Ultrabroadband nonlinear enhancement of mid-infrared frequency upconversion in hyperbolic metamaterials.

Metamaterials have demonstrated significant potential for enhancing nonlinear processes at the nanoscale. The presence of narrowband hot-spots and highly inhomogeneous mode-field distributions often limit the enhancement of nonlinear interactions over larger spatial scales. This has posed a formidable challenge in achieving simultaneous enhancement across a broadband spectral range, significantly constraining the potential of photonic nanostructures in enhancing nonlinear frequency conversion. Here, we propose a broadband resonant mode matching method through near-field examinations that supports the multipole modes and enables the development of an ultrabroadband-enhanced 3-5 µm mid-infrared frequency upconversion technique utilizing a hyperbolic triangular pyramidal metasurface. The gap-plasma mode of the hyperbolic metamaterial multilayer system excites narrowly high-order resonances at near-infrared pump light wavelengths, while the slow-light effect generated by the dipoles achieves ultrabroadband near-field enhancement at mid-infrared wavelengths. The symmetry breaking of the triangular structure localizes these resonant modes at the tips, enabling mode-matched modulation at different wavelengths, and thus boosting the nonlinear frequency conversion process. Our approach provides a promising platform for metasurface-based frequency conversion techniques.

Amino-functionalization enhanced CO2 reduction reaction in pure water.

The electrochemical reduction of carbon dioxide (CO2RR) to carbon monoxide represents a cost-effective pathway towards realizing carbon neutrality. To suppress the hydrogen evolution reaction (HER), the presence of alkali cations is critical, which can however lead to precipitate formation on the electrode, adversely impacting the device stability. Employing pure water as the electrolyte in zero-gap CO2 electrolyzers can address this challenge, albeit at the cost of diminished catalyst performance due to the absence of alkali cations. In this study, we introduce a novel approach by implementing amino modifications on the catalyst surface to mimic the function of alkali metal cations, while simultaneously working in pure water. This modification enhances the adsorption of carbon dioxide and protons, thereby facilitating the CO2RR while concurrently suppressing the HER. Utilizing this strategy in a zero-gap CO2 electrolyzer with pure water as the anolyte resulted in an impressive carbon monoxide faradaic efficiency (FECO) of 95.5% at a current density of 250 mA cm-2, while maintaining stability for over 180 hours without any maintenance.

Engineering Partially Oxidized Gold via Oleylamine Modifier as a High-Performance Anode Catalyst in a Direct Borohydride Fuel Cell.

Direct borohydride fuel cell (DBFC) is considered a promising energy storage device due to its high theoretical cell voltage and energy density. For DBFC, an Au catalyst has been used as an anode for achieving an ideal eight-electron reaction. However, the poor activity of the Au catalyst for borohydride oxidation reaction (BOR) limits its large-scale application because of the weak BH4- adsorption. We found, by density functional theory calculations, that the adsorption of BH4- on the oxidized Au surface is stronger than that on the metallic Au surface, which can promote the process of the oxidation of BH4- to *BH3 during the BOR. Here, we reported an oleylamine-modified partially oxidized Au supported on carbon powder (AuC-OLA) with a stable oxidation state. The obtained catalyst delivered a high peak power density of 143 mW/cm2, which is 2 times higher than that of a commercial 40% AuC (Pretemek). The in situ Fourier transform infrared studies showed that the activity of AuC-OLA for BOR is ascribed to the enhanced adsorption for BH4- on the partially oxidized Au surface. These findings will promote the reasonable design of efficient Au electrocatalysts for DBFCs.

Epigenetic recording of stimulation history reveals BLIMP1-BACH2 balance in determining memory B cell fate upon recall challenge.

Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1-BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.

High recallability of memory B cells requires ZFP318-dependent transcriptional regulation of mitochondrial function.

Expression of the transcriptional regulator ZFP318 is induced in germinal center (GC)-exiting memory B cell precursors and memory B cells (MBCs). Using a conditional ZFP318 fluorescence reporter that also enables ablation of ZFP318-expressing cells, we found that ZFP318-expressing MBCs were highly enriched with GC-derived cells. Although ZFP318-expressing MBCs constituted only a minority of the antigen-specific MBC compartment, their ablation severely impaired recall responses. Deletion of Zfp318 did not alter the magnitude of primary responses but markedly reduced MBC participation in recall. CD40 ligation promoted Zfp318 expression, whereas B cell receptor (BCR) signaling was inhibitory. Enforced ZFP318 expression enhanced recall performance of MBCs that otherwise responded poorly. ZFP318-deficient MBCs expressed less mitochondrial genes, had structurally compromised mitochondria, and were susceptible to reactivation-induced cell death. The abundance of ZFP318-expressing MBCs, instead of the number of antigen-specific MBCs, correlated with the potency of prime-boost vaccination. Therefore, ZFP318 controls the MBC recallability and represents a quality checkpoint of humoral immune memory.

Blood brain barrier-targeted lipid nanoparticles improved the neuroprotection of Ferrostatin-1 against cerebral ischemic damage in an experimental stroke model.

Cerebral ischemic stroke is a serious disease with high mortality and disability rates. However, few neuroprotective drugs have been used for ischemic stroke in the clinic. Two main reasons may be responsible for this failure: difficulty in penetrating the blood-brain barrier (BBB) and easily inactivated in the blood circulation. Ferroptosis, a lipid oxidation-related cell death, plays significant roles in cerebral ischemia-reperfusion injury. We utilized RVG29, a peptide derived from Rabies virus glycoprotein, to obtain BBB-targeted lipid nanoparticles (T-LNPs) in order to investigate whether T-LNPs improved the neuroprotective effects of Ferrostatin-1 (Fer1, an inhibitor of ferroptosis) against cerebral ischemic damage. T-LNPs significantly increased BBB penetration following oxygen/glucose deprivation exposure in an in vitro BBB model and enhanced the fluorescence distribution in brain tissues at 6 h post-administration in a cerebral ischemic murine model. Moreover, T-LNPs encapsulated Fer1 (T-LNPs-Fer1) significantly enhanced the inhibitory effects of Fer1 on ferroptosis by maintaining the homeostasis of NADPH oxidase 4 (NOX4) and glutathione peroxidase 4 (GPX4) signals in neuronal cells after cerebral ischemia. T-LNPs-Fer1 significantly suppressed oxidative stress [heme oxygenase-1 expression and malondialdehyde (the product of lipid ROS reaction)] in neurons and alleviated ischemia-induced neuronal cell death, compared to Fer1 alone without encapsulation. Furthermore, T-LNPs-Fer1 significantly reduced cerebral infarction and improved behavior functions compared to Fer1-treated cerebral ischemic mice after 45-min ischemia/24-h reperfusion. These findings showed that the T-LNPs helped Fer1 penetrate the BBB and improved the neuroprotection of Fer1 against cerebral ischemic damage in experimental stroke, providing a feasible translational strategy for the development of clinical drugs for the treatment of ischemic stroke.

Chromium-Induced High Covalent Co-O Bonds for Efficient Anodic Catalysts in PEM Electrolyzer.

The proton exchange membrane water electrolyzer (PEMWE), crucial for green hydrogen production, is challenged by the scarcity and high cost of iridium-based materials. Cobalt oxides, as ideal electrocatalysts for oxygen evolution reaction (OER), have not been extensively applied in PEMWE, due to extremely high voltage and poor stability at large current density, caused by complicated structural variations of cobalt compounds during the OER process. Thus, the authors sought to introduce chromium into a cobalt spinel (Co3O4) catalyst to regulate the electronic structure of cobalt, exhibiting a higher oxidation state and increased Co-O covalency with a stable structure. In-depth operando characterizations and theoretical calculations revealed that the activated Co-O covalency and adaptable redox behavior are crucial for facilitating its OER activity. Both turnover frequency and mass activity of Cr-doped Co3O4 (CoCr) at 1.67 V (vs RHE) increased by over eight times than those of as-synthesized Co3O4. The obtained CoCr catalyst achieved 1500 mA cm-2 at 2.17 V and exhibited notable durability over extended operation periods - over 100 h at 500 mA cm-2 and 500 h at 100 mA cm-2, demonstrating promising application in the PEMWE industry.

Poly-γ-glutamic acid enhanced the yield and photosynthesis of soybeans by adjusting soil aggregates and water distribution.

BACKGROUND: Poly-γ-glutamic acid (γ-PGA) is employed extensively in agriculture to enhance soil water retention; however, the underlying mechanism by which γ-PGA improves soil structure and soybean productivity in arid regions remains poorly understood. A micro-scale field experiment was conducted in the arid region of northwest China, employing five concentrations of γ-PGA to investigate its impacts on soybean yield, photosynthesis, and water-use efficiency, as well as soil aggregates and water distribution. The five levels of γ-PGA were 0 (CK), 10 (P1), 20 (P2), 40 (P3), and 80 kg ha-1 (P4). RESULTS: The results demonstrated that the application of γ-PGA significantly improved soybean yield, photosynthesis, and chlorophyll content. It resulted in a decrease in soil aggregate content with a maximum diameter of less than 0.053 mm and an increase in the stability of soil aggregates in the uppermost layer of the soil (0-30 cm). The application of γ-PGA significantly increased soil water content, particularly in the uppermost layer of the soil, and effectively reduced water consumption and improving water use efficiency in soybeans. Overall, the P3 treatment exhibited the most pronounced improvement of soybean yield, photosynthesis, water-use efficiency, as well as distribution of soil aggregates and water. The correlation matrix heatmap also revealed a strong correlation between improvement of soybean yield or photosynthesis at various γ-PGA application levels and the enhancement of soil stability or soil water content. CONCLUSION: The multivariate regression analysis revealed that an optimal application level of 46 kg ha-1 γ-PGA could enhance effectively both yield and water use efficiency of soybean in the arid region of northwest China. © 2024 Society of Chemical Industry.

Facile Preparation of a Photo-Cross-Linked Silk Fibroin-Poly Ionic Liquid Hydrogel with Antifreezing and Ion Conductive Properties.

The silk fibroin (SF)/ionic liquid (IL) based hydrogel is a kind of remarkable substrate for flexible devices because of its subzero-temperature elasticity, electrical conductivity, and water retention, although the procedure of the gelation is considered complex and time-consuming. In this work, we introduced an approximate method for the development of novel photo-cross-linked SF/IL hydrogel, that is, SF-IMA/PIL hydrogel via the modification of silk fibroin chain with 2-isocyanatoethyl methacrylate (SF-IMA) in a certain ionic liquid with an unsaturated double bond. The chemical cross-linking between methacrylated SF and IL was triggered by UV light, while the physical cross-linking of the hydrogel was attributed to the ß-sheet formation of SF in SF-IMA/IL mixed solution. In addition to being a UV-induced three-dimensional (3D) printable one, the SF-IMA/PIL hydrogel performed significant ionic conductivity between room temperature and -50 °C and water retention within a wide range of relative humidity, which were the featured advantages as the ionic liquid involved. Moreover, the static and dynamic mechanical tests demonstrated that the hydrogel reserved its great elasticity at -50 °C and displayed its stiffness transition temperatures between -100 and -70 °C.

Neuronal Zinc Transporter ZnT3 Modulates Cerebral Ischemia-Induced Blood-Brain Barrier Disruption.

Zinc plays important roles in both physiological and pathological processes in the brain. Accumulation of free zinc in ischemic tissue is recognized to contribute to blood-brain barrier (BBB) disruption following cerebral ischemia, but little is known either about the source of free zinc in microvessels or the mechanism by which free zinc mediates ischemia-induced BBB damage. We utilized cellular and animal models of ischemic stroke to determine the source of high levels of free zinc and the mechanism of free zinc-mediated BBB damage after ischemia. We report that cerebral ischemia elevated the level of extracellular fluid (ECF-Zn) of ischemic brain, leading to exacerbated BBB damage in a rat stroke model. Specifically suppressing zinc release from neurons, utilizing neuronal-specific zinc transporter 3 (ZnT3) knockout mice, markedly reduced ECF-Zn and BBB permeability after ischemia. Intriguingly, the activity of zinc-dependent metalloproteinase-2 (MMP-2) was modulated by ECF-Zn levels. Elevated ECF-Zn during ischemia directly bound to MMP-2 in extracellular fluid, increased its zinc content and augmented MMP-2 activity, leading to the degradation of tight junction protein in cerebral microvessels and BBB disruption. These findings suggest the role of neuronal ZnT3 in modulating ischemia-induced BBB disruption and reveal a novel mechanism of MMP-2 activation in BBB disruption after stroke, demonstrating ZnT3 as an effective target for stroke treatment.

One Co-MOF with F Active Sites for Separation of C2H2 from CO2, C2H4, and CH4.

Separating acetylene (C2H2) from other light hydrocarbons and carbon dioxide (CO2) mixtures under mild conditions poses significant challenges due to the remarkably similar properties between C2H2 and those gases. For the goal of C2H2 separation, a F-functionalized organic linker, H2F-PyIP = 2-fluorine-5-(4-pyridyl)isophthalic acid, was designed, and the corresponding metal-organic framework (MOF), {[Co2(F-PyIP)2DMF]·4H2O}n (1), was constructed. The MOF with open channels decorated by the active sites of the F groups revealed the exceptional C2H2 uptake and selectivity over CO2, C2H4, and CH4. The breakthrough experiments with different molar ratios of C2H2-C2H4, C2H2-CO2, and other gas mixtures further verified superior separation capacity of the MOF. In particular, the dynamic separation time intervals for gas mixtures (C2H2/CO2 = 1:1, 1:5, 1:10, and 1:20) fell in the range 30-44 min, highlighting the potential of the MOF for tackling the challenging C2H2/CO2 separation process.

Active Sites Decorated Nonpolar Pore-Based MOF for One-step Acquisition of C2 H4 and Recovery of C3 H6.

Herein, a 2-fold interpenetrated metal-organic framework (MOF) Zn-BPZ-TATB with accessible N/O active sites in nonpolar pore surfaces was reported for one-step C2 H4 purification from C2 H6 or C3 H6 mixtures as well as recovery of C3 H6 from C2 H6 /C3 H6 /C2 H4 mixtures. The MOF exhibits the favorable C2 H6 and C3 H6 uptakes (>100 cm3 g-1 at 298 K under 100 kPa) as well as selective adsorption of C2 H6 and C3 H6 over C2 H4 . The C3 H6 - and C2 H6 -selective feature were investigated detailedly by experimental tests as well as sorption kinetic studyies. Molecular modelling revealed the multiple interactions between C3 H6 or C2 H6 molecules and methyl groups as well as triazine rings in pores. Zn-BPZ-TATB not only can directly generate 323.4 L kg-1 and 15.4 L kg-1 of high-purity (≥99.9 %) C2 H4 from C3 H6 /C2 H4 and C2 H6 /C2 H4 mixtures, but also provide a large high-purity (≥99.5 %) C3 H6 recovery capacity of 60.1 L kg-1 from C3 H6 /C2 H4 mixtures. More importantly, the high-purity C3 H6 (≥99.5 %) and C2 H4 (≥99.9 %) with the productivities of 38.2 and 12.7 L kg-1 can be simultaneously obtained from C2 H6 /C3 H6 /C2 H4 mixtures through a single adsorption/desorption cycle.

Cu-MOFs with Rich Open Metal and F Sites for Separation of C2H2 from CO2 and CH4.

Herein, we used the 4-fluoro-[1,1'-biphenyl]-3,4',5-tricarboxylic acid (H3fbptc) ligand to design and construct a new metal-organic framework (MOF), [Cu3(fbptc)2(H2O)3]·3NMP (1), which possesses rich accessible metal sites and F functional groups in the porous walls and shows high uptake for C2H2 (119.3 cm3 g-1) and significant adsorption selectivity for C2H2 over CH4 (14.4) and CO2 (3.6) at 298 K and 100 kPa. In particular, for the gas mixtures of C2H2-CH4 and C2H2-CO2, the MOF reveals large breakthrough time ratios (C2H2/CH4 = 13, C2H2/CO2 = 5.9), which are particularly prominent in dynamic breakthrough experiments, also confirming the excellent potential for the practical separation of C2H2 from two-component mixtures (C2H2-CH4 and C2H2-CO2) and even three-component mixtures (C2H2-CO2-CH4).

Upregulated TNF-α and lactate following ERK-SGK1 activation in the spinal dorsal horn underlies chronic postsurgical pain.

Skin/muscle incision and retraction (SMIR) during surgeries can lead to chronic postsurgical pain (CPSP). The underlying mechanisms are still unclear. In the present study, we showed that SMIR of the thigh induced phosphorylation of extracellular signal-regulated kinase (ERK), followed by serum- and glucocorticoid-inducible kinase-1 (SGK1) activation in the spinal dorsal horn. Intrathecal injection of PD98059, an ERK inhibitor, or GSK650394, a SGK1 inhibitor, significantly attenuated mechanical pain hypersensitivity in SMIR rats. The level of tumor necrosis factor α and lactate in spinal cord was significantly decreased by PD98059 or GSK650394 injection. Furthermore, PD98059 decreased the activation of SGK1 in the spinal dorsal horn. These results indicate that ERK-SGK1 activation followed by proinflammatory mediator release in the spinal dorsal horn underlies CPSP.

Poly-γ-glutamic acid improved biological nitrogen fixation, water-nitrogen productivity, and nitrate residue in cotton/soybean intercropping.

BACKGROUND: Poly-γ-glutamic acid (γ-PGA) can promote crop growth and improve soil properties efficiently. However, the optimal application rate of γ-PGA in legume/non-legume intercropping systems is still unclear. A potted experiment was conducted to investigate the effects of five γ-PGA rates (0%, 0.1%, 0.2%, 0.3%, and 0.4%, represented by CK, P1, P2, P3, and P4, respectively) on biological nitrogen (N) fixation (BNF), water-N productivity, and nitrate distribution in a cotton/soybean intercropping system. RESULTS: The results showed that the growth indicators (plant height, stem diameter, leaf area index, root dry weight, root length) of cotton and soybean increased first and then decreased with increasing γ-PGA rates, and all growth indicators of cotton and soybean showed peaks in P3 and P2 treatments. The stable 15 N isotope method indicated that γ-PGA promoted the BNF capacity of soybean and soil. In particular, the percentage of N derived from the atmosphere (Ndfa) in soybean reached 61.94% in the P2 treatment. Poly-γ-glutamic acid improved the water-N productivity, and the total N partial factor productivity (NPFP) and water productivity (WP) in P3 treatment increased by 23.80% and 43.86% compared with the CK treatment. The γ-PGA mitigation of potential nitrate residue also decreased first and then increased with increasing γ-PGA rates. CONCLUSION: Multivariate regression analysis showed that 0.22% of the optimal γ-PGA application rate could obtain a higher yield and water-N productivity in cotton/soybean intercropping system simultaneously. © 2023 Society of Chemical Industry.

Enhanced lysosomal escape of cell penetrating peptide-functionalized metal-organic frameworks for co-delivery of survivin siRNA and oridonin.

In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the clinical application of siRNA faces several challenges. Insufficient efficacy, poor bioavailability, poor stability, and lack of responsiveness to a single therapy are the main problems affecting tumor therapy. Here, we designed a cell-penetrating peptide (CPP)-modified metal organic framework nanoplatform (named PEG-CPP33@ORI@survivin siRNA@ZIF-90, PEG-CPP33@NPs) for targeted co-delivery of oridonin (ORI), a natural anti-tumor active ingredient) and survivin siRNA in vivo. This can improve the stability and bioavailability of siRNA and the efficacy of siRNA monotherapy. The high drug-loading capacity and pH-sensitive properties of zeolite imidazolides endowed the PEG-CPP33@NPs with lysosomal escape abilities. The Polyethylene glycol (PEG)-conjugated CPP (PEG-CPP33) coating significantly improved the uptake in the PEG-CPP33@NPs in vitro and in vivo. The results showed that the co-delivery of ORI and survivin siRNA greatly enhanced the anti-tumor effect of PEG-CPP33@NPs, demonstrating the synergistic effect between ORI and survivin siRNA. In summary, the novel targeted nanobiological platform loaded with ORI and survivin siRNA presented herein showed great advantages in cancer therapy, and provides an attractive strategy for the synergistic application of chemotherapy and gene therapy.

15 N labeling technology reveals enhancement of nitrogen uptake and transfer by root interaction in cotton/soybean intercropping.

BACKGROUND: Biological nitrogen fixation in legumes and their transfer of nitrogen to non-legumes in legume/non-legume intercropping systems are considered to be important for the improvement of productivity. However, research on interspecific interaction and root nitrogen transfer in cotton/soybean intercropping systems has rarely been undertaken. In this study, the roots of cotton and soybean were separated with either complete root barriers (CB), using plastic film, or semi-root barriers (SB), using nylon net. No root barrier (NB) was used as the control. RESULTS: The results showed that cotton produced more above-ground dry matter (DM) than soybean. The above-ground DM and nitrogen uptake of cotton was greatest with the NB treatment. The above-ground DM and nitrogen uptake of soybean was greatest with the CB treatment. At the harvest stage, the nitrogen transfer rate from soybean to cotton was 22.47% with the SB treatment and 40.41% with the NB treatment. Interspecific root interaction increased the nitrogen transfer amount, especially for the cotton roots in the 0-15 cm soil layer and for the soybean roots in the 0-30 cm soil layer. The root distribution of soybean was the key factor affecting nitrogen transfer amount, and nitrogen transfer amount was the key factor affecting nitrogen uptake of cotton in the cotton/soybean intercropping system. CONCLUSION: These results indicated that nitrogen transfer from soybean to cotton through root interaction improved cotton above-ground DM and nitrogen uptake. © 2023 Society of Chemical Industry.

Multistep Dissolution of Lamellar Crystals Generates Superthin Amorphous Ni(OH)2 Catalyst for UOR.

Urea oxidation reaction (UOR) is an ideal replacement of the conventional anodic oxygen evolution reaction (OER) for efficient hydrogen production due to the favorable thermodynamics. However, the UOR activity is severely limited by the high oxidation potential of Ni-based catalysts to form Ni3+ , which is considered as the active site for UOR. Herein, by using in situ cryoTEM, cryo-electron tomography, and in situ Raman, combined with theoretical calculations, a multistep dissolution process of nickel molybdate hydrate is reported, whereby NiMoO4 ·xH2 O nanosheets exfoliate from the bulk NiMoO4 ·H2 O nanorods due to the dissolution of Mo species and crystalline water, and further dissolution results in superthin and amorphous nickel (II) hydroxide (ANH) flocculus catalyst. Owing to the superthin and amorphous structure, the ANH catalyst can be oxidized to NiOOH at a much lower potential than conventional Ni(OH)2 and finally exhibits more than an order of magnitude higher current density (640 mA cm-2 ), 30 times higher mass activity, 27 times higher TOF than those of Ni(OH)2 catalyst. The multistep dissolution mechanism provides an effective methodology for the preparation of highly active amorphous catalysts.

Zinc accumulation aggravates cerebral ischemia/reperfusion injury by promoting inflammation.

Intracellular zinc accumulation has been shown to be associated with neuronal death after cerebral ischemia. However, the mechanism of zinc accumulation leading to neuronal death in ischemia/reperfusion (I/R) is still unclear. Intracellular zinc signals are required for the production of proinflammatory cytokines. The present study investigated whether intracellular accumulated zinc aggravates I/R injury through inflammatory response, and inflammation-mediated neuronal apoptosis. Male Sprague-Dawley rats were treated with vehicle or zinc chelator TPEN 15 mg/kg before a 90-min middle cerebral artery occlusion (MCAO). The expressions of proinflammatory cytokines TNF-α, IL-6, NF-κB p65, and NF-κB inhibitory protein IκB-α, as well as anti-inflammatory cytokine IL-10 were assessed at 6 or 24 h after reperfusion. Our results demonstrated that the expression of TNF-α, IL-6, and NF-κB p65 increased after reperfusion, while the expression of IκB-α and IL-10 decreased, suggesting that cerebral ischemia triggers inflammatory response. Furthermore, TNF-α, NF-κB p65, and IL-10 were all colocalized with the neuron-specific nuclear protein (NeuN), suggesting that the ischemia-induced inflammatory response occurs in neurons. Moreover, TNF-α was also colocalized with the zinc-specific dyes Newport Green (NG), suggesting that intracellular accumulated zinc might be associated with neuronal inflammation following cerebral I/R. Chelating zinc with TPEN reversed the expression of TNF-α, NF-κB p65, IκB-α, IL-6, and IL-10 in ischemic rats. Besides, IL-6-positive cells were colocalized with TUNEL-positive cells in the ischemic penumbra of MCAO rats at 24 h after reperfusion, indicating that zinc accumulation following I/R might induce inflammation and inflammation-associated neuronal apoptosis. Taken together, this study demonstrates that excessive zinc activates inflammation and that the brain injury caused by zinc accumulation is at least partially due to specific neuronal apoptosis induced by inflammation, which may provide an important mechanism of cerebral I/R injury.

Nitric oxide promotes cerebral ischemia/reperfusion injury through upregulating hypoxia-inducible factor1-α-associated inflammation and apoptosis in rats.

Nitric oxide (NO) was one of the key factors to sustain hypoxia-inducible factor-1- α (HIF-1α) activation during hypoxia. However, the mechanism by which NO production promotes upregulation of HIF-1α to cause cerebral ischemia/reperfusion (I/R) injury remains unclear. The present study investigated whether eliminating NO would decrease HIF-1α level, and then reduce the subsequent inflammatory actions as well as neuronal apoptotic death in middle cerebral artery occlusion (MCAO) rats. Our results revealed that HIF-1α was correlated with 3-NT, a marker for nitrosative/oxidative stress, in the brain of MCAO rats. Treatment with NOS inhibitor L-NAME suppressed HIF-1α/3-NT double-positive cells, suggesting that HIF-1α was correlated with NO overproduction during cerebral I/R. Furthermore, pro-inflammatory cytokines TNF-α, IL-1ß and NF-κB p65 were significantly increased and colocalized with HIF-1α in the brain of MCAO rats, all of which could be attenuated by NO inhibition, suggesting that eliminating NO reduced MCAO-induced HIF-1α upregulation, which in turn exerted anti-inflammatory actions. Accordingly, cleaved caspase-3, as well as HIF-1α and TUNEL double-positive cells in ischemic brain were also decreased by L-NAME treatment. These results suggest that NO accumulation after cerebral ischemia leads to HIF-1α upregulation, which may activate pro-inflammatory cytokines, resulting in neuronal apoptotic death. These findings demonstrate a novel mechanism of NO-induced cerebral I/R injury.