The Traditional Herbal Medicine, Dangkwisoo-San, Prevents Cerebral Ischemic Injury through Nitric Oxide-Dependent Mechanisms

Dangkwisoo-San (DS) is an herbal extract that is widely used in traditional Korean medicine to treat traumatic ecchymosis and pain by promoting blood circulation and relieving blood stasis. However, the effect of DS in cerebrovascular disease has not been examined experimentally. The protective effects of DS on focal ischemic brain were investigated in a mouse model. DS stimulated nitric oxide (NO) production in human brain microvascular endothelial cells (HBMECs). DS (10–300 μg/mL) produced a concentration-dependent relaxation in mouse aorta, which was significantly attenuated by the nitric oxide synthase (NOS) inhibitor L-NAME, suggesting that DS causes vasodilation via a NO-dependent mechanism. DS increased resting cerebral blood flow (CBF), although it caused mild hypotension. To investigate the effect of DS on the acute cerebral injury, C57/BL6J mice received 90 min of middle cerebral artery occlusion followed by 22.5 h of reperfusion. DS administered 3 days before arterial occlusion significantly reduced cerebral infarct size by 53.7% compared with vehicle treatment. However, DS did not reduce brain infarction in mice treated with the relatively specific endothelial NOS (eNOS) inhibitor, N5-(1-iminoethyl)-L-ornithine, suggesting that the neuroprotective effect of DS is primarily endothelium-dependent. This correlated with increased phosphorylation of eNOS in the brains of DS-treated mice. DS acutely improves CBF in eNOS-dependent vasodilation and reduces infarct size in focal cerebral ischemia. These data provide causal evidence that DS is cerebroprotective via the eNOS-dependent production of NO, which ameliorates blood circulation

PMC-12, a Prescription of Traditional Korean Medicine, Improves Amyloid β

PMC-12 is a prescription used in traditional Korean medicine that consists of a mixture of four herbal medicines, Polygonum multiflorum, Rehmannia glutinosa, Polygala tenuifolia, and Acorus gramineus, which have been reported to have various pharmacological effects on age-related neurological diseases. In the present study, we investigated whether PMC-12 improves cognitive deficits associated with decreased neuroinflammation in an amyloid-β-(Aβ-) induced mouse model and exerts the antineuroinflammatory effects in lipopolysaccharide-(LPS-) stimulated murine BV2 microglia. Intracerebroventricular injection of Aβ25-35 in mice resulted in impairment in learning and spatial memory, whereas this was reversed by oral administration of PMC-12 (100 and 500 mg/kg/day) in dose-dependent manners. Moreover, PMC-12 reduced the increase of Aβ expression and activation of microglia and astrocytes in the Aβ25-35-injected brain. Furthermore, quantitative PCR data showed that inflammatory mediators were significantly decreased by administration of PMC-12 in Aβ-injected brains. Consistent with the in vivo data, PMC-12 significantly reduced the inflammatory mediators in LPS-stimulated BV2 cells without cell toxicity. Moreover, PMC-12 exhibited anti-inflammatory properties via downregulation of ERK, JNK, and p38 MAPK pathways. These findings suggest that the protective effects of PMC-12 may be mediated by its antineuroinflammatory activities, resulting in the attenuation of memory impairment; accordingly, PMC-12 may be useful in the prevention and treatment of AD

Albumin-Like Protein is the Major Protein Constituent of Luminal Fluid in the Human Endolymphatic Sac

The endolymphatic sac (ES) is an inner ear organ that is connected to the cochleo-vestibular system through the endolymphatic duct. The luminal fluid of the ES contains a much higher concentration of proteins than any other compartment of the inner ear. This high protein concentration likely contributes to inner ear fluid volume regulation by creating an osmotic gradient between the ES lumen and the interstitial fluid. We characterized the protein profile of the ES luminal fluid of patients (n = 11) with enlarged vestibular aqueducts (EVA) by proteomics. In addition, we investigated differences in the protein profiles between patients with recent hearing deterioration and patients without hearing deterioration. The mean total protein concentration of the luminal fluid was 554.7±94.6 mg/dl. A total of 58 out of 517 spots detected by 2-DE were analyzed by MALDI-TOF MS. The protein profile of the luminal fluid was different from the profile of plasma. Proteins identified from 29 of the spots were also present in the MARC-filtered human plasma; however, the proteins identified from the other 25 spots were not detected in the MARC-filtered human plasma. The most abundant protein in the luminal fluid was albumin-like proteins, but most of them were not detected in MARC-filtered human plasma. The concentration of albumin-like proteins was higher in samples from patients without recent hearing deterioration than in patients with recent hearing deterioration. Consequently, the protein of ES luminal fluid is likely to be originated from both the plasma and the inner ear and considering that inner ear fluid volumes increase abnormally in patients with EVA following recent hearing deterioration, it is tempting to speculate that albumin-like proteins may be involved in the regulation of inner ear fluid volume through creation of an osmotic gradient during pathological conditions such as endolymphatic hydrops

Cilostazol Prevents Tumor Necrosis Factor-␣-Induced Cell Death by Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Activation of Akt/Cyclic AMP Response Element-Binding Protein Phosphorylation

ABSTRACT This study examines the signaling mechanism by which cilostazol prevents neuronal cell death. Cilostazol (ϳ0.1-100 M) prevented tumor necrosis factor-␣ (TNF-␣)-induced decrease in viability of SK-N-SH and HCN-1A cells, which was antagonized by 1 M iberiotoxin, a maxi-K channel blocker. TNF-␣ did not suppress the viability of the U87-MG cell, a phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null glioblastoma cell, but it did decrease viability of U87-MG cells transfected with expression vectors for the sense PTEN, and this decrease was also prevented by cilostazol. Cilostazol as well as 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS-1619) and (3S)-(ϩ)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one (BMS 204352), maxi-K channel openers, prevented increased DNA fragmentation evoked by TNF-␣, which were antagonizable by iberiotoxin. TNF-␣-induced increased PTEN phosphorylation and decreased Akt/ cyclic AMP response element-binding protein (CREB) phosphorylation were significantly prevented by cilostazol, those of which were antagonized by both iberiotoxin and paxilline, maxi-K channel blockers. The same results were evident in U87-MG cells transfected with expression vectors for sense PTEN. Cilostazol increases the K ϩ current in SK-N-SH cells by activating maxi-K channels without affecting the ATP-sensitive K ϩ channel. Thus, our results for the first time provide evidence that cilostazol prevents TNF-␣-induced cell death by suppression of PTEN phosphorylation and activation of Akt/CREB phosphorylation via mediation of the maxi-K channel opening. Recent research has shown that the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is implicated in the regulation of several cellular functions, including cell viability from apoptosi

Cordycepin inhibits lipopolysaccharide-induced inflammation by the suppression of NF-êB through Akt and p38 inhibition in RAW 264.7 macrophage cells. European Journal of Pharmacology 545

ABSTRACT This work describes the pharmacological inhibition by cilostazol and its metabolites, OPC-13015 and OPC-13213, of the apoptosis in the human umbilical vein endothelial cells (HUVECs) damaged by lipopolysaccharide (LPS) in comparison with its analog, cilostamide. Cilostazol and OPC-31213 caused a significant suppression of cell death induced by LPS (1 g/ml) in a concentration-dependent manner but a modest suppression by cilostamide and OPC-13015. These compounds potently inhibited the 5,5-dimethyl-1-pyrroline-1-oxide (DMPO)/ ⅐ OH adduct formation and significantly reduced the increased intracellular reactive oxygen species (ROS) and tumor necrosis factor-␣ (TNF-␣) production induced by LPS (1 g/ml). An apoptotic death of HUVECs by 1 g/ml LPS (DNA ladders on electrophoresis) was strongly suppressed by all these compounds. Incubation with LPS caused a marked decrease in Bcl-2 protein, which was significantly reversed by cilostazol and its analogs. The greatly increased Bax protein expression and cytochrome c release by LPS were, in contrast, suppressed by cilostazol and, to a lesser degree, by others. In conclusion, cilostazol and its analogs exert a strong protection against apoptotic cell death by scavenging hydroxyl radicals and intracellular ROS with reduction in TNF-␣ formation and by increasing Bcl-2 protein expression and decreasing Bax protein and cytochrome c release

Roles of Time Hazard in Perceptual Decision Making under High Time Pressure

The drift diffusion model (DDM) has been successful in capturing the joint dynamics of accuracy and latency data in various perceptual decision making tasks. We evaluated how well the DDM describes dynamics of perceptual decision when subjects were under a varying degree of time pressure. We collected choice and latency responses from human subjects, who discriminated the size of a thin ring stimulus with a varying degree of uncertainty. The degree of time pressure was manipulated both by giving subjects an explicit instruction of different time limits across sessions (0.7 ∼ 1.2 s) and by providing feedback to responses that were made later than those time limits. When fitted to the data of choice and latency, the three major variants of the DDM (with static bounds & gain, with time-varying bounds, and with time-varying gain) showed a systematic pattern of latency-dependent prediction errors. Here we propose a new variant of the DDM, which adopts a ‘boundary for time hazard’ on the time axis in addition to the choice boundary on the choice-evidence axis in decision space. Our model did not exhibit the biased pattern of errors and was superior than the other models in goodness of fit to the data

Regulation of Airway Inflammation by G-protein Regulatory Motif Peptides of AGS3 protein

Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and lung infections have critical consequences on mortality and morbidity in humans. The aims of the present study were to examine the mechanisms by which CXCL12 affects MUC1 transcription and airway inflammation, which depend on activator of G-protein signaling (AGS) 3 and to identify specific molecules that suppress CXCL12-induced airway inflammation by acting on G-protein-coupled receptors. Herein, AGS3 suppresses CXCL12-mediated upregulation of MUC1 and TNF alpha by regulating G(alpha i). We found that the G-protein regulatory (GPR) motif peptide in AGS3 binds to G(alpha i) and downregulates MUC1 expression; in contrast, this motif upregulates TNF alpha expression. Mutated GPR Q34A peptide increased the expression of MUC1 and TGF beta but decreased the expression of TNF alpha and IL-6. Moreover, CXCR4-induced dendritic extensions in 2D and 3D matrix cultures were inhibited by the GPR Q34A peptide compared with a wild-type GPR peptide. The GPR Q34A peptide also inhibited CXCL12-induced morphological changes and inflammatory cell infiltration in the mouse lung, and production of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid and the lungs. Our data indicate that the GPR motif of AGS3 is critical for regulating MUC1/Muc1 expression and cytokine production in the inflammatory microenvironment.Basic Science Research Program through the National Research Foundation of Korea (NRF) grant - Korea government [2015R1A2A2A01004633]; National Research Foundation of Korea, - Korean government (MEST) [2014-R1A1A2055774]Open access.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Negative spin Hall magnetoresistance of normal metal/ferromagnet bilayers

In normal metal/ferromagnet bilayers, the spin Hall magnetoresistance originating from the spin Hall effect of normal metal possesses positive sign regardless of the sign of spin Hall conductivity of normal metal. Here, the authors report negative spin Hall magnetoresistance of Ta/NiFe bilayers due to interfacial spin orbit coupling at interfaces

Direct observation of spin accumulation and spin-orbit torque driven by Rashba-Edelstein effect in an InAs quantum-well layer

© 2021 American Physical Society.For semiconductor spintronics, efficient spin generation in semiconductor and spin transfer to ferromagnetic metal (FM) are essentially required. Two-dimensional electron gas (2DEG) of semiconductor quantum wells is a promising system for generating spin via the Rashba-Edelstein effect (REE) because of its strong inversion symmetry breaking. In this study, we investigate spin accumulation through REE and spin Hall effect (SHE) in the 2DEG of an InAs quantum well. We use spatial- and polarization-resolved measurements of spin, which reveals that REE dominates SHE in 2DEG. Furthermore, REE in 2DEG induces a spin-orbit torque on FM in a 2DEG/insulator/FM heterostructure. Using direction- and time-resolved measurements of FM magnetization, we determine a sizeable fieldlike torque, which is attributed to the phonon-mediated spin transport from 2DEG to FM.11Nsciescopu