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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.

Natural polyphenols are known for their variety of pharmacological properties including chemosensitizing of anticancer drugs. A dietary polyphenol, ferulic acid, was observed for the first time enhancing epirubicin-induced apoptosis in MDA-MB-231 human breast cells via the endoplasmic reticulum (ER) stress pathway. The combined index of 10 μM ferulic acid and epirubicin was less than 0.9, which indicates ferulic acid could significantly enhance the sensitivity of MDA-MB-231 cells to epirubicin. Flow cytometry analysis showed that apoptosis by epirubicin (1 μM) in MDA-MB-231 cells was enhanced by ferulic acid (10 μM). Western blot analysis demonstrated apoptosis was induced by increasing the expression of Bax, downregulating the level of Bcl-2 and activating caspase-3. Furthermore, it was observed that the synergism of ferulic acid (10 μM) and epirubicin (1 μM) increased the expression levels of the ER stress-related proteins such as PDI, IRE1α and PEPK while the results should be opposite after using the ER stress inhibitors. In conclusion, our results indicate that ferulic acid could be served as a potential officinal adjuvant for breast cancer treatment.

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.

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.

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.

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 $$

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

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.

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.