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High-altitude polycythemia (HAPC) occurs in high-altitude (HA) environments and involves an imbalance between erythropoiesis and eryptosis. Spleen/splenic macrophages are an important primary tissue/cell of eryptosis and iron recycling. However, the role of the spleen in the pathogenesis of HAPC and the effect of hypobaric hypoxia (HH) on the biology of the spleen and splenic macrophages are still unclear. We used a mouse hypobaric hypoxia (HH) exposure model to simulate anin vivostudy of 6000 m HA exposure. Forin vitrostudies, we used a primary splenic macrophage model treated with 1% hypoxia. We found that the HH-treated mouse model promoted erythropoiesis and led to erythrocytosis. In addition, HH exposure resulted in marked splenic contraction followed by splenomegaly for up to 14 days. HH exposure impaired the red blood cell (RBC) handling capacity of the spleen, which was caused by a decrease in splenic macrophages in the red pulp. Moreover, HH treatment for 7 and 14 days promoted iron mobilization and ferroptosis in the spleen, as reflected by the expression of metabolism-related proteins and ferroptosis-related proteins. All of the protein expression levels were similar to the gene expression levels in human peripheral blood mononuclear cells. Single-cell sequencing of the spleen further demonstrated a significant decrease in macrophages in the spleen 7 days after HH exposure. Inin vitrostudies, we confirmed that primary splenic macrophages decreased and induced ferroptosis following hypoxic treatment, which was reversed by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Taken together, HH exposure induces splenic ferroptosis, especially in red pulp macrophages, which further inhibits the clearance of RBCs from the spleen. As such, it promotes the retention of RBCs in the spleen and causes splenomegaly, which may further lead to the persistent production of RBCs and ultimately to the development of HAPC.

The protective effect of intermittent hypoxia (IH) preconditioning against oxidative injury in hepatic cells was investigated and the involvement of the PINK1/Parkin-mediated mitophagy regulated by nuclear respiratory factor 1 (NRF-1) was evaluated. The results showed that IH preconditioning protected HepG2 cells against oxygen and glucose deprivation/reperfusion (OGD/Rep)-induced injury and protected WRL68 cells against H2O2 or AMA-induced oxidative injury. IH preconditioning up-regulated the protein level of NRF-1, PINK1, Parkin, and LC3 II, promoted the recruitment of the cytosolic Parkin, indicating the initiation of the PINK1/Parkin-mediated mitophagy in WRL68 cells. When NRF-1 was down-regulated by NRF-1 specific shRNA, the protein level of PINK1 and Parkin as well as the mitophagy level were significantly decreased. After IH preconditioning, the protein level of PINK1 and the recruitment of Parkin in CCCP-treated group were significantly higher than that of the control group, indicating the increased mitophagy capacity. And the increased mitophagy capacity induced by IH preconditioning was also reduced by down-regulation of NRF-1. Furthermore, the protective effect of IH preconditioning against H2O2-induced oxidative injury in WRL68 cells was inhibited when NRF-1 or PINK1 was down-regulated by specific shRNA. Mitochondrial ROS generation may be responsible for the increased expression of NRF-1 induced by IH preconditioning. In conclusion, the PINK1/Parkin-mediated mitophagy regulated by NRF-1 was involved in IH preconditioning-induced protective effect against oxidative cellular injury in hepatic cells.

Background/Aims: The studies in the patients with iron deficiency anemia (IDA) implied the existence of the association of ghrelin with iron or hepcidin levels in the plasma under the pathophysiological conditions. We hypothesized that fasting may be able to affect iron metabolism via ghrelin under the physiological conditions. Methods: We investigated the effects of fasting on serum ghrelin and iron contents in healthy volunteers (23–31 years) and C57BL/6 male mice (8-week-olds) under the physiological conditions. Results: Fasting induced a significant elevation in both total ghrelin and acylated ghrelin and a reduction in iron levels in the serum of both human and mice. Correlation analysis demonstrated that total ghrelin or acylated ghrelin is negatively correlated with iron in the serum in human and mice. Conclusion: Ghrelin has a role to reduce serum iron under the conditions of fasting.

The extensive existing knowledge on bi-directional communication between astrocytes and neurons led us to hypothesize that not only ischemia-preconditioned (IP) astrocytes can protect neurons but also IP neurons protect astrocytes from lethal ischemic injury. Here, we demonstrated for the first time that neurons have a significant role in protecting astrocytes from ischemic injury. The cultured medium from IP neurons (IPcNCM) induced a remarkable reduction in LDH and an increase in cell viability in ischemic astrocytes in vitro. Selective neuronal loss by kainic acid injection induced a significant increase in apoptotic astrocyte numbers in the brain of ischemic rats in vivo. Furthermore, TUNEL analysis, DNA ladder assay, and the measurements of ROS, GSH, pro- and anti-apoptotic factors, anti-oxidant enzymes and signal molecules in vitro and/or in vivo demonstrated that IP neurons protect astrocytes by an EPO-mediated inhibition of pro-apoptotic signals, activation of anti-apoptotic proteins via the P13K/ERK/STAT5 pathways and activation of anti-oxidant proteins via up-regulation of anti-oxidant enzymes. We demonstrated the existence of astro-protection by IP neurons under ischemia and proposed that the bi-directionally protective communications between cells might be a common activity in the brain or peripheral organs under most if not all pathological conditions.

In the light of recent studies, we hypothesized that aspirin might have the functions to regulate the expression of iron transport proteins and then affect cellular iron levels. To test this hypothesis, we investigated the effects of aspirin on expression of iron uptake protein transferrin receptor 1 (TfR1), iron release protein ferroportin 1 (Fpn1) and iron storage protein ferritin using Western blot analysis and on tumor necrosis factor (TNF)-αlpha, interleukin (IL)-6, interleukin (IL)-10 and hepcidin using quantitative real-time PCR in BV-2 microglial cells treated with lipopolysaccharides (LPS). We found that aspirin significantly down-regulated TfR1, while also up-regulated Fpn1 and ferritin expressions in BV-2 microglial cells in vitro. We also showed that TfR1 and Fpn1 expressions were significantly higher, while ferritin contents, IL-6, TNF-alpha and hepcidin mRNA levels were lower in cells treated with aspirin plus LPS than those in cells treated with LPS only. We concluded that aspirin has a negative effect on cell iron contents under 'normal' conditions and could partly reverse LPS-induced-disruption in cell iron balance under in vitro inflammatory conditions. Our findings also suggested that hepcidin might play a dominant role in the control of TfR1 expression by aspirin in the cells treated with LPS.

Universal structure and thorough analysis were proposed for a kind of polymer optical switch using N-th order microring resonator side-coupled Mach–Zehnder interferometer (MRR-SC-MZI). Formulation and expression of output power, insertion loss and crosstalk were derived, and detailed design and optimization were carried out. Analytical results indicate that all devices for N≥1 can perform normal switching function, and 8≥N≥2 is preferred for dropping the driving voltage below 5 V. For the seven MRR-SC-MZI EO switches (N=2–8) whose cross-state voltages are within 0–2.32 V, their bar-state voltages are within 0.96–4.83 V and their insertion losses are within 0.35–0.85 dB at bar state, whereas those within 0.14–1.70 dB at cross state; their crosstalk are within −20.79 to −31.11 dB at bar state, whereas those are within −13.86 to −20.36 dB at cross state; their 3-dB electrical bandwidths are within 18.5–28.0 GHz, and 3-dB optical bandwidths for the two output ports are within 18.1–40.0 GHz and 32.0~55 GHz, respectively. Comparison indicates that the driving voltages of the proposed MRR-SC-MZI switching devices are 10–250 times smaller than those of the traditional MZI EO switches with the same EO region length, device length and structural parameters. Therefore, due to small footprint size and low driving voltage, this switching configuration can be densely integrated onto optoelectronic chips.

Structure and design were proposed for a kind of novel multifunctional M × N microring array side-coupled Mach-Zehnder interferometer (MZI) electrooptic switch/ filter. The device can be operated as a notch or bandpass filter by applying voltages on the under-reference MZI arm, and it can also serve as an optical switch by applying voltage on microrings. The dependence relations of the device's performances on RSA size (M and N) are thoroughly analyzed and concluded. As a switch, for making driving voltages under both operation states below 5 V, N and M should be within the range of 2-8. For the seven switches (M = 1, 8 ≥ N ≥ 2), their insertion losses are within 0.85-0.35 dB at bar state and within 0.14-1.70 dB at cross state; the crosstalk are within -20.79- -31.11 dB at bar state and within -13.86--20.36 dB at cross state; and their 3-dB electrical bandwidths are 18.5-30.5 GHz, whereas their 3-dB optical bandwidths for ports 1 and 2 are 18.1-40.0 GHz and 19.0-55.0 GHz, respectively. In addition, the needed energy per bit under 10-GHz switching operations is within 0.092-0.697 pJ. Therefore, the proposed multifunctional device shows potential applications, including filtering, routing, and switching, in optical networks-on-chip.

As basic routing element, structure and principle of cross-coupling two-ring resonator are presented, and waveguide parameters are optimized for phase-matching and single-mode propagation. Using eight-group basic elements, a new one-stage five-port polymer optical router is proposed, and it can optically route four channel wavelength data streams along definite-path in 2-D plane. Under the selected four channel wavelengths, the insertion losses along all routing paths are within 0.03–0.62 dB, the maximum crosstalk of all routing operations is less than −39 dB, and the device footprint size is about 0.31 mm 2 . A universal novel structure and routing scheme of N -stage cascaded five-port optical router are presented, and it contains 4 N channel wavelengths that can be routed by the device. Compared with the previously reported silicon optical routers, this polymer device possesses similar ring radius (~10 μm) and device size ( 2 ). Because of simple processing technology, low cost and good scalability, this device shows potential application of wideband signal routing in optical networks-on-chip (ONoC).

Optimization and simulation are performed for a polymer four-port microring optical router with three channel wavelengths, which contains four-group basic routing elements with two different ring radii. In terms of microring resonance theory, coupled mode theory and transfer matrix method, expressions of output power of basic routing element and optical router are derived. In order to realize single-mode propagation, low optical transmission loss and phase match between microring waveguide and channel waveguide, the device parameters are optimized. With the selected three channel wavelengths of 1550 nm, 1552 nm and 1554 nm, characteristics are calculated and analyzed, including output spectrum, insertion loss and crosstalk. Simulation results indicate that the device has 12 possible I/O routing paths, the insertion losses of three channel wavelengths along their routing paths are within the range of 0.02–0.61 dB, the maximum crosstalk between the on-port along each routing path and other off-ports is less than −39 dB, and the device footprint size is ∼0.13 mm2. Based on the proposed structure, through proper selection on ring radius, the routing structure can also be used for other channel wavelengths. Therefore, the designed structure shows wide applications in integrated optical networks-on-chip (NoC).

Universal structure and thorough analysis are proposed for a kind of (2N + 1)th order polymer microring resonator Mach–Zehnder interferometer (MRR-MZI) electro-optic (EO) switch. Formulas and expressions of output power, insertion loss and crosstalk are derived, and detailed design and optimization are carried out. Analytical results indicate that, besides the first-order MRR-MZI EO switch (N = 0), other devices for N ≥ 1 can all perform normal switching function, and 5 ≥ N ≥ 2 is preferred for dropping the crosstalk below −10 dB. For the four MRR EO switches (N = 2–5), their switching voltages are 0.99, 0.73, 0.57 and 0.47 V, respectively; their insertion losses are within the range of 1.15–2.26 dB at bar state, whereas those are within the range of 1.95–2.42 dB at cross state; their crosstalks are within the range of 11.04–17.82 dB at bar state, whereas those are within the range of 10.34–12.51 dB at cross state. Compared with the traditional MZI EO switch, the voltage–length product (0.21 V mm) of this switching element is decreased by ~111.7 times under the same waveguide parameters. Therefore, due to small footprint size and extremely low switching voltage, this switching configuration can be densely integrated onto optoelectronic chips.

Universal model and investigation are proposed for a novel 2×2 polymer electro-optic (EO) switch based on two-group 2N+1 vertical-turning series-coupled microrings. For realizing boxlike spectrum (drop port) as well as low crosstalk and insertion loss, resonance order and coupling gaps are optimized. The microring resonator (MRR) switches with N≥1 reveal favorable boxlike flat spectrum as when compared with the simple device with only one microring (N=0), and 1≤N≤5 is required for obtaining

A novel 1×2 polymer electro-optic (EO) switch based on seven vertical-turning serial-coupled microrings is proposed for dropping crosstalk and obtaining flat boxlike spectrum. The device structure, theory and formulation are presented, and the microring resonance order and coupling gaps are optimized. The switching voltage of the device for obtaining crosstalk lower than −30 dB under through state is decided to be about 1.86 V. Under the operation voltages of 0 V (drop state) and 1.86 V (through state), the switching performance is characterized, and the output spectrum is analyzed. The calculation results show that the crosstalk at through state and that at drop state are −30.2 dB and −53.2 dB, respectively, while the insertion losses are 0.86 dB and 3.18 dB, respectively. Owning to the seven serial-coupled microrings resonance structure, the proposed switch reveals the favorable boxlike spectrum compared with the simple device with only one microring, and thus the crosstalk under drop state is improved from −26.8 dB to −53.2 dB. Due to the low crosstalk, this device can be used in optical networks-on-chip for signal switching and routing.

Device architecture and design scheme of a universal $$N$$ -stage cascaded polymer four-port optical router with scalable 3 $$N$$ channel wavelengths are proposed. Basic cross-coupling two-microring resonator routing element based on polymer materials is optimized for single-mode transmission, low optical loss and phase-match between microring waveguide and channel waveguide. Then, a one-stage four-port optical router is constructed using four-group basic routing elements, which has 12 possible I/O routing paths and 3 channel wavelengths. The insertion losses of each channel wavelength along every routing path are within the range of 0.04–0.63 dB, the maximum crosstalk between the on-port along each routing path and other off-ports is less than $$-39$$ dB, and the device footprint size is $$\sim $$ 0.13 mm $$^{2}$$ . Compared with the previously reported four-port silicon optical routers, this device possesses similar ring radius ( $$\sim $$ 10 $$\upmu $$ m) and device size ( $$

In this paper, the light fastness and glossiness of natural yellow silk fabric were analyzed. The test items included the mechanical property, light color fastness, perspiration color fastness, and rubbing color fastness. The relation between the glossiness and different specification of the silk fabric was discussed. Finally, the glossiness of fabric with different degumming rate was observed. The experimental results reveal that the fracture strength of fabric reduces significantly. The fabrics light fastness runs up to 1~2 degree, perspiration color fastness can reach 5 degree as well as rubbing color fastness. For the 8/5 satin fabric, the glossiness is low. Glossiness of the plain weave is less than the one of the twill fabric. After 48h lighting, the glossiness decreases while the reflectivity increases. When the lighting time increases from 48h to 96h, the glossiness increases gradually. After degumming finishing, glossiness of the fabric decreases, while the reflectivity increases. The fabric can achieve a relatively fine glossiness at degumming rate of 17.34%.

A 2×2 cross/bar polymer electro-optic (EO) routing switch is proposed, which is composed of two passive channel waveguides and two active EO polymer microrings with bending radius of only 13.76 μm. Detailed structure, theory and formulation are provided to characterize the output power of the switch. For obtaining fundamental mode propagation, small bending loss and phase-matching between channel waveguide and microring resonator (MRR) waveguide, the structural parameters are optimized under the wavelength of 1550 nm. Analyses and simulations on output power and output spectra indicate that a switching voltage of 5 V is desired to realize the exchange between cross state and bar state, the crosstalk under cross state and that under bar state are about −28.8 dB and −39.9 dB, respectively, and the insertion losses under these two states are about 2.42 dB and 0.13 dB, respectively. Compared with our four EO switches reported before, this device possesses ultra-compact size of 0.233 mm×0.233 mm as well as low crosstalk and insertion loss, and therefore it can serve as a good candidate for constructing large-scale optical routers or switching arrays in photonic network-on-chip (NoC).

In order to improve plastic property of AZ31 alloy tubes at room temperature and expand application of cold rolling process in magnesium (Mg) alloys, solution treatment (T4) and cryogenic treatment of AZ31 tubes obtained by drawing were investigated in this work. The results indicate that T4 can improve the microstructure of the alloy, refine grains and eliminate twins. The optimized T4 parameter is 300 °C for 8 h, in which the average grain size of 12 μm can be obtained and elongation reaches to Max of 16.1% and tensile strength reaches to 242 MPa. Moreover, tensile strength was decreased to 211 MPa, while, elongation was improved to 25.4% by T4+cryogenic treatment at-196 °C.

A high-linear bias-free polymer Y-fed coupler electro-optic (EO) modulator with push-pull poled two section waveguides is proposed. Using Fourier transformation, a novel formulation technique is presented to numerically model and characterize the device performances. As an EO modulator, the half-wave voltage is 2.6852 V, and the 3-dB modulation bandwidth is ~ 143 GHz. As an EO switch, the insertion loss and crosstalk are

Generic model and thorough investigation are proposed for a novel $$1\times 2$$ polymer electro-optic (EO) switch based on one-group $$2N+1$$ vertical-turning serial-coupled microrings. For realizing boxlike flat spectrum as well as low crosstalk and insertion loss, resonance order and coupling gaps are optimized. The MRR switches with $$N \ge 1$$ reveal favorable boxlike spectrum as when compared with the simple device with only one microring ( $$N = 0$$ ). For obtaining $$

The self-imaging theory is improved for designing a polymer multimode interference Mach–Zehnder interferometer electro-optic switch. The electro-optic overlap factor is enhanced from 0.6510 to 0.9658 through adopting an embedded coplanar waveguide electrode. Considering the mode dispersion effect, formulations of time-domain response are derived, and switching characteristics are analyzed. The total device length is about 7.175 mm, the switching voltage is 2.622 V, and the switching time is 29.90 ps. The lightwave 3-dB bandwidth is 20 nm, the insertion loss is less than 2.70 dB, and the crosstalk under cross and bar states are less than −55 dB and −45 dB, respectively.

A novel non-resonance 2×2 polymer electro–optic (EO) switch with flatting spectral response is proposed by employing two-section reversed active Mach–Zehnder interferometers (MZIs), a passive middle directional coupler (M-DC) and two passive phase generating couplers (PGCs). Two crosstalk compensations are performed by optimizing the PGCs to broaden the spectrum under bar-state and optimizing the two active MZIs to broaden the spectrum under cross-state. The bar-state and cross-state voltages are 0 and ±4 V, respectively, with the two optimized MZI EO region lengths of 4068 and 5941 μm. Sufficiently considering wavelength dispersion of material and waveguide, a wide spectrum over 130 nm (1473–1603 nm) is achieved for dropping the crosstalk below −30 dB, and within this range, an insertion loss of 1.8–12.3 dB is observed. Under the same crosstalk level, this spectrum is over 2 times of that of the traditional 2×2 MZI switch (60 nm) based on the same materials. This broadband 2×2 switch is more attractive than our previously reported broadband 1×1 switch due to cross/bar routing operations other than simple ON/OFF functions.

The significant positive correlation between ghrelin and iron and hepcidin levels in the plasma of children with iron deficiency anemia prompted us to hypothesize that ghrelin may affect iron metabolism. Here, we investigated the effects of fasting or ghrelin on the expression of hepcidin, ferroportin 1 (Fpn1), transferrin receptor 1 (TfR1), ferritin light chain (Ft-L) proteins, and ghrelin, and also hormone secretagogue receptor 1 alpha (GHSR1α) and ghrelin O-acyltransferase (GOAT) mRNAs in the spleen and/or macrophage. We demonstrated that fasting induces a significant increase in the expression of ghrelin, GHSR1α, GOAT, and hepcidin mRNAs, as well as Ft-L and Fpn1 but not TfR1 proteins in the spleens of mice in vivo. Similar to the effects of fasting on the spleen, ghrelin induced a significant increase in the expression of Ft-L and Fpn1 but not TfR1 proteins in macrophages in vitro. In addition, ghrelin was found to induce a significant enhancement in phosphorylation of ERK as well as translocation of pERK from the cytosol to nuclei. Furthermore, the increased pERK and Fpn1 induced by ghrelin was demonstrated to be preventable by pre-treatment with either GHSR1α antagonist or pERK inhibitor. Our findings support the hypothesis that fasting upregulates Fpn1 expression, probably via a ghrelin/GHSR/MAPK signaling pathway.

The inconsistent of responses of IRP1 and HIF-1 alpha to hypoxia and the similar tendencies in the changes of IRP1 and pCREB contents led us to hypothesize that pCREB might be involved in the regulation of IRP1 under hypoxia. Here, we investigated the role of pCREB in IRP1 expression in HepG2 cells under hypoxia using quantitative PCR, western blot, immunofluorescence, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). We demonstrated that 1) Hypoxia increased pCREB levels inside of the nucleus; 2) Putative CREs were found in the IRP1 gene; 3) Nuclear extracts of HepG2 cells treated with hypoxia could bind to CRE1 and CRE3, and 100-fold competitor of putative CREs could abolish the binding activity to varying degrees; 4) pCREB was found in the CRE1 and CRE3 DNA-protein complexes of EMSA; 5) CRE1 and CRE3 binding activity of IRP1 depended on CREB activation but not on HIF-1; 6) Increased IRP1 expression under hypoxia could be prevented by LY294002; 7) ChIP assays demonstrated that pCREB binds to IRP1 promoter; and 8) HIF-1 and/or HIF-2 siRNA had no effect on the expression of pCREB and IRP1 proteins in cells treated with hypoxia for 8 hours. Our findings evidenced for the involvement of pCREB in IRP1 expression and revealed a dominant role of PI3K/Akt pathway in CREB activation under hypoxia and also suggested that dual-regulation of IRP1 expression by HIF-1 and pCERB or other transcription factor(s) under hypoxia might be a common mechanism in most if not all of hypoxia-inducible genes.

Association of a high-serum ferritin with poor outcome showed that iron might play a detrimental role in the brain after intracerebral hemorrhage (ICH). Here, we investigated changes in serum iron, ferritin, transferrin (Tf) and ceruloplasmin (CP) in patients with ICH (n = 100) at day 1 (admission), 3, 7, 14 and 21 and those in control subjects (n = 75). The hematoma and edema volumes were also determined in ICH-patients on admission and at day 3. The Modified Rankin Scale (mRS) of 59 patients was ≥3 (poor outcome) and 41

In order to study the shading property of the fabric, there are several parameters of the fabrics were tested, they are include the transmission and reflectivity for the Ultraviolet light, the transmission and reflectivity for the visible light. From the test results, following conclusions can be gotten: under same situation, the percent of void for the fabric will affect the transmission of the Ultraviolet light and the visible light. When the interweaving frequency is bigger and the float is shorter, the reflectivity of the Ultraviolet light is lower and the reflectivity of the visible is higher.

In order to study the influences of fabric specification on vertical depth of honeycomb weaves, 11 kinds of honeycomb weaves fabric were designed in this paper by using different yarn linear density and weave repeat unit. The results show that the vertical depth of honeycomb weaves would increase as the yarn linear density increasing when the linear density was comparatively larger. With the increasing of weave repeat unit, vertical depth of honeycomb weaves is significantly increased. According to these results, 3D integrated vertical structure with honeycombed-core was designed, which used honeycomb weaves as the sandwich structure and plain weaves as the upside face and underside face. At the same time, the looming draft of this structure was drawn.

The exact roles of activated microglia and fractalkine (CX3CL1)/fractalkine receptor (CX3CR1) signaling are not fully understood in brain ischemic injury and the findings reported are controversial. Here, we investigated the effects of CX3CR1 siRNA on the expression of CX3CR1, p38 mitogen-activated protein kinase (p38MAPK), Protein Kinase C (PKC) and inflammatory cytokines, microglia activation, white matter lesions, and cognitive function in mice treated with bilateral common carotid artery stenosis (BCAS) in vivo as well as effects of exogenous CX3CL1, CX3CR1 siRNA, and SB2035080 on expression of inflammatory cytokines in BV2 microglia treated with oxygen–glucose deprivation (OGD) in vitro. We showed that CX3CR1 siRNA significantly inhibited the increased expression of CX3CR1, p38MAPK, PKC as well as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and also attenuated microglia activation, white matter lesions, and cognitive deficits induced by BCAS in mice brain. We also showed that exogenous CX3CL1 could induce a further enhancement in TNF-α and IL-1β expression, which could be suppressed by CX3CR1 siRNA or by the p38MAPK inhibitor in OGD-treated BV2 microglial cells in vitro. Our findings indicated that CX3CL1/CX3CR1-mediated microglial activation plays a detrimental role in ischemic brain via p38MAPK/PKC signaling and also suggested that CX3CL1/CX3CR1 axis might be a putative therapeutic target to disrupt the cascade of deleterious events that lead to brain ischemic injury.

Based on current knowledge on the role of the CX3CL1/CX3CR1 axis in the regulation of microglial activation and on the involvement of activated microglia in damaging oligodendrocytes, we hypothesized that CX3CL1/CX3CR1 axis is associated with the development of ischemic oligodendrocyte and white matter injury. We investigated the effects of CX3CL1, CX3CR1 shRNA, and p38MAPK inhibitor on the apoptosis, proliferation, and myelin proteolipid protein (PLP) expression in oligodendrocytes in co-cultures with BV2 microglia under ischemia. We demonstrated that CX3CL1 markedly increased the numbers of apoptotic oligodendrocytes, decreased PLP expression in oligodendrocytes, and inhibited the increased proliferation of oligodendrocytes induced by ischemia in co-cultures. All these effects of CX3CL1 were suppressed by pre-treatment of BV2 microglia with CX3CR1 shRNA to silence CX3CR1 expression or SB203580 to inhibit p38MAPK pathway. Our findings support that CX3CL1/CX3CR1 axis plays a key role in the development of ischemia-induced oligodendrocyte injury via p38MAPK signaling pathway.

Our recent investigation showed that hepcidin can reduce iron in the brain of iron-overloaded rat by down-regulating iron-transport proteins. It has also been demonstrated that iron is a major generator of reactive oxygen species. We therefore hypothesized that hepcidin could prevent iron accumulation and thus reduce iron-mediated oxidative stress in iron-overloaded rats. To test this hypothesis, we investigated the effects of pre-treatment of rats with recombinant-hepcidin-adenovirus (ad-hepcidin) on the contents of iron, dichlorofluorescein and 8-isoprostane in the brain. Hepcidin expression was detected by real-time PCR and immunofluorescence analysis. Iron contents were measured using Perl's staining as well as graphite furnace atomic absorption spectrophotometry. Dichlorofluorescein and 8-isoprostane were determined using a fluorescence spectrophotometer and an ELISA kit, respectively. We found that hepcidin contents in the cortex, hippocampus, striatum and substantia nigra of rats treated with ad-hepcidin are 3.50, 2.98, 2.93 and 4.07 fold of those of the control rats respectively. Also, we demonstrated that the increased iron as well as dichlorofluorescein and 8-isoprostane levels in all four brain regions, induced by injection of iron dextran, could be effectively prevented by pre-treatment of the rats with ad-hepcidin. We concluded that pre-treatment with ad-hepcidin could increase hepcidin expression and prevent the increase in iron and reduce reactive oxygen species in the brain of iron-overloaded rats.

Transferrin receptor (TfR1) and divalent metal transporter 1 (DMT1) are important proteins for cellular iron uptake, and both are regulated transcriptionally through the binding of hypoxia-inducible factor 1 (HIF-1) to hypoxia-responsive elements (HREs) under hypoxic conditions. These proteins are also regulated post-transcriptionally through the binding of iron regulatory protein 1 (IRP1) to iron-responsive elements (IREs) located in the mRNA untranslated region (UTR) to control cellular iron homeostasis. In iron-deficient cells, IRP1-IRE interactions stabilize TfR1 and DMT1 mRNAs, enhancing iron uptake. However, little is known about the impact of IRP1 on the regulation of cellular iron homeostasis under hypoxia. Thus, to investigate the role of IRP1 in hypoxic condition, overexpression and knockdown assays were performed using HepG2 cells. The overexpression of IRP1 suppressed the hypoxia-induced increase in TfR1 and DMT1 (+IRE) expression and reduced the stability of TfR1 and DMT1 (+IRE) mRNAs under hypoxia, whereas IRP1 knockdown further increased the hypoxia-induced expression of both proteins, preventing the decrease in IRE-dependent luciferase activity induced by hypoxia. Under hypoxic conditions, ferrous iron uptake, the labile iron pool (LIP), and total intracellular iron reduced when IRP1 was overexpressed and further increased when IRP1 was knocked down. IRP1 expression declined and TfR1/DMT1 (+IRE) expression increased with the time of hypoxia prolonged, whereas the binding of IRP1 to the IRE of TfR1/DMT1 mRNA maintained. In summary, IRP1 suppressed TfR1/DMT1 (+IRE) expression, limited the cellular iron content and decreased lactate dehydrogenase (LDH) release induced by hypoxia.

Iron accumulates progressively in the brain with age, and iron-induced oxidative stress has been considered as one of the initial causes for Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the role of hepcidin in peripheral organs and its expression in the brain, we hypothesized that this peptide has a role to reduce iron in the brain and hence has the potential to prevent or delay brain iron accumulation in iron-associated neurodegenerative disorders. Here, we investigated the effects of hepcidin expression adenovirus (ad-hepcidin) and hepcidin peptide on brain iron contents, iron transport across the brain-blood barrier, iron uptake and release, and also the expression of transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin 1 (Fpn1) in cultured microvascular endothelial cells and neurons. We demonstrated that hepcidin significantly reduced brain iron in iron-overloaded rats and suppressed transport of transferrin-bound iron (Tf-Fe) from the periphery into the brain. Also, the peptide significantly inhibited expression of TfR1, DMT1, and Fpn1 as well as reduced Tf-Fe and non-transferrin-bound iron uptake and iron release in cultured microvascular endothelial cells and neurons, while downregulation of hepcidin with hepcidin siRNA retrovirus generated opposite results. We concluded that, under iron-overload, hepcidin functions to reduce iron in the brain by downregulating iron transport proteins. Upregulation of brain hepcidin by ad-hepcidin emerges as a new pharmacological treatment and prevention for iron-associated neurodegenerative disorders.

Neuroinflammation is closely related to brain iron homeostasis. Our previous study demonstrated that lipopolysaccharides (LPS) can regulate expression of iron-regulatory peptide hepcidin; however, the mechanism is undefined. Here, we demonstrated that intracerebroventricular injection of LPS in rat brain upregulated hepcidin and downregulated ferroportin 1 in the cortex and substantia nigra. LPS increased hepcidin expression in neurons only when they were co-cultured with BV-2 microglia, and the upregulation was suppressed by IL-6 neutralizing antibody in vitro. In addition, IL-6 but not IL-1α, IL-1β, or tumor necrosis factor-alpha increased hepcidin expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in cortical neurons and MES23.5 dopaminergic neurons. These effects were blocked by the STAT3 inhibitor, stattic. Our results show that neurons are the major source of increased hepcidin expression in response to LPS challenge but microglia play a key mediator role by releasing IL-6 and recruiting the STAT3 pathway. We conclude that LPS upregulates hepcidin expression in neurons via microglia and the IL-6/STAT3 signaling pathway.

To investigate the protective effects of ginkgolide B and hypoxic preconditioning against acute hypoxia injury in mice.Ordinary pressure acute hypoxia model in mice was adopted to observe the ethology, the duration of the death and the degree of brain edema. Meanwhile the expression of RTP801 mRNA and erythropoietin (EPO) were measured by RT-PCR and Western blot, respectively.Ginkgolide B and hypoxic preconditioning could both prolong the survival time of hypoxia under ordinary pressure,and significantly decreased the degree of brain edema. Besides ginkgolide B and hypoxic preconditioning could both up-regulate the expression of RTP801mRNA and EPO.Ginkgolide B has the similar effect to hypoxic preconditioning against acute hypoxia. Both of these protective effects may be associated with the up-regulation of the expression of RTP801 mRNA and EPO.

Device architecture and design scheme of an N × N scalable electrooptic (EO) routing switch array (RSA) are proposed using electric-field-induced EO polymeric microrings. The basic 2 × 2 /cross/bar EO switching element is optimized under 1550-nm wavelength, and the ring radius is only 13.76 μm with