequency of the variant (A419V) to be very rare in our Taiwan PD and controls (?0.6%). Further studies were conducted in two other Chinese populations (Singapore and China), comprising of a total of 3004 subjects including 1517 PD patients and 1487 control subjects. However, our multi-center Chinese study revealed that the frequency of the variant was rare (?0.4%) and was not associated with risk of PD, suggesting that the variant is not a major risk factor for PD among Chinese, at least in our study population.

Marine Cyclotripeptide X-13 Promotes Angiogenesis in Zebrafish and Human Endothelial Cells Via PI3K/Akt/eNOS Signaling Pathways

Marine Drugs. Jun, 2012  |  Pubmed ID: 22822374

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.

In-vitro Assessment of a New Portable Ballistic Lithotripter with Percutaneous and Ureteroscopic Models

Journal of Endourology. Nov, 2012  |  Pubmed ID: 22873666

The EMS Swiss LithoBreaker is a new, portable, electrokinetic lithotripter. We compared its tip velocity and displacement characteristics with a handheld, pneumatic lithotripter LMA StoneBreaker.™ We also evaluated fragmentation efficiency using in vitro models of percutaneous and ureteroscopic stone fragmentation.

M-HIFU Inhibits Tumor Growth, Suppresses STAT3 Activity and Enhances Tumor Specific Immunity in a Transplant Tumor Model of Prostate Cancer

PloS One. 2012  |  Pubmed ID: 22911830

In this study, we explored the use of mechanical high intensity focused ultrasound (M-HIFU) as a neo-adjuvant therapy prior to surgical resection of the primary tumor. We also investigated the role of signal transducer and activator of transcription 3 (STAT3) in M-HIFU elicited anti-tumor immune response using a transplant tumor model of prostate cancer.

Hypoxia Inducible Factor-1alpha Mediates Protection of DL-3-n-butylphthalide in Brain Microvascular Endothelial Cells Against Oxygen Glucose Deprivation-induced Injury

Neural Regeneration Research. Apr, 2012  |  Pubmed ID: 25722681

Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on oxygen glucose deprivation -induced hypoxia inducible factor-1α expression. In this study, we hypothesized that DL-3-n-butylphthalide can protect against oxygen glucose deprivation-induced injury of newborn rat brain microvascular endothelial cells by means of upregulating hypoxia inducible factor-1α expression. MTT assay and Hoechst staining results showed that DL-3-n-butylphthalide protected brain microvascular endothelial cells against oxygen glucose deprivation-induced injury in a dose-dependent manner. Western blot and immunofluorescent staining results further confirmed that the protective effect was related to upregulation of hypoxia inducible factor-1α. Real-time RT-PCR reaction results showed that DL-3-n-butylphthalide reduced apoptosis by inhibiting downregulation of pro-apoptotic gene caspase-3 mRNA expression and upregulation of apoptosis-executive protease bcl-2 mRNA expression; however, DL-3-n-butylphthalide had no protective effects on brain microvascular endothelial cells after knockdown of hypoxia inducible factor-1α by small interfering RNA. These findings suggest that DL-3-n-butylphthalide can protect brain microvascular endothelial cells against oxygen glucose deprivation-induced injury by upregulating bcl-2 expression and downregulating caspase-3 expression though hypoxia inducible factor-1α pathway.

LRRK2 G2385R and LRRK2 R1628P Increase Risk of Parkinson's Disease in a Han Chinese Population from Southern Mainland China

Parkinsonism & Related Disorders. Mar, 2013  |  Pubmed ID: 22981185

The Study on the Frontoparietal Networks by Continuous Theta Burst Stimulation in Healthy Human Subjects

Behavioural Brain Research. Mar, 2013  |  Pubmed ID: 23183220

Frontoparietal networks (FPNs) including the regions of the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC) have been implicated in visuospatial attention. However, the functional interactions among different regions of dorsal FPNs remain elusive. The Attention Network Test (ANT) and continuous theta burst stimulation (cTBS) were used to investigate the functional interactions in healthy subjects. During the ANT task, subjects receiving right PPC cTBS responded significantly slower in spatial cue condition, had deficits in both alerting and orienting indices compared with those receiving either the sham cTBS or left PPC cTBS. In addition, subjects receiving left-DLPFC cTBS showed significant improvements on alerting and conflict indices whereas significant deficits on the orienting index compared with those receiving the sham cTBS. Moreover, compared with subjects exposed to the sham cTBS condition, subjects exposed to cTBS to the right-DLPFC exhibited significant decreases in the efficiency of the alerting and conflict indices whereas significant increases in the orienting index. Furthermore, there were significant differences in the alerting, orienting and conflict effect indices between subjects receiving the left-DLPFC-cTBS and those receiving the right-DLPFC-cTBS. These results suggest that the right DLPFC played a pivotal role in executive control process, whereas the right PPC was associated with orienting attentional function. The current study not only supports the model of inter-hemispheric rivalry for visuospatial attention, but also indicates inter-regional competition between the different areas of the FPNs.

Turbulent Water Coupling in Shock Wave Lithotripsy

Physics in Medicine and Biology. Feb, 2013  |  Pubmed ID: 23322027

Previous studies have demonstrated that stone comminution decreases with increased pulse repetition frequency as a result of bubble proliferation in the cavitation field of a shock wave lithotripter (Pishchalnikov et al 2011 J. Acoust. Soc. Am. 130 EL87-93). If cavitation nuclei remain in the propagation path of successive lithotripter pulses, especially in the acoustic coupling cushion of the shock wave source, they will consume part of the incident wave energy, leading to reduced tensile pressure in the focal region and thus lower stone comminution efficiency. We introduce a method to remove cavitation nuclei from the coupling cushion between successive shock exposures using a jet of degassed water. As a result, pre-focal bubble nuclei lifetime quantified by B-mode ultrasound imaging was reduced from 7 to 0.3 s by a jet with an exit velocity of 62 cm s(-1). Stone fragmentation (percent mass <2 mm) after 250 shocks delivered at 1 Hz was enhanced from 22 ± 6% to 33 ± 5% (p = 0.007) in water without interposing tissue mimicking materials. Stone fragmentation after 500 shocks delivered at 2 Hz was increased from 18 ± 6% to 28 ± 8% (p = 0.04) with an interposing tissue phantom of 8 cm thick. These results demonstrate the critical influence of cavitation bubbles in the coupling cushion on stone comminution and suggest a potential strategy to improve the efficacy of contemporary shock wave lithotripters.

Xyloketal B Exhibits Its Antioxidant Activity Through Induction of HO-1 in Vascular Endothelial Cells and Zebrafish

Marine Drugs. Feb, 2013  |  Pubmed ID: 23429283

We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here investigated whether xyloketal B exhibits its antioxidant activity through induction of HO-1. In human umbilical vein endothelial cells (HUVECs), xyloketal B significantly induced HO-1 gene expression and translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) in a concentration- and time-dependent manner. The protection of xyloketal B against angiotensin II-induced apoptosis and reactive oxygen species (ROS) production could be abrogated by the HO-1 specific inhibitor, tin protoporphyrin-IX (SnPP). Consistently, the suppressive effects of xyloketal B on NADPH oxidase activity could be reversed by SnPP in zebrafish embryos. In addition, xyloketal B induced Akt and Erk1/2 phosphorylation in a concentration- and time-dependent manner. Furthermore, PI3K inhibitor LY294002 and Erk1/2 inhibitor U0126 suppressed the induction of HO-1 and translocation of Nrf-2 by xyloketal B, whereas P38 inhibitor SB203580 did not. In conclusion, xyloketal B can induce HO-1 expression via PI3K/Akt/Nrf-2 pathways, and the induction of HO-1 is mainly responsible for the antioxidant and antiapoptotic actions of xyloketal B.

Assessment of a Modified Acoustic Lens for Electromagnetic Shock Wave Lithotripters in a Swine Model

The Journal of Urology. Sep, 2013  |  Pubmed ID: 23485509

The acoustic lens of the Modularis electromagnetic shock wave lithotripter (Siemens, Malvern, Pennsylvania) was modified to produce a pressure waveform and focal zone more closely resembling that of the original HM3 device (Dornier Medtech, Wessling, Germany). We assessed the newly designed acoustic lens in vivo in an animal model.

Lifespan Extension by N-butanol Extract from Seed of Platycladus Orientalis in Caenorhabditis Elegans

Journal of Ethnopharmacology. May, 2013  |  Pubmed ID: 23523941

As a traditional Chinese medicine, seed of Platycladus orientalis(Linnaeus) Franco has been extensively used as a tonic and sedative remedy. The present study was conducted to investigate whether lifespan was extended and the mechanisms of n-butanol extract from seed of Platycladus orientalis (BSPO) in Caenorhabditis elegans. The findings could provide the pharmacological basis for a treatment in traditional medicine.

Physical Exercise Improves Functional Recovery Through Mitigation of Autophagy, Attenuation of Apoptosis and Enhancement of Neurogenesis After MCAO in Rats

BMC Neuroscience. Apr, 2013  |  Pubmed ID: 23565939

Physical exercise improves functional recovery after stroke through a complex mechanism that is not fully understood. Transient focal cerebral ischemia induces autophagy, apoptosis and neurogenesis in the peri-infarct region. This study is aimed to examine the effects of physical exercise on autophagy, apoptosis and neurogenesis in the peri-infarct region in a rat model of transient middle cerebral artery occlusion (MCAO).

Upregulation of Myeloid Cell Leukemia-1 Potentially Modulates Beclin-1-dependent Autophagy in Ischemic Stroke in Rats

BMC Neuroscience. May, 2013  |  Pubmed ID: 23688351

The mechanisms that underlie autophagy in cerebral ischemia remain poorly defined. Myeloid cell leukemia-1 (Mcl1), an anti-apoptotic member of the Bcl-2 family of proteins, regulates the balance between autophagy and apoptosis. However, little is known regarding its expression profile and contribution to cell fate in the brain following ischemic stroke.

Salvianolic Acid A, a Polyphenolic Derivative from Salvia Miltiorrhiza Bunge, As a Multifunctional Agent for the Treatment of Alzheimer's Disease

Molecular Diversity. Aug, 2013  |  Pubmed ID: 23703159

The effects of Salvianolic acid A (Sal A) on the treatment of Alzheimer's disease (AD) were investigated. Sal A significantly inhibits amyloid beta [Formula: see text] self-aggregation and disaggregates pre-formed [Formula: see text] fibrils, reduces metal-induced [Formula: see text] aggregation through chelating metal ions, and blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells. Sal A protects cells against [Formula: see text]-induced toxicity. Furthermore, Sal A, possibly because of the effects of decreasing toxicity effects of [Formula: see text] species, alleviates [Formula: see text]-induced paralysis in transgenic Caenorhabditis elegans. Circular dichroism (CD) experiments and Molecular dynamic (MD) simulations demonstrate that Sal A inhibits [Formula: see text] self-aggregation through binding to the C-terminus of [Formula: see text], and therefore stabilizing the [Formula: see text]-helical conformations. Altogether, our data show that Sal A, as the multifunctional agent, is likely to be promising therapeutics for AD.

Absence of Mutations in Exon 6 of the TARDBP Gene in 207 Chinese Patients with Sporadic Amyotrohic Lateral Sclerosis

PloS One. 2013  |  Pubmed ID: 23874513

Mutations in the TARDBP gene, which encodes the Tar DNA binding protein, have been shown to causes of both familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS). Recently, several novel TARDBP exon 6 mutants have been reported in patients with ALS in Europe and America but not in Asia. To further examine the spectrum and frequency of TARDBP exon 6 mutations, we investigated their frequency in ethnic Chinese patients with sporadic ALS. TARDBP exon 6 was screened by direct sequencing in 207 non-SOD1 SALS patients and 230 unrelated healthy controls but no mutations were identified. Our data indicate that exon 6 mutations in TARDBP are not a common cause of SALS in Han Chinese population from Southern Mainland China.

A Heuristic Model of Stone Comminution in Shock Wave Lithotripsy

The Journal of the Acoustical Society of America. Aug, 2013  |  Pubmed ID: 23927195

A heuristic model is presented to describe the overall progression of stone comminution in shock wave lithotripsy (SWL), accounting for the effects of shock wave dose and the average peak pressure, P+(avg), incident on the stone during the treatment. The model is developed through adaptation of the Weibull theory for brittle fracture, incorporating threshold values in dose and P+(avg) that are required to initiate fragmentation. The model is validated against experimental data of stone comminution from two stone types (hard and soft BegoStone) obtained at various positions in lithotripter fields produced by two shock wave sources of different beam width and pulse profile both in water and in 1,3-butanediol (which suppresses cavitation). Subsequently, the model is used to assess the performance of a newly developed acoustic lens for electromagnetic lithotripters in comparison with its original counterpart both under static and simulated respiratory motion. The results have demonstrated the predictive value of this heuristic model in elucidating the physical basis for improved performance of the new lens. The model also provides a rationale for the selection of SWL treatment protocols to achieve effective stone comminution without elevating the risk of tissue injury.

Experimentally Validated Multiphysics Computational Model of Focusing and Shock Wave Formation in an Electromagnetic Lithotripter

The Journal of the Acoustical Society of America. Aug, 2013  |  Pubmed ID: 23927200

A multiphysics computational model of the focusing of an acoustic pulse and subsequent shock wave formation that occurs during extracorporeal shock wave lithotripsy is presented. In the electromagnetic lithotripter modeled in this work the focusing is achieved via a polystyrene acoustic lens. The transition of the acoustic pulse through the solid lens is modeled by the linear elasticity equations and the subsequent shock wave formation in water is modeled by the Euler equations with a Tait equation of state. Both sets of equations are solved simultaneously in subsets of a single computational domain within the BEARCLAW framework which uses a finite-volume Riemann solver approach. This model is first validated against experimental measurements with a standard (or original) lens design. The model is then used to successfully predict the effects of a lens modification in the form of an annular ring cut. A second model which includes a kidney stone simulant in the domain is also presented. Within the stone the linear elasticity equations incorporate a simple damage model.

Longitudinal Cortical Volume Changes Correlate with Motor Recovery in Patients After Acute Local Subcortical Infarction

Stroke; a Journal of Cerebral Circulation. Oct, 2013  |  Pubmed ID: 23929747

Secondary changes in the volume of motor-related cortical regions and the relationship with functional recovery during the acute stage after cerebral infarction have not been determined. In the present study, we quantified changes in gray matter (GM) volume in motor-related cortical regions and analyzed their correlations to clinical scores in patients with focal cerebral infarct.

Stroke-prone Renovascular Hypertensive Rat As an Animal Model for Stroke Studies: from Artery to Brain

Journal of the Neurological Sciences. Nov, 2013  |  Pubmed ID: 23953678

High blood pressure is a main risk factor for both initial and recurrent stroke. Compared to the post stroke situation in normotension, the brain lesion is larger in hypertension, and the treatments may not be as effective. Thus, the results from healthy individuals may not be directly applied to the hypertensive. In fact, the high prevalence of hypertension in stroke patients and its devastating effect urge the necessity to integrate arterial hypertension in the study of stroke in order to better mimic the clinical situations. The first step to do so is to have an appropriate hypertensive animal model for stroke studies. Stroke-prone renovascular hypertensive rat (RHRSP) introduced in 1998, is an animal model with acquired hypertension independent of genetic deficiency. The blood pressure begins to increase during the first week after constriction of bilateral renal arteries, and becomes sustained since around the 3rd month. Because the morphological and physiological changes of cerebral arteries are similar to those in hypertensive patients, the rats represent a higher than 60% incidence of spontaneous stroke. The animal model has several advantages: one hundred percent development of hypertension without gene modification, high similarity to human hypertension in cerebrovascular pathology and physiology, and easy establishment with low cost. Thus, the model has been extensively used in the investigation of ischemic stroke, and has been shown as a reliable animal model. This paper reviewed the features of RHRSP and its applications in the treatment and prevention of stroke, as well as the investigations of secondary lesions postischemic stroke.

Frontoparietal Regions May Become Hypoactive After Intermittent Theta Burst Stimulation over the Contralateral Homologous Cortex in Humans

Journal of Neurophysiology. Dec, 2013  |  Pubmed ID: 24047912

Brain injury to the dorsal frontoparietal networks, including the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC), commonly cause spatial neglect. However, the interaction of these different regions in spatial attention is unclear. The aim of the present study was to investigate whether hyperexcitable neural networks can cause an abnormal interhemispheric inhibition. The Attention Network Test was used to test subjects following intermittent theta burst stimulation (iTBS) to the left or right frontoparietal networks. During the Attention Network Test task, all subjects tolerated each conditioning iTBS without any obvious iTBS-related side effects. Subjects receiving real-right-PPC iTBS showed significant enhancement in both alerting and orienting efficiency compared with those receiving either sham-right-PPC iTBS or real-left-PPC iTBS. Moreover, subjects exposed to the real-right-DLPFC iTBS exhibited significant improvement in both alerting and executive control efficiency, compared with those exposed to either the sham-right-DLPFC or real-left-DLPFC conditioning. Interestingly, compared with subjects exposed to the sham-left-PPC stimuli, subjects exposed to the real-left-PPC iTBS had a significant deficit in the orienting index. The present study indicates that iTBS over the contralateral homologous cortex may induce the hypoactivity of the right PPC through interhemispheric competition in spatial orienting attention.

Association Between Improved Trunk Stability and Walking Capacity Using Ankle-foot Orthosis in Hemiparetic Patients with Stroke: Evidence from Three-dimensional Gait Analysis

Chinese Medical Journal. Oct, 2013  |  Pubmed ID: 24157148

Restoration of both normal movement of the pelvis and centre of mass is a primary goal of walking rehabilitation in post-stroke patients because these movements are essential components of effective gait. The aim of this study is to quantitatively analyze the effect of ankle-foot orthosis on walking ability, and to investigate the correlation between improvements in trunk motion and walking capacity.

Scutellarin Attenuates Hypertension-induced Expression of Brain Toll-like Receptor 4/nuclear Factor Kappa B

Mediators of Inflammation. 2013  |  Pubmed ID: 24223475

Hypertension is associated with low-grade inflammation, and Toll-like receptor 4 (TLR4) has been shown to be linked to the development and maintenance of hypertension. This study aimed to investigate the effects of scutellarin (administered by oral gavage daily for 2 weeks) on brain TLR4/nuclear factor kappa B-(NF- κ B-) mediated inflammation and blood pressure in renovascular hypertensive (using the 2-kidney, 2-clip method) rats. Immunofluorescence and western immunoblot analyses revealed that hypertension contributed to the activation of TLR4 and NF- κ B, accompanied by significantly enhanced expression of proinflammatory mediators, such as tumor necrosis factor- α (TNF- α ), interleukin-1 β (IL-1 β ), and interleukin-18 (IL-18). Furthermore, expression of the antiapoptotic protein, myeloid cell leukemia-1 (Mcl1), was decreased, and the pro-apoptotic proteins, Bax and cleavedcaspase-3 p17 were increased in combined cerebral cortical/striatal soluble lysates. Scutellarin significantly lowered blood pressure and attenuated the number of activated microglia and macrophages in brains of hypertensive rats. Furthermore, scutellarin significantly reduced the expression of TLR4, NF- κ B p65, TNF- α , IL-1 β , IL-18, Bax and cleaved-caspase-3 p17, and increased the expression of Mcl1. Overall, these results revealed that scutellarin exhibits anti-inflammatory and anti-apoptotic properties and decreases blood pressure in hypertensive rats. Therefore, scutellarin may be a potential therapeutic agent in hypertension-associated diseases.

Synthesis and Neuroprotective Action of Xyloketal Derivatives in Parkinson's Disease Models

Marine Drugs. Dec, 2013  |  Pubmed ID: 24351912

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1-39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson's disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD.

Cerebrolysin Reduces Amyloid-β Deposits, Apoptosis and Autophagy in the Thalamus and Improves Functional Recovery After Cortical Infarction

Journal of the Neurological Sciences. Feb, 2014  |  Pubmed ID: 24315581

Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (p<0.05). Aβ deposits and BACE1 were obviously reduced by Cerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p < 0.05). Coincidently, Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all p<0.05). These findings suggest that Cerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

Optimising Outcome Assessment to Improve Quality and Efficiency of Stroke Trials

Expert Review of Pharmacoeconomics & Outcomes Research. Feb, 2014  |  Pubmed ID: 24350886

Substantial progress has been made in treatment of stroke and much of this has been driven by large scale, multi-centre, randomised controlled trials. Although stroke is a frequent cause of mortality, stroke-related disability and functional decline is of equal or greater concern to patients and carers. Thus, to prove efficacy of an intervention for stroke, we need robust methods of describing recovery. Various functional assessment scales are available, the tool recommended as trial end point by many specialist societies and regulatory authorities is the modified Rankin Scale (mRS). We will use the mRS as exemplar to discuss contemporary research around functional assessment for stroke trials, including recent work around structured assessments, assessor training and end point adjudication panels. We will present an overview and critique of these studies and give examples where strategies to improve mRS assessment are impacting on the quality of stroke clinical trials.

AlzPlatform: an Alzheimer's Disease Domain-specific Chemogenomics Knowledgebase for Polypharmacology and Target Identification Research

Journal of Chemical Information and Modeling. Apr, 2014  |  Pubmed ID: 24597646

Alzheimer's disease (AD) is one of the most complicated progressive neurodegeneration diseases that involve many genes, proteins, and their complex interactions. No effective medicines or treatments are available yet to stop or reverse the progression of the disease due to its polygenic nature. To facilitate discovery of new AD drugs and better understand the AD neurosignaling pathways involved, we have constructed an Alzheimer's disease domain-specific chemogenomics knowledgebase, AlzPlatform (www.cbligand.org/AD/ ) with cloud computing and sourcing functions. AlzPlatform is implemented with powerful computational algorithms, including our established TargetHunter, HTDocking, and BBB Predictor for target identification and polypharmacology analysis for AD research. The platform has assembled various AD-related chemogenomics data records, including 928 genes and 320 proteins related to AD, 194 AD drugs approved or in clinical trials, and 405,188 chemicals associated with 1, 023,137 records of reported bioactivities from 38,284 corresponding bioassays and 10, 050 references. Furthermore, we have demonstrated the application of the AlzPlatform in three case studies for identification of multitargets and polypharmacology analysis of FDA-approved drugs and also for screening and prediction of new AD active small chemical molecules and potential novel AD drug targets by our established TargetHunter and/or HTDocking programs. The predictions were confirmed by reported bioactivity data and our in vitro experimental validation. Overall, AlzPlatform will enrich our knowledge for AD target identification, drug discovery, and polypharmacology analyses and, also, facilitate the chemogenomics data sharing and information exchange/communications in aid of new anti-AD drug discovery and development.

Improving the Lens Design and Performance of a Contemporary Electromagnetic Shock Wave Lithotripter

Proceedings of the National Academy of Sciences of the United States of America. Apr, 2014  |  Pubmed ID: 24639497

The efficiency of shock wave lithotripsy (SWL), a noninvasive first-line therapy for millions of nephrolithiasis patients, has not improved substantially in the past two decades, especially in regard to stone clearance. Here, we report a new acoustic lens design for a contemporary electromagnetic (EM) shock wave lithotripter, based on recently acquired knowledge of the key lithotripter field characteristics that correlate with efficient and safe SWL. The new lens design addresses concomitantly three fundamental drawbacks in EM lithotripters, namely, narrow focal width, nonidealized pulse profile, and significant misalignment in acoustic focus and cavitation activities with the target stone at high output settings. Key design features and performance of the new lens were evaluated using model calculations and experimental measurements against the original lens under comparable acoustic pulse energy (E+) of 40 mJ. The -6-dB focal width of the new lens was enhanced from 7.4 to 11 mm at this energy level, and peak pressure (41 MPa) and maximum cavitation activity were both realigned to be within 5 mm of the lithotripter focus. Stone comminution produced by the new lens was either statistically improved or similar to that of the original lens under various in vitro test conditions and was significantly improved in vivo in a swine model (89% vs. 54%, P = 0.01), and tissue injury was minimal using a clinical treatment protocol. The general principle and associated techniques described in this work can be applied to design improvement of all EM lithotripters.

Protective Effects of Puerarin Against Aß40-induced Vascular Dysfunction in Zebrafish and Human Endothelial Cells

European Journal of Pharmacology. Jun, 2014  |  Pubmed ID: 24690262

Aß40-induced vascular dysfunction has been implicated in the pathogenesis of Alzheimer׳s disease (AD). In the present study, we investigated the possible protective effects of puerarin against Aß40-induced vascular damage and impairment to angiogenesis in transgenic TG (fli1:EGFP) zebrafish and human endothelial cells. Aß40 peptides at 5μM caused an obvious reduction of vessel branches in the subintestinal vein basket, induced NADPH oxidase-derived reactive oxygen species and impaired vascular endothelial growth factor (VEGF)-dependent angiogenesis. Pretreatment with puerarin attenuated Aβ40-induced vessel reduction and impairment to angiogenesis in a dose-dependent manner. In addition, Aß40 decreased VEGF-dependent phosphorylation of Akt and eNOS, whereas puerarin treatment attenuated these detrimental effects. Furthermore, the restoration of Aß40-induced-angiogenesis impairment by puerarin was abolished by either the PI3 kinase inhibitor LY294002 (10μM) or eNOS inhibitor L-NAME. The present study suggests that puerarin exerts its protective action probably through reduction of NADPH oxidase-derived reactive oxygen species overproduction and activation of the PI3K/Akt/eNOS pathways.

Exogenous Fractalkine Enhances Proliferation of Endothelial Cells, Promotes Migration of Endothelial Progenitor Cells and Improves Neurological Deficits in a Rat Model of Ischemic Stroke

Neuroscience Letters. May, 2014  |  Pubmed ID: 24704182

Fractalkine/CX3CL1, also called neurotactin, has been described as an angiogenic agent, and its expression is up-regulated in the penumbra after ischemia. This study was conducted to investigate the neovascular potential of fractalkine on rat models of transient middle cerebral artery occlusion (MCAO). Rats receiving intracerebroventricular injections of fractalkine were found to have improved neurological deficits, reduced cerebral infarct size and increased neuron survival for both doses (100ng and 1μg). Fractalkine exerted angiogenic effects that showed dose-dependent higher vascular densities in the peri-infarct area. Furthermore, exogenous fractalkine increased the proliferation of endothelial cells in a dose-dependent manner and enhanced the migration of endothelial progenitor cells at the higher dose (1μg) in ischemic penumbra. In conclusion, intracerebroventricular administration of fractalkine reduces ischemic damage by promoting neuroprotection and by inducing endothelial cell proliferation and endothelial progenitor cell migration, thereby enhancing neovascularization in the peri-infarct region.

Enriched Endogenous Omega-3 Fatty Acids in Mice Protect Against Global Ischemia Injury

Journal of Lipid Research. Jul, 2014  |  Pubmed ID: 24875538

Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (ω-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous ω-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model.

Identification of Marine Neuroactive Molecules in Behaviour-based Screens in the Larval Zebrafish

Marine Drugs. May, 2014  |  Pubmed ID: 24886868

High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1-36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37-42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.

Tremor and Clinical Fluctuation Are Related to Sleep Disorders in Chinese Patients with Parkinson's Disease

Translational Neurodegeneration. 2014  |  Pubmed ID: 25349692

To study the relationship between sleep disturbances and symptoms in patients with Parkinson's disease (PD).

Shock Wave Lithotripsy: the New Phoenix?

World Journal of Urology. Feb, 2015  |  Pubmed ID: 25081010

Following its introduction in 1980, shock wave lithotripsy (SWL) rapidly emerged as the first-line treatment for the majority of patients with urolithiasis. Millions of SWL therapies have since been performed worldwide, and nowadays, SWL still remains to be the least invasive therapy modality for urinary stones. During the last three decades, SWL technology has advanced in terms of shock wave generation, focusing, patient coupling and stone localization. The implementation of multifunctional lithotripters has made SWL available to urology departments worldwide. Indications for SWL have evolved as well. Although endoscopic treatment techniques have improved significantly and seem to take the lead in stone therapy in the western countries due to high stone-free rates, SWL continues to be considered as the first-line therapy for the treatment of most intra-renal stones and many ureteral stones.

Structural Remodeling of White Matter in the Contralesional Hemisphere is Correlated with Early Motor Recovery in Patients with Subcortical Infarction

Restorative Neurology and Neuroscience. 2015  |  Pubmed ID: 25698108

This study aimed to identify brain areas with white matter changes that contribute to motor recovery of affected limbs during acute to sub-acute phases of subcortical infarction.

Paeonolum Protects Against MPP(+)-induced Neurotoxicity in Zebrafish and PC12 Cells

BMC Complementary and Alternative Medicine. Apr, 2015  |  Pubmed ID: 25925762

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 2% of the population aged over 65 years old. Mitochondrial defects and oxidative stress actively participate in degeneration of dopaminergic (DA) neurons in PD. Paeonolum, a main component isolated from Moutan cortex, has potent antioxidant ability. Here, we have examined the effects of paeonolum against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells.

Role of α-synuclein in Cognitive Dysfunction: Studies in Drosophila Melanogaster

Molecular Medicine Reports. Aug, 2015  |  Pubmed ID: 25954925

α-Synuclein (α-Syn) is hypothesized to have a critical role in sporadic and genetic cases of Parkinson's disease (PD) in which Lewy bodies, as the hallmark of PD, are formed from abnormal aggregates of α-Syn. To determine the role of α-Syn in the motor and cognitive dysfunction observed in PD, a Drosophila melanogaster model was established to investigate the electrophysiological and ethological changes caused by overexpression of α-Syn. The present data indicated that α-Syn overexpression reduced the synaptic transmission of cholinergic neurons by modulating the calcium channel currents in the projection neurons in the antennal lobe region of the Drosophila brain, as well as the learning and memory ability of the flies. However, the locomotor ability of the Drosophila remained unaffected. The present findings suggested that α-Syn may be associated with senile dementia in patients with PD.

Deletion of Aquaporin-4 is Neuroprotective During the Acute Stage of Micro Traumatic Brain Injury in Mice

Neuroscience Letters. Jun, 2015  |  Pubmed ID: 25957560

Micro traumatic brain injury (TBI) is the most common type of brain injury, but the mechanisms underlying it are poorly understood. Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet, which plays an important role in brain edema. However, little is known about the role of AQP4 in micro TBI. Here, we examined the role of AQP4 in the pathogenesis of micro TBI in a closed-skull brain injury model, using two-photon microscopy. Our results indicate that AQP4 deletion reduced cell death, water content, astrocyte swelling and lesion volume during the acute stage of micro TBI. Our data revealed that astrocyte swelling is a decisive pathophysiological factor in the acute phase of this form of micro brain injury. Thus, treatments that inhibit AQP4 could be used as a neuroprotective strategy for micro TBI.

Ebselen Reduces Autophagic Activation and Cell Death in the Ipsilateral Thalamus Following Focal Cerebral Infarction

Neuroscience Letters. Jul, 2015  |  Pubmed ID: 26091880

Previous studies have demonstrated that both oxidative stress and autophagy play important roles in secondary neuronal degeneration in the ipsilateral thalamus after distal middle cerebral artery occlusion (MCAO). This study aimed to investigate whether oxidative stress is associated with autophagy activation within the ipsilateral thalamus after distal MCAO. Sixty stroke-prone renovascular hypertensive rats were subjected to distal MCAO or sham operation, and were killed at 14 days after MCAO. Mn-SOD, LC3-II, Beclin-1 and p62 expression were evaluated by immunostaining and immunoblotting. Secondary damage in the thalamus was assessed with Nissl staining and immunostaining. The association of oxidative stress with autophagy activation was investigated by the antioxidant, ebselen. We found that treatment with ebselen at 24h after MCAO significantly reduced the expression of Mn-SOD in the ipsilateral thalamus at 14 days following focal cerebral infarction. In parallel, it prevented the elevation of LC3-II and Beclin-1, and the reduction of p62. Furthermore, ebselen attenuated the neuronal loss and gliosis in the ipsilateral thalamus. These results suggested that ebselen reduced oxidative stress, autophagy activation and secondary damage in the ipsilateral thalamus following MCAO. There are associations between oxidative stress, autophagy activation and secondary damage in the thalamus after MCAO.

Allopurinol Protects Against Ischemic Insults in a Mouse Model of Cortical Microinfarction

Brain Research. Oct, 2015  |  Pubmed ID: 26187758

Microinfarcts are common in patients with cognitive decline and dementia. Allopurinol (ALLO), a xanthine oxidase (XO) enzyme inhibitor, has been found to reduce proinflammatory molecules and oxidative stress in the vasculature. We here examined the effect of pre-treatment with allopurinol on the cortical microinfarction. C57BL/6J mice were subjected to a permanent single penetrating arteriole occlusion induced by two-photon laser irradiation. Infarction volume, the activation of glial cells and nitrosative stress in the ischemic brain was assessed using immunohistochemistry. Pre-treatment with ALLO achieved 42% reduction of infarct volume and significantly reduced microglia infiltration, astrocyte proliferation and nitrosative stress in the ischemic brain. These data indicate that ALLO protects against microinfarcts possibly through inhibition of nitrosative stress and attenuation of microglia infiltration as well as astrocytes reactivation.

GABA-ergic Interneurons Involved in Transcallosal Inhibition of the Visual Cortices in Vivo in Mice

Physiology & Behavior. Nov, 2015  |  Pubmed ID: 26318391

In the current study we investigated the role of the corpus callosum, particularly the gamma-aminobutyric acid-ergic (GABAergic) projection neurons involved in interhemispheric inhibition (IHI). In order to explore IHI in primary visual cortices, we adopted a protocol whereby we performed a direct current lesion of the unilateral primary visual cortex with or without posterior callosotomy, and used two-photon Ca(2+)in vivo imaging on the opposite unaffected region to detect neural activities in mice. Following this procedure, the numbers of vesicular GABAergic transporters (VGATs) and GABAergic interneurons in the unaffected primary cortex were determined using immunofluorescence staining. Results indicated that following unilateral visual cortical lesioning without callosotomy, the neuronal Ca(2+) activities in the opposite side were significantly increased. However, the neuronal activities of the unaffected visual cortex in animals with unilateral cortical lesion with callosotomy were not significantly different. Additionally, there was no significant difference in the numbers of GABAergic interneurons in the unaffected region between each group, while the number of VGATs in the unaffected region was significantly decreased following unilateral visual cortical lesion without callosotomy, which was unchanged once with callosotomy. Finally, callosotomy alone without cortical lesioning produced no change in neuronal activities, the number of GABAergic interneurons or VGATs. Our results demonstrate that IHI between the homologous primary visual cortices occurs via the corpus callosum, and further indicate the important involvement of long-range GABAergic interneurons in transcallosal inhibition.

Cognitive Impairments in LRRK2-Related Parkinson's Disease: A Study in Chinese Individuals

Behavioural Neurology. 2015  |  Pubmed ID: 26346174

LRRK2 S1647T has been identified as a polymorphic risk variant for Parkinson's disease (PD) in Chinese individuals. As LRRK2 is the most common genetic cause for PD, it has drawn great interest regarding whether cognitive impairments in PD are related with LRRK2.

Long-term Efficacy of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A 5-year Follow-up Study in China

Chinese Medical Journal. Sep, 2015  |  Pubmed ID: 26365958

Subthalamic nucleus deep brain stimulation (STN DBS) is effective against advanced Parkinson's disease (PD), allowing dramatic improvement of Parkinsonism, in addition to a significant reduction in medication. Here we aimed to investigate the long-term effect of STN DBS in Chinese PD patients, which has not been thoroughly studied in China.

Hereditary Endotheliopathy with Retinopathy and Encephalopathy: Pathological and Genetic Studies of a Family

International Journal of Clinical and Experimental Pathology. 2015  |  Pubmed ID: 26464653

The objective of this study was to examine the clinical, pathological and genetic features of a family suffering from hereditary endotheliopathy with retinopathy and encephalopathy.

Cell Membrane Deformation and Bioeffects Produced by Tandem Bubble-induced Jetting Flow

Proceedings of the National Academy of Sciences of the United States of America. Dec, 2015  |  Pubmed ID: 26663913

Cavitation with bubble-bubble interaction is a fundamental feature in therapeutic ultrasound. However, the causal relationships between bubble dynamics, associated flow motion, cell deformation, and resultant bioeffects are not well elucidated. Here, we report an experimental system for tandem bubble (TB; maximum diameter = 50 ± 2 μm) generation, jet formation, and subsequent interaction with single HeLa cells patterned on fibronectin-coated islands (32 × 32 μm) in a microfluidic chip. We have demonstrated that pinpoint membrane poration can be produced at the leading edge of the HeLa cell in standoff distance Sd ≤ 30 μm, driven by the transient shear stress associated with TB-induced jetting flow. The cell membrane deformation associated with a maximum strain rate on the order of 10(4) s(-1) was heterogeneous. The maximum area strain ([Formula: see text]) decreased exponentially with Sd (also influenced by adhesion pattern), a feature that allows us to create distinctly different treatment outcome (i.e., necrosis, repairable poration, or nonporation) in individual cells. More importantly, our results suggest that membrane poration and cell survival are better correlated with area strain integral ([Formula: see text]) instead of [Formula: see text], which is characteristic of the response of materials under high strain-rate loadings. For 50% cell survival the corresponding area strain integral was found to vary in the range of 56 ∼ 123 μs with [Formula: see text] in the range of 57 ∼ 87%. Finally, significant variations in individual cell's response were observed at the same Sd, indicating the potential for using this method to probe mechanotransduction at the single cell level.

Synphilin-1 Attenuates Mutant LRRK2-induced Neurodegeneration in Parkinson's Disease Models

Human Molecular Genetics. Feb, 2016  |  Pubmed ID: 26744328

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with pleomorphic pathology including deposits of aggregated protein and neuronal degeneration. The pathogenesis of LRRK2-linked Parkinson's disease (PD) is not fully understood. Here, using co-immunoprecipitation, we found that LRRK2 interacted with synphilin-1 (SP1), a cytoplasmic protein that interacts with α-synuclein and has implications in PD pathogenesis. LRRK2 interacted with the N-terminus of SP1 whereas SP1 predominantly interacted with the C-terminus of LRRK2, including kinase domain. Co-expression of SP1 with LRRK2 increased LRRK2-induced cytoplasmic aggregation in cultured cells. Moreover, SP1 also attenuated mutant LRRK2-induced toxicity and reduced LRRK2 kinase activity in cultured cells. Knockdown of SP1 by siRNA enhanced LRRK2 neuronal toxicity. In vivo Drosophila studies, co-expression of SP1 and mutant G2019S-LRRK2 in double transgenic Drosophila increased survival and improved locomotor activity. Expression of SP1 protects against G2019S-LRRK2-induced dopamine neuron loss and reduced LRRK2 phosphorylation in double transgenic fly brains. Our findings demonstrate that SP1 attenuates mutant LRRK2-induced PD-like phenotypes and plays a neural protective role.

Intravenous PEP-1-GDNF is Protective After Focal Cerebral Ischemia in Rats

Neuroscience Letters. Mar, 2016  |  Pubmed ID: 26876444

Glial cell line-derived neurotrophic factor (GDNF) is a potential therapeutic protein on a variety of central nervous system diseases including ischemic stroke. However, GDNF is a large molecule that cannot cross the blood-brain barrier (BBB), which is still intact in the early hours after stroke when neural rescue is possible. PEP-1 protein transduction domain can deliver protein cargo across the cell membrane and the BBB. In the present study, we generated a novel fusion protein PEP-1-GDNF and examined whether PEP-1-GDNF is protective in focal cerebral ischemia. PEP-1-GDNF (200 μg/kg) or PBS was intravenously applied over 5 min immediately after reperfusion of 90 min transient middle cerebral artery occlusion (MCAO). After 28 days, rats were deeply anesthetized and decapitated. Behavioral tests were performed during this period. The results showed that PEP-1-GDNF significantly reduced the infarct volume and improved behavioral function. Further, PEP-1-GDNF promoted the cell proliferation and differentiation in the dentate gyrus of the hippocampus and attenuated ischemia-induced learning and memory damage.

Melatonin Attenuates HLRRK2-induced Sleep Disturbances and Synaptic Dysfunction in a Drosophila Model of Parkinson's Disease

Molecular Medicine Reports. May, 2016  |  Pubmed ID: 26985725

Sleep problems are the most common non-motor symptoms in Parkinson's disease (PD), and are more difficult to treat than the motor symptoms. In the current study, the role of human leucine-rich repeat kinase 2 (hLRRK2), the most common genetic cause of PD, was investigated with regards to sleep problems, and the therapeutic potential of melatonin in hLRRK2‑associated sleep problems was explored in Drosophila. hLRRK2 was selectively expressed in the mushroom bodies (MBs) in Drosophila and sleep patterns were measured using the Drosophila Activity Monitoring System. MB expression of hLRRK2 resulted in sleep problems, presynaptic dysfunction as evidenced by reduced miniature excitatory postsynaptic current (mEPSC) and excitatory postsynaptic potential (EPSP) frequency, and excessive synaptic plasticity such as increased axon bouton density. Treatment with melatonin at 4 mM significantly attenuated the sleep problems and rescued the reduction in mEPSC and EPSP frequency in the hLRRK2 transgenic flies. The present study demonstrates that MB expression of hLRRK2 in flies recapitulates the clinical features of the sleep disturbances in PD, and that melatonin attenuates hLRRK2-induced sleep disorders and synaptic dysfunction, suggesting the therapeutic potential of melatonin in PD patients carrying LRRK2 mutations.

Xyloketal-derived Small Molecules Show Protective Effect by Decreasing Mutant Huntingtin Protein Aggregates in Caenorhabditis Elegans Model of Huntington's Disease

Drug Design, Development and Therapy. 2016  |  Pubmed ID: 27110099

Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

Deferoxamine Inhibits Microglial Activation, Attenuates Blood-brain Barrier Disruption, Rescues Dendritic Damage, and Improves Spatial Memory in a Mouse Model of Microhemorrhages

Journal of Neurochemistry. Aug, 2016  |  Pubmed ID: 27167158

Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100 mg/kg) was administered 6 h after microhemorrhage induction, followed by every 12 h for three consecutive days. The water maze task was conducted 7 days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages.

Clinical Efficacy of Combined Sodium Dimercaptopropanesulfonate and Zinc Treatment in Neurological Wilson's Disease with D-penicillamine Treatment Failure

Therapeutic Advances in Neurological Disorders. Jul, 2016  |  Pubmed ID: 27366238

There are limited pharmacological treatments for patients with neurological Wilson's disease (WD) and a history of copper-chelating treatment failure.

Effects of Stone Size on the Comminution Process and Efficiency in Shock Wave Lithotripsy

Ultrasound in Medicine & Biology. Nov, 2016  |  Pubmed ID: 27515177

The effects of stone size on the process and comminution efficiency of shock wave lithotripsy (SWL) were investigated in experiments, numerical simulations and scale analysis. Cylindrical BegoStone phantoms with approximately equal height and diameter of either 4, 7 or 10 mm, in a total aggregated mass of about 1.5 g, were treated in an electromagnetic shock wave lithotripter field. The resultant stone comminution was found to correlate closely with the average peak pressure, P+(avg), incident on the stones. The P+(avg) threshold necessary to initiate stone fragmentation in water increased from 7.9 to 8.8 to 12.7 MPa, respectively, as stone size decreased from 10 to 7 to 4 mm. Similar changes in the P+(avg) threshold were observed for the 7- and 10-mm stones treated in 1,3-butanediol, in which cavitation is suppressed, suggesting that the observed size dependency is due to changes in stress distribution within stones of different size. Moreover, the slope of the correlation curve between stone comminution and ln(P¯+(avg)) in water increased with decreasing stone size, whereas the opposite trend was observed in 1,3-butanediol. The progression of stone comminution in SWL exhibited size-dependence: the 7- and 10-mm stones fragmented into progressively smaller pieces, whereas a significant portion (>30%) of the 4-mm stones reached a stalemate within the size range of 2.8 ∼ 4 mm, even after 1000 shocks. Analytical scaling considerations suggest size-dependent fragmentation behavior, a hypothesis further supported by numerical model calculations that reveal changing patterns of constructive and destructive wave interference and, thus, variations in the maximum tensile stress or stress integral produced in cylindrical and spherical stone of different sizes.

Transgenic Over-expression of Slit2 Enhances Disruption of Blood-brain Barrier and Increases Cell Death After Traumatic Brain Injury in Mice

Neuroscience Letters. Sep, 2016  |  Pubmed ID: 27521753

Traumatic brain injury (TBI) is the leading cause of mortality and disability among male adolescents and young adults; and mild traumatic brain injury is the most common type of traumatic brain injury. The disruption of blood-brain barrier (BBB) plays an important role in brain trauma. Previously, we have found that slit2, a member of slit protein family, increases permeability of BBB. In the present study, we examined the role of slit2 in the pathogenesis of mild TBI in a mouse model of micro TBI. Rhodamine BandPI (PropidiumIodide) staining were used to detect the permeability of BBB and cell death, respectively. The leakage of Rhodamine B and cell death were significantly increased in Slit2-Tg mice than in C57 control mice after micro TBI. The present results suggest that over expression of slit2 plays a detrimental role in the pathophysiology of mild TBI.

Association of DYRK1A Polymorphisms with Sporadic Parkinson's Disease in Chinese Han Population

Neuroscience Letters. Oct, 2016  |  Pubmed ID: 27546826

α-Synuclein plays important roles in the development of Parkinson's disease (PD) pathologies. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has a wide range of phosphorylation targets including α-synuclein. Posphorylated α-synuclein is more neurotoxic to dopamine (DA) neurons, but little is known about the genetic variation of DYRK1A in patients with PD. The present investigation aimed to explore the possible association of DYRK1A gene with PD in Chinese Han population. A total of 268 PD patients and 268 healthy-matched individuals in Chinese Han population were enrolled. Genotyping of rs8126696, rs2835740, and rs1137600 single nucleotide polymorphisms (SNPs) were performed on the Sequenom MassARRAY platform. Results revealed TT genotype in SNP rs8126696 denoted a significant difference between PD patients and controls (OR=1.710, 95% CI=1.116-2.619, P=0.014), and the frequency of rs8126696 TT genotype was significantly higher in male PD patients than male controls (OR=2.012, 95%CI: 1.125-3.599, p=0.018). The genotypes in rs2835740 and rs1137600 showed no significant difference between PD patients and controls. These results suggest that TT genotype derived from SNP rs8126696 of DYRK1A gene is a possible risk factor for sporadic PD, especially for males in this Chinese Han population.

Unfolded Protein Response is Activated in the Ipsilateral Thalamus Following Focal Cerebral Infarction in Hypertensive Rats

Clinical and Experimental Pharmacology & Physiology. Aug, 2016  |  Pubmed ID: 27558464

Focal cerebral cortical infarction causes secondary neurodegeneration in the remote regions, such as the ventroposterior nucleus of the thalamus. Retrograde degeneration of thalamocortical fibers is considered as the principle mechanism, but the exact molecular events remain to be elucidated. This study aimed to investigate whether unfolded protein response (UPR) is activated in thalamic neurons following distal middle cerebral artery occlusion (MCAO) in stroke-prone renovascular hypertensive rats. Immunostaining and immunoblotting were performed to evaluate the expression of Grp78 and its downstream effectors in the thalamus at 3, 7, and 14 days after MCAO. Secondary thalamic degeneration was assessed with Nissl staining and NeuN immunostaining. Neuronal death was not apparent at 3 days post-ischemia but was evident in the thalamus at 7 and 14 days after MCAO. Grp78 level was reduced in the ipsilateral thalamus at 3 and 7 days after MCAO. In parallel, phosphorylated eIF2α and ATF4 levels were elevated, indicating the activation of UPR. In contrast, ATF6α and CHOP levels were not changed. These results suggest that UPR is activated before neuronal death in the ipsilateral thalamus after MCAO and may represent a key early event in the secondary thalamic degeneration. This article is protected by copyright. All rights reserved.

Comparison of the Nanopulse Lithotripter to the Holmium Laser: Stone Fragmentation Efficiency and Impact on Flexible Ureteroscope Deflection and Flow

Journal of Endourology. Nov, 2016  |  Pubmed ID: 27736195

The Nanopulse Lithotripter (NPL; Lithotech Medical, Israel) is a novel intracorporeal device that uses a nanosecond duration electrical discharge through a reusable flexible coaxial probe to endoscopically fragment urinary stones. This device was compared with a holmium laser lithotripsy (HoL) with regard to stone fragmentation efficiency (SFE) and its impact on flexible ureteroscope (URS) deflection and flow of irrigation.

Collateral Blood Flow in Different Cerebrovascular Hierarchy Provides Endogenous Protection in Cerebral Ischemia

Brain Pathology (Zurich, Switzerland). Nov, 2016  |  Pubmed ID: 27859886

Collateral blood flow as vascular adaptions to focal cerebral ischemia is well recognized. However, few studies directly investigate the dynamics of collateral vessel recruitment in vivo and little is known about the effect of collateral blood flow in different cerebrovascular hierarchy on the neuropathology after focal ischemic stroke. Here, we report that collateral blood flow is critically involved in blood vessel compensations following regional ischemia. We occluded a pial arteriole using femtosecond laser ablating under the intact thinned skull and documented the changes of collateral flow around the surface communication network and between the surface communication network and subsurface microcirculation network using in vivo two photon microscopy imaging. Occlusion of the pial arteriole apparently increased the diameter and collateral blood flow of its leptomeningeal anastomoses, which significantly reduced the cortical infarction size. This result suggests that the collateral flow via surface communicating network connected with leptomeningeal anastomoses could greatly impact on the extent of infarction. We then further occluded the target pial arteriole and all of its leptomeningeal anastomoses. Notably, this type of occlusion led to reversals of blood flow in the penetrating arterioles mainly proximal to the occluded pial arteriole in a direction from the subsurface microcirculation network to surface arterioles. Interesting, the cell death in the area of ischemic penumbra was accelerated when we performed occlusion to cease the reversed blood flow in those penetrating arterioles, suggesting that the collateral blood flow from subsurface microcirculation network exerts protective roles in delaying cell death in the ischemic penumbra. In conclusion, we provide the first experimental evidence that collateral blood vessels at different cerebrovascular hierarchy are endogenously compensatory mechanisms in brain ischemia. This article is protected by copyright. All rights reserved.

Potential Protective Effects of Autophagy Activated in MPP+ Treated Astrocytes

Experimental and Therapeutic Medicine. Nov, 2016  |  Pubmed ID: 27882077

Astrocytes, which have various important functions, have previously been associated with Parkinsons disease (PD), particularly in 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of PD. MPP+ is the toxic metabolite of MPTP and is generated by the enzymatic activity of monoamine oxidase B, which is predominantly located in astrocytes. MPP+ acts as a mitochondrial complex I inhibitor. Autophagy is an evolutionarily conserved self-digestion pathway in eukaryotic cells, which occurs in response to various types of stress, including starvation and oxidative stress. Lithium treatment has previously been shown to induce autophagy in astrocytes by inhibiting the enzyme inositol monophosphatase, which may aid in the treatment of neurodegenerative diseases, including Huntington's disease, in which the toxic protein is an autophagy substrate. Therefore, using western blotting and MTT assay, the present study aimed to investigate the protective effects of lithium-induced autophagy against astrocyte injury caused by MPP+ treatment, as well as the potential underlying mechanisms. The results of the present study suggested that lithium was able to induce autophagy in astrocytes treated with MPP+, and this likely occurred via activation of the phosphoinositide 3-kinase/AKT pathway.

Genome-wide Association Study of Parkinson's Disease in East Asians

Human Molecular Genetics. Dec, 2016  |  Pubmed ID: 28011712

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analyzing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters, adjusted for the first three principal components. 88 SNPs with association P<10(-4) were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P<0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16 Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR>1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci.

Omega-3 Polyunsaturated Fatty Acids Promote Amyloid-β Clearance from the Brain Through Mediating the Function of the Glymphatic System

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Jan, 2017  |  Pubmed ID: 27789520

Impairment of amyloid-β (Aβ) clearance leads to Aβ accumulation in the brain during the development of Alzheimer's disease (AD). Strategies that can restore or improve the clearance function hold great promise in delaying or preventing the onset of AD. Here, we show that n-3 polyunsaturated fatty acids (PUFAs), by use of fat-1 transgenic mice and oral administration of fish oil, significantly promote interstitial Aβ clearance from the brain and resist Aβ injury. Such beneficial effects were abolished in Aqp4-knockout mice, suggesting that the AQP4-dependent glymphatic system is actively involved in the promoting the effects of n-3 PUFAs on the clearance of extracellular Aβ. Imaging on clarified brain tissues clearly displayed that n-3 PUFAs markedly inhibit the activation of astrocytes and protect the AQP4 polarization in the affected brain region after Aβ injection. The results of the present study prove a novel mechanism by which n-3 PUFAs exert protective roles in reducing Aβ accumulation via mediating the glymphatic system function.-Ren, H., Luo, C., Feng, Y., Yao, X., Shi, Z., Liang, F., Kang, J. X., Wan, J.-B., Pei, Z., Su, H. Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system.

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