Electrical Characteristics of CMOS-Compatible SiOx-Based Resistive-Switching Devices.

The electrical characteristics and resistive switching properties of memristive devices have been studied in a wide temperature range. The insulator and electrode materials of these devices (silicon oxide and titanium nitride, respectively) are fully compatible with conventional complementary metal-oxide-semiconductor (CMOS) fabrication processes. Silicon oxide is also obtained through the low-temperature chemical vapor deposition method. It is revealed that the as-fabricated devices do not require electroforming but their resistance state cannot be stored before thermal treatment. After the thermal treatment, the devices exhibit bipolar-type resistive switching with synaptic behavior. The conduction mechanisms in the device stack are associated with the effect of traps in the insulator, which form filaments in the places where the electric field is concentrated. The filaments shortcut the capacitance of the stack to different degrees in the high-resistance state (HRS) and in the low-resistance state (LRS). As a result, the electron transport possesses an activation nature with relatively low values of activation energy in an HRS. On the contrary, Ohm's law and tunneling are observed in an LRS. CMOS-compatible materials and low-temperature fabrication techniques enable the easy integration of the studied resistive-switching devices with traditional analog-digital circuits to implement new-generation hardware neuromorphic systems.

Synaptic Characteristics of Amorphous Boron Nitride-Based Memristors on a Highly Doped Silicon Substrate for Neuromorphic Engineering.

In this study, the resistive switching and synaptic properties of a complementary metal-oxide semiconductor-compatible Ti/a-BN/Si device are investigated for neuromorphic systems. A gradual change in resistance is observed in a positive SET operation in which Ti diffusion is involved in the conducting path. This operation is extremely suitable for synaptic devices in hardware-based neuromorphic systems. The isosurface charge density plots and experimental results confirm that boron vacancies can help generate a conducting path, whereas the conducting path generated by a Ti cation from interdiffusion forms is limited. A negative SET operation causes a considerable decrease in the formation energy of only boron vacancies, thereby increasing the conductivity in the low-resistance state, which may be related to RESET failure and poor endurance. The pulse transient characteristics, potentiation and depression characteristics, and good retention property of eight multilevel cells also indicate that the positive SET operation is more suitable for a synaptic device owing to the gradual modulation of conductance. Moreover, pattern recognition accuracy is examined by considering the conductance values of the measured data in the Ti/a-BN/Si device as the synaptic part of a neural network. The linear and symmetric synaptic weight update in a positive SET operation with an incremental voltage pulse scheme ensures higher pattern recognition accuracy.

Neuronal dynamics in HfOx/AlOy-based homeothermic synaptic memristors with low-power and homogeneous resistive switching.

We studied the pseudo-homeothermic synaptic behaviors by integrating complimentary metal-oxide-semiconductor-compatible materials (hafnium oxide, aluminum oxide, and silicon substrate). A wide range of temperatures, from 25 °C up to 145 °C, in neuronal dynamics was achieved owing to the homeothermic properties and the possibility of spike-induced synaptic behaviors was demonstrated, both presenting critical milestones for the use of emerging memristor-type neuromorphic computing systems in the near future. Biological synaptic behaviors, such as long-term potentiation, long-term depression, and spike-timing-dependent plasticity, are developed systematically, and comprehensive neural network analysis is used for temperature changes and to conform spike-induced neuronal dynamics, providing a new research regime of neurocomputing for potentially harsh environments to overcome the self-heating issue in neuromorphic chips.

Bone Tissue Engineering Strategies in Co-Delivery of Bone Morphogenetic Protein-2 and Biochemical Signaling Factors.

Administration of bone morphogenetic protein-2 (BMP-2), which is commercially approved by the food and drug administration to damaged bone sites has been investigated for the purpose of bone tissue regeneration. BMP-2 can promote osteoblastic differentiation of mesenchymal stem cells as well as regeneration of bone formation in early phase. This review highlights various factors such as vitamin D, dexamethasone, platelet-derived growth factor, placental growth factor, BMP-7, and NEL-like protein-1 that enhance and stimulate angiogenesis, cell differentiation, and bone regeneration. These biochemical signals and growth factors (GFs) accelerate bone repair and remodeling either synergistically or individually. Delivery systems and scaffolds are used for sustained release of these cargo molecules and support at damaged bone sites. Compared with direct administration of BMP-2, current studies have demonstrated that a combination of multiple GFs and/or therapeutic chemical factors with delivery platforms synergistically facilitates bone regeneration. Therefore, in the future, multiple combinations of various GFs, chemicals, and materials could provide patients and surgeons with non-invasive treatment options without secondary surgery and pain. To the end, this review summarizes the biological functions and synergistic effects of dual administration modalities involving BMP-2 as well as recent developments in bone tissue engineering applications.

Scaling Effect on Silicon Nitride Memristor with Highly Doped Si Substrate.

A feasible approach is reported to reduce the switching current and increase the nonlinearity in a complementary metal-oxide-semiconductor (CMOS)-compatible Ti/SiNx /p+ -Si memristor by simply reducing the cell size down to sub-100 nm. Even though the switching voltages gradually increase with decreasing device size, the reset current is reduced because of the reduced current overshoot effect. The scaled devices (sub-100 nm) exhibit gradual reset switching driven by the electric field, whereas that of the large devices (≥1 µm) is driven by Joule heating. For the scaled cell (60 nm), the current levels are tunable by adjusting the reset stop voltage for multilevel cells. It is revealed that the nonlinearity in the low-resistance state is attributed to Fowler-Nordheim tunneling dominating in the high-voltage regime (≥1 V) for the scaled cells. The experimental findings demonstrate that the scaled metal-nitride-silicon memristor device paves the way to realize CMOS-compatible high-density crosspoint array applications.

Analog Synaptic Behavior of a Silicon Nitride Memristor.

In this paper, we present a synapse function using analog resistive-switching behaviors in a SiNx-based memristor with a complementary metal-oxide-semiconductor compatibility and expandability to three-dimensional crossbar array architecture. A progressive conductance change is attainable as a result of the gradual growth and dissolution of the conducting path, and the series resistance of the AlOy layer in the Ni/SiNx/AlOy/TiN memristor device enhances analog switching performance by reducing current overshoot. A continuous and smooth gradual reset switching transition can be observed with a compliance current limit (>100 µA), and is highly suitable for demonstrating synaptic characteristics. Long-term potentiation and long-term depression are obtained by means of identical pulse responses. Moreover, symmetric and linear synaptic behaviors are significantly improved by optimizing pulse response conditions, which is verified by a neural network simulation. Finally, we display the spike-timing-dependent plasticity with the multipulse scheme. This work provides a possible way to mimic biological synapse function for energy-efficient neuromorphic systems by using a conventional passive SiNx layer as an active dielectric.

In Vitro Antioxidant and In Vivo Hypolipidemic Effects of the King Oyster Culinary-Medicinal Mushroom, Pleurotus eryngii var. ferulae DDL01 (Agaricomycetes), in Rats with High-Fat Diet-Induced Fatty Liver and Hyperlipidemia.

We investigated the effect of the culinary-medicinal mushroom Pleurotus eryngii var. ferulae DDL01 on oxidative damage in the liver and brain and a high-fat/high-cholesterol-induced hyperlipidemic model. In in vitro studies, the water extracts of the fruiting bodies showed strong scavenging activities of DPPH (139.46 ± 3.2 µg) and hydroxyl (139.46 ± 3.2 µg) radicals. Moreover, the extracts showed Fe2+ chelating and reducing abilities, as well as a large amount of polyphenols and an inhibitory effect on lipid peroxidation in the liver and brain tissues. The rats were fed a pellet diet (7.5 g/rat/day) containing P. eryngii var. ferulae DDL01 (PD) for 3 weeks. In the high-fat/high-cholesterol-induced hyperlipidemic rat model, administration of PD caused a significant decrease (P < 0.05) in the levels of serum triacylglycerols, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, aspartate aminotransferase, and alanine aminotransferase and a significant increase (P < 0.05) in the level of high-density lipoprotein cholesterol. PD administration significantly decreased high-fat/high-cholesterol-induced hepatic lipid accumulation. Treatment with the extracts (up to 500 µg/mL) did not significantly affect the viability of HepG2 and 3T3-L1 cells. Our findings suggest that this mushroom has potential as an antiatherogenic dietary source in the development of therapeutic agents and functional foods.

A novel anticoagulant protein with antithrombotic properties from the mosquito Culex pipiens pallens.

A newly discovered protein, named 'CPP protein', which possesses antithrombotic and anticoagulant properties, was purified from the salivary gland of the mosquito Culex pipiens pallens. CPP protein was found to have an estimated molecular mass of 21.7kDa, and to be active at 60°C, and pH 7.0. The anticoagulation activity of CPP protein was strongly inhibited by calcium ions. CPP protein inhibited fibrin clot formation and platelet activation, and it degraded blood clots. It also inhibited the enzymatic activities of activated factor X and thrombin. In addition, CPP protein prolonged the activated partial thromboplastin time and prothrombin time. CPP protein demonstrated antithrombotic effect in two mouse models, a thrombin-induced acute thromboembolism model, and an ex vivo coagulation model. CPP protein at a dose of 20mg/kg was devoid of hemorrhagic activity. These results suggest that CPP protein could have potential as a therapeutic agent for thrombosis, due to its antithrombotic properties and lack of hemorrhagic activity.

Anti-thrombotic effect of rutin isolated from Dendropanax morbifera Leveille.

Dendropanax morbifera H. Lev. is well known in Korean traditional medicine for improvement of blood circulation. In this study, rutin, a bioflavonoid having anti-thrombotic and anticoagulant activities was isolated from a traditional medicinal plant, D. morbifera H. Lev. The chemical characteristics of rutin was studied to be quercetin 3-O-α-l-rhamnopyranosyl-(1-6)-ß-d-glucopyranoside using high performance liquid chromatography mass spectrometry (HPLC-MS), proton nuclear magnetic resonance ((1)H NMR) and carbon-13 nuclear magnetic resonance ((13)C NMR). Turbidity and fibrin clotting studies revealed that rutin reduces fibrin clot in concentration dependent manner. Rutin was found to prolong activated partial thromboplastin time (aPTT), prothrombin time (PT) and closure time (CT). Furthermore, it decreased the activity of pro-coagulant protein, thrombin. In vivo study showed that rutin exerted a significant protective effect against collagen and epinephrine (or thrombin) induced acute thromboembolism in mice. These results suggest that rutin has a potent to be an anti-thrombotic agent for cardiovascular diseases.

Purification and characterization of a fibrinolytic enzyme from Petasites japonicus.

A new, direct-acting chymotrypsin-like fibrinolytic serine protease was purified from Petasites japonicus, a medicinal herb. The molecular mass of the discovered enzyme was estimated to be 40.0 kDa as determined using sodium dodecyl sulfate polyacrylamide gel electrophoresis, fibrin zymography, and gel filtration chromatography. The N-terminal sequence of the purified enzyme was determined to be GQEDHFLQVSLTSA. The proteolytic activity of the enzyme was found to be inhibited by serine protease inhibitors phenylmethylsulfonyl fluoride and 4-(amidinophenyl) methanesulfonyl fluoride. An assay of enzyme activity on fibrin plates revealed that it could hydrolyze the fibrin directly. The enzyme displayed a potent fibrin(ogen)olytic activity, hydrolyzing the Aα-, α-, and Bß-subunits of the human fibrinogen. The enzyme prolonged activated partial thromboplastin time and had little effect on prothrombin time. It prevented carrageenan-induced thrombus formation in mouse tails and did not increase the bleeding time. Our findings indicate that the extracted enzyme we present here has the potential for clinical use as an agent for the treatment of thrombosis.

Novel thrombolytic protease from edible and medicinal plant Aster yomena (Kitam.) Honda with anticoagulant activity: purification and partial characterization.

A thrombolytic protease named kitamase possessing anticoagulant property was purified from edible and medicinal plant Aster yomena (Kitam.) Honda. Kitamase showed a molecular weight of 50 kDa by SDS-PAGE and displayed a strong fibrin zymogram lysis band corresponding to the similar molecular mass. The enzyme was active at high temperatures (50°C). The fibrinolytic activity of kitamase was strongly inhibited by EDTA, EGTA, TPCK and PMSF, inhibited by Zn(2+). The Km and Vmax values for substrate S-2251 were determined as 4.31 mM and 23.81 mM/mg respectively. It dissolved fibrin clot directly and specifically cleaved the α, Aα and γ-γ chains of fibrin and fibrinogen. In addition, kitamase delayed the coagulation time and increased activated partial thromboplastin time and prothrombin time. Kitamase exerted a significant protective effect against collagen and epinephrine induced pulmonary thromboembolism in mice. These results suggest that kitamase may have the property of metallo-protease like enzyme, novel fibrino(geno)lytic enzyme and a potential to be a therapeutic agent for thrombosis.

Rutin from Dendropanax morbifera Leveille protects human dopaminergic cells against rotenone induced cell injury through inhibiting JNK and p38 MAPK signaling.

Dendropanax morbifera Leveille (Araliaceae) is well known in Korean traditional medicine for a variety of diseases. Rotenone is a commonly used neurotoxin to produce in vivo and in vitro Parkinson's disease models. This study was designed to elucidate the processes underlying neuroprotection of rutin, a bioflavonoid isolated from D. morbifera Leveille in cellular models of rotenone-induced toxicity. We found that rutin significantly decreased rotenone-induced generation of reactive oxygen species levels in SH-SY5Y cells. Rutin protected the increased level of intracellular Ca(2+) and depleted level of mitochondrial membrane potential (ΔΨm) induced by rotenone. Furthermore, it prevented the decreased ratio of Bax/Bcl-2 caused by rotenone treatment. Additionally, rutin protected SH-SY5Y cells from rotenone-induced caspase-9 and caspase-3 activation and apoptotic cell death. We also observed that rutin repressed rotenone-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation. These results suggest that rutin may have therapeutic potential for the treatment of neurodegenerative diseases associated with oxidative stress.

Celastrol from 'Thunder God Vine' protects SH-SY5Y cells through the preservation of mitochondrial function and inhibition of p38 MAPK in a rotenone model of Parkinson's disease.

Celastrol, a potent natural triterpene and one of the most promising medicinal molecules, is known to possess a broad range of biological activity. Rotenone, a pesticide and complex I inhibitor, is commonly used to produce experimental models of Parkinson's disease both in vivo and in vitro. The present study was designed to examine the effects of celastrol on cell injury induced by rotenone in the human dopaminergic cells and to elucidate the possible mechanistic clues in its neuroprotective action. We demonstrate that celastrol protects SH-SY5Y cells from rotenone-induced cellular injury and apoptotic cell death. Celastrol also prevented the increased generation of reactive oxygen species and mitochondrial membrane potential (ΔΨm) loss induced by rotenone. Similarly, celastrol treatment inhibited cytochrome c release, Bax/Bcl-2 ratio changes, and caspase-9/3 activation. Celastrol specifically inhibited rotenone-evoked p38 mitogen-activated protein kinase activation in SH-SY5Y cells. These data suggest that celastrol may serve as a potent agent for prevention of neurotoxin-induced neurodegeneration through multiple mechanisms and thus has therapeutic potential for the treatment of neurodegenerative diseases.

Leaf extract of Rhus verniciflua Stokes protects dopaminergic neuronal cells in a rotenone model of Parkinson's disease.

OBJECTIVES: The present study investigated the neuroprotective effects of Rhus verniciflua Stokes (RVS) leaf extract on rotenone-induced apoptosis in human dopaminergic cells, SH-SY5Y. METHODS: Cells were pretreated with RVS extract for 1 h then treated with vehicle or rotenone for 24 h. Cell viability, cell cytotoxicity, cell morphology and nuclear morphology were examined by MTT assay, lactate dehydrogenase release assay, phase contrast microscopy and staining with Hoechast 33342, respectively. Reactive oxygen species were measured by 2'7'-dichlorofluorescein diacetate and fragmented DNA was observed by TUNEL assay. Mitochondrial membrane potential was determined by Rhodamine 123. Pro-apoptotic and anti-apoptotic proteins and tyrosine hydroxylase were analysed by Western blotting. KEY FINDINGS: Results showed that RVS suppressed rotenone-induced reactive oxygen species generation, cellular injury and apoptotic cell death. RVS also prevented rotenone-mediated changes in Bax/Bcl-2 levels, mitochondrial membrane potential dissipation and Caspase 3 activation. Moreover, RVS pretreatment increased the tyrosine hydroxylase levels in SH-SY5Y cells. CONCLUSIONS: These findings demonstrate that RVS protects SH-SY5Y cells against rotenone-induced injury and suggest that RVS may have potential therapeutic value for neurodegenerative disease associated with oxidative stress.

Expression and production of therapeutic recombinant human platelet-derived growth factor-BB in Pleurotus eryngii.

Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) is widely used in many therapeutic applications. Until now, there has been no report on rhPDGF-BB expressed in fungi. In this study, we tested whether Pleurotus eryngii could support the expression of human therapeutic rhPDGF-BB protein. A binary vector pCAMBIA1304 containing the hPDGF-BB gene was constructed and introduced into P. eryngii via Agrobacterium tumefaciens-mediated transformation. The transformation of hPDGF-BB gene was confirmed by Southern blot and PCR, whereas the expression was confirmed by Western blot analysis. The recombinant hPDGF-BB reached a maximum expression level of 1.98% of total soluble protein in transgenic mycelia and was in dimeric form. A bioassay revealed that hPDGF-BB expressed in P. eryngii increased proliferation of NIH-3T3 cells similarly to standard material. These results suggest that P. eryngii can be a robust system for the production of human therapeutic proteins including the hPDGF-BB.

Detoxified extract of Rhus verniciflua stokes inhibits rotenone-induced apoptosis in human dopaminergic cells, SH-SY5Y.

Rhus verniciflua Stokes (RVS), traditionally used as a food supplement and in traditional herbal medicine for centuries in Korea, is known to possess various pharmacological properties. Environmental neurotoxins such as rotenone, a specific inhibitor of complex I provide models of Parkinson's disease (PD) both in vivo and in vitro. In this study, we investigated the neuroprotective effect of RVS against rotenone-induced toxicity in human dopaminergic cells, SH-SY5Y. Cells exposed to rotenone for 24 h-induced cellular injury and apoptotic cell death. Pretreatment of cells with RVS provided significant protection to SH-SY5Y cells. Further, RVS offered remarkable protection against rotenone-induced oxidative stress and markedly inhibited mitochondrial membrane potential (MMP) disruption. RVS also attenuated the up-regulation of Bax, Caspase-9 and Caspase-3 and down-regulation of Bcl-2. Moreover, pretreatment with RVS prevented the decrease in tyrosine hydroxylase (TH) levels in SH-SY5Y cells. Interestingly, RVS conferred profound protection to human dopaminergic cells by preventing the downregulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). These results suggest that RVS may protect dopaminergic neurons against rotenone-induced apoptosis by multiple functions and contribute to neuroprotection in neurodegenerative diseases, such as PD.

A detoxified extract of Rhus verniciflua Stokes upregulated the expression of BDNF and GDNF in the rat brain and the human dopaminergic cell line SH-SY5Y.

Rhus verniciflua Stokes (RVS) has traditionally been used as a food supplement and a traditional herbal medicine for centuries in Korea. This study attempted to evaluate the effects of RVS on the expression of Brain derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells and the rat brain. The results indicated that RVS is a potent inducer of Neurotrophic factor (NTF) production both in vitro and in vivo. Treatment with 10 µg/ml and 10 mg/kg RVS for 4 h of SH-SY5Y cells and rats yielded significant increases in BDNF and GDNF protein levels. We also detected BDNF and GDNF immunoreactive neurons in the rat brain. Both BDNF and GDNF-immunohistochemical staining was markedly enhanced in the animals treated with RVS. These results suggest that RVS serves as an ideal adjuvant in regard to regulating NTF expression, and can contribute to neuroprotection in neurodegenerative diseases.

Antioxidant and antimelanogenic properties of chestnut flower extract.

In this study, we analyzed the antioxidant and antimelanogenic properties of a variety of solvent extracts of pre-bloom and full-bloom chestnut flowers. Among the solvent extracts, a pre-bloom methanol extract (preM) and an ethanol extract (preE) showed the highest amounts of phenolics (467.92+/-0.45 and 456.24+/-5.88 mg of gallic acid equivalent/g of extract) and flavonoids (60.96+/-1.86 and 41.59+/-8.57 mg of quercetin equivalent/g of extract). These extracts exhibited the highest DPPH radical and reducing activities, as well as the greatest mushroom tyrosinase inhibition activity. In addition, preE effectively protected the skin against ultraviolet (UV) rays. Further, extracts were tested for cytotoxicity on human melanoma cells (SK-MEL-2), and we observed that all the extracts were non-cytotoxic for the cells. Their effects on tyrosinase and melanin inhibitory action were further assessed, and we found that all the extracts reduced the tyrosinase activity and melanin formation of SK-MEL-2 cells as effectively as arbutin. Moreover, the protein level expression of tyrosinase decreased dramatically. However, the protein levels of the other melanogenic enzymes, tyrosinase-related protein 1 (TRP1) and dopachrome tautomerase (DCT), were not altered significantly. Therefore, the antimelanogenic effects of chestnut flower extracts were attributable to their inhibitory effects on tyrosinase via their anti-oxidative action, making them a strong candidate for use in food, cosmetics, and pharmaceutical applications.

Neuroprotective effect of Rosmarinus officinalis extract on human dopaminergic cell line, SH-SY5Y.

Hydrogen peroxide (H2O2) is a major Reactive Oxygen Species (ROS), which has been implicated in many neurodegenerative conditions including Parkinson's disease (PD). Rosmarinus officinalis (R. officinalis) has been reported to have various pharmacological properties including anti-oxidant activity. In this study, we investigated the neuroprotective effects of R. officinalis extract on H2O2-induced apoptosis in human dopaminergic cells, SH-SY5Y. Our results showed that H2O2-induced cytotoxicity in SH-SY5Y cells was suppressed by treatment with R. officinalis. Moreover, R. officinalis was very effective in attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H2O2. R. officinalis extract effectively suppressed the up-regulation of Bax, Bak, Caspase-3 and -9, and down-regulation of Bcl-2. Pretreatment with R. officinalis significantly attenuated the down-regulation of tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC) gene in SH-SY5Y cells. These findings indicate that R. officinalis is able to protect the neuronal cells against H2O2-induced injury and suggest that R. officinalis might potentially serve as an agent for prevention of several human neurodegenerative diseases caused by oxidative stress and apoptosis.

Antioxidant activity and protective effects of Tripterygium regelii extract on hydrogen peroxide-induced injury in human dopaminergic cells, SH-SY5Y.

The present work was conducted to investigate the antioxidant activity and neuroprotective effects of Tripterygium regelii extract (TRE) on H(2)O(2)-induced apoptosis in human dopaminergic cells, SH-SY5Y. TRE possessed considerable amounts of phenolics (282.73 mg tannic acid equivalents/g of extract) and flavonoids (101.43 mg naringin equivalents/g of extract). IC(50) values for reducing power and DPPH radical scavenging activity were 52.51 and 47.83 microg, respectively. The H(2)O(2) scavenging capacity of TRE was found to be 57.68 microM x microg(-1) min(-1). By examining the effects of TRE on SH-SY5Y cells injured by H(2)O(2), we found that after incubation of cells with TRE prior to H(2)O(2) exposure, the H(2)O(2) induced cytotoxicity was significantly reversed and the apoptotic features such as change in cellular morphology, nuclear condensation and DNA fragmentation was inhibited. Moreover, TRE was very effective attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H(2)O(2). TRE extract effectively suppressed the up-regulation of Bax, Caspase-3 and -9, and down-regulation of Bcl-2. Moreover, TRE pretreatment evidently increased the tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) in SH-SY5Y cells. These findings demonstrate that TRE protects SH-SY5Y cells against H(2)O(2)-induced injury and antioxidant properties may account for its neuroprotective actions and suggest that TRE might potentially serve as an agent for prevention of neurodegenerative disease associated with oxidative stress.