Engineering Spatially Adjacent Redox Sites with Synergistic Spin Polarization Effect to Boost Photocatalytic CO2 Methanation.

The integration of oxidation and reduction half-reactions to amplify their synergy presents a considerable challenge in CO2 photoconversion. Addressing this challenge requires the construction of spatially adjacent redox sites while suppressing charge recombination at these sites. This study introduces an innovative approach that utilizes spatial synergy to enable synergistic redox reactions within atomic proximity and employs spin polarization to inhibit charge recombination. We incorporate Mn into Co3O4 as a catalyst, in which Mn sites tend to enrich holes as water activation sites, while adjacent Co sites preferentially capture electrons to activate CO2, forming a spatial synergy. The direct H transfer from H2O at Mn sites facilitates the formation of *COOH on adjacent Co sites with remarkably favorable thermodynamic energy. Notably, the incorporation of Mn induces spin polarization in the system, significantly suppressing the recombination of photogenerated charges at redox sites. This effect is further enhanced by applying an external magnetic field. By synergizing spatial synergy and spin polarization, Mn/Co3O4 exhibits a CH4 production rate of 23.4 µmol g-1 h-1 from CO2 photoreduction, showcasing a 28.8 times enhancement over Co3O4. This study first introduces spin polarization to address charge recombination issues at spatially adjacent redox sites, offering novel insights for synergistic redox photocatalytic systems.

Selective adsorption of polycyclic aromatic hydrocarbons by isostructural hydrogen-bonded organic frameworks.

Two isostructural hydrogen-bonded organic frameworks (HOFs) with 1-D hexagonal-shaped pores were crystallised using the molecules biphenyl-3,3',5,5'-tetracarboxylic acid (BPTCA) and [1,1':4',1'']terphenyl- 3,3'',5,5''-tetracarboxylic acid (TPTCA). The desolvated HOFs, named BPTCA-2 and TPTCA-2, exhibited selective adsorption towards naphthalene and anthracene, respectively, during competitive adsorption experiments.

Chrysomycin A Regulates Proliferation and Apoptosis of Neuroglioma Cells via the Akt/GSK-3ß Signaling Pathway In Vivo and In Vitro.

Glioblastoma (GBM) is a major type of primary brain tumor without ideal prognosis and it is therefore necessary to develop a novel compound possessing therapeutic effects. Chrysomycin A (Chr-A) has been reported to inhibit the proliferation, migration and invasion of U251 and U87-MG cells through the Akt/GSK-3ß signaling pathway, but the mechanism of Chr-A against glioblastoma in vivo and whether Chr-A modulates the apoptosis of neuroglioma cells is unclear. The present study aims to elucidate the potential of Chr-A against glioblastoma in vivo and how Chr-A modulates the apoptosis of neuroglioma cells. Briefly, the anti-glioblastoma activity was assessed in human glioma U87 xenografted hairless mice. Chr-A-related targets were identified via RNA-sequencing. Apoptotic ratio and caspase 3/7 activity of U251 and U87-MG cells were assayed via flow cytometry. Apoptosis-related proteins and possible molecular mechanisms were validated via Western blotting. The results showed that Chr-A treatment significantly inhibits glioblastoma progression in xenografted hairless mice, and enrichment analysis suggested that apoptosis, PI3K-Akt and Wnt signaling pathways were involved in the possible mechanisms. Chr-A increased the apoptotic ratio and the activity of caspase 3/7 in U251 and U87-MG cells. Western blotting revealed that Chr-A disturbed the balance between Bax and Bcl-2, activating a caspase cascade reaction and downregulating the expression of p-Akt and p-GSK-3ß, suggesting that Chr-A may contribute to glioblastoma regression modulating in the Akt/GSK-3ß signaling pathway to promote apoptosis of neuroglioma cells in vivo and in vitro. Therefore, Chr-A may hold therapeutic promise for glioblastoma.

Chrysomycin A Inhibits the Proliferation, Migration and Invasion of U251 and U87-MG Glioblastoma Cells to Exert Its Anti-Cancer Effects.

Chrysomycin A (Chr-A), an antibiotic from Streptomyces, is reported to have anti-tumor and anti-tuberculous activities, but its anti-glioblastoma activity and possible mechanism are not clear. Therefore, the current study was to investigate the mechanism of Chr-A against glioblastoma using U251 and U87-MG human cells. CCK8 assays, EdU-DNA synthesis assays and LDH assays were carried out to detect cell viability, proliferation and cytotoxicity of U251 and U87-MG cells, respectively. Transwell assays were performed to detect the invasion and migration abilities of glioblastoma cells. Western blot was used to validate the potential proteins. Chr-A treatment significantly inhibited the growth of glioblastoma cells and weakened the ability of cell migration and invasion by down regulating the expression of slug, MMP2 and MMP9. Furthermore, Chr-A also down regulated Akt, p-Akt, GSK-3ß, p-GSK-3ß and their downstream proteins, such as ß-catenin and c-Myc in human glioblastoma cells. In conclusion, Chr-A may inhibit the proliferation, migration and invasion of glioblastoma cells through the Akt/GSK-3ß/ß-catenin signaling pathway.

Network Pharmacology Analysis and Experimental Validation of Kaempferol in the Treatment of Ischemic Stroke by Inhibiting Apoptosis and Regulating Neuroinflammation Involving Neutrophils.

Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in the treatment of cerebral ischemia. First, network pharmacology analysis identified the biological process of kaempferol, suggesting that kaempferol may partly help in treating ischemic stroke by regulating apoptosis and inflammatory response. Then, we evaluated the efficacy of kaempferol in the acute stage of ischemic stroke and elucidated its effects and possible mechanisms on cell apoptosis and neuroinflammation involved by neutrophils. The results showed that kaempferol could significantly reduce the modified neurological severity score (mNSS), and reduce the volume of cerebral infarction and the degree of cerebral edema. In terms of anti-apoptosis, kaempferol could significantly reduce the number of TUNEL-positive cells, inhibit the expression of pro-apoptotic proteins and promote the expression of anti-apoptotic proteins. Kaempferol may play an anti-apoptotic role by up-regulating the expression level of the BDNF-TrkB-PI3K/AKT signaling pathway. In addition, we found that kaempferol inhibited neuron loss and the activation of glial cells, as well as the expression level of the inflammatory protein COX-2 and the classic pro-inflammatory signaling pathway TLR4/MyD88/NF-κB in the ischemic brain, reduced MPO activity and neutrophil counts in peripheral blood, and down-regulated neutrophil aggregation and infiltration in the ischemic brain. Western blot revealed that kaempferol down-regulated the activation of the JAK1/STAT3 signaling pathway in neutrophils and ischemic brains. Our study showed that kaempferol inhibited the activation and number of neutrophils in the rat peripheral blood and brain, which may be related to the down-regulation of the JAK1/STAT3 pathway.

ST2825, a Small Molecule Inhibitor of MyD88, Suppresses NF-κB Activation and the ROS/NLRP3/Cleaved Caspase-1 Signaling Pathway to Attenuate Lipopolysaccharide-Stimulated Neuroinflammation.

Neuroinflammation characterized by microglia activation is the mechanism of the occurrence and development of various central nervous system diseases. ST2825, as a peptide-mimetic MyD88 homodimerization inhibitor, has been identified as crucial molecule with an anti-inflammatory role in several immune cells, especially microglia. The purpose of the study was to investigate the anti-neuroinflammatory effects and the possible mechanism of ST2825. Methods: Lipopolysaccharide (LPS) was used to stimulate neuroinflammation in male BALB/c mice and BV2 microglia cells. The NO level was determined by Griess Reagents. The levels of pro-inflammatory cytokines and chemokines were determined by ELISA. The expressions of inflammatory proteins were determined by real-time PCR and Western blotting analysis. The level of ROS was detected by DCFH-DA staining. Results: In vivo, the improved levels of LPS-induced pro-inflammatory factors, including TNF-α, IL-6, IL-1ß, MCP-1 and ICAM-1 in the cortex and hippocampus, were reduced after ST2825 treatment. In vitro, the levels of LPS-induced pro-inflammatory factors, including NO, TNF-α, IL-6, IL-1ß, MCP-1, iNOS, COX2 and ROS, were remarkably decreased after ST2825 treatment. Further research found that the mechanism of its anti-neuroinflammatory effects appeared to be associated with inhibition of NF-κB activation and down-regulation of the NLRP3/cleaved caspase-1 signaling pathway. Conclusions: The current findings provide new insights into the activity and molecular mechanism of ST2825 for the treatment of neuroinflammation.

Enhanced surface properties of a graphene oxide reinforced high-entropy alloy composite prepared by spark plasma sintering.

Graphene oxide (GO) has been proved to be a potential reinforcement. In this paper, 0.3 wt%, 0.6 wt%, and 1.0 wt% GO reinforced Fe22Co24Cr20Ni23Al11 high-entropy alloy (HEA) composites and pure HEA were synthesized by spark plasma sintering (SPS) to improve the surface properties of HEA. The surface properties including hardness and wear resistance of various samples were comparatively investigated. The experimental results indicated that the surface hardness and wear resistance were enhanced as the content of GO increased (when the GO content was less than 0.6 wt%), which were attributed to the grain refinement strengthening and lubrication effect of GO. However, as the content of GO incrementally increased to 1.0 wt%, the hardness exhibited a descending trend and the coefficient of friction (COF) increased, resulting from the agglomeration of GO. Accordingly, the residual indentation and wear track of HEA/0.6 wt% GO exhibited a minimum depth, which further confirmed the results of the nanoindentation and wear tests.

TLR4-IN-C34 Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses via Downregulating TLR4/MyD88/NF-κB/NLRP3 Signaling Pathway and Reducing ROS Generation in BV2 Cells.

TLR4 signal activated by lipopolysaccharide (LPS) is involved in the pathological process of the central nervous system (CNS) diseases and the suppression of TLR4 signal may become an effective treatment. TLR4-IN-C34, a TLR4 inhibitor, is expected to become a candidate compound with anti-neuroinflammatory response. In the present study, the anti-neuroinflammatory effects and possible mechanism of TLR4-IN-C34 were investigated in BV2 microglia cells stimulated by LPS. The results showed that TLR4-IN-C34 decreased the levels of pro-inflammatory factors and chemokines including NO, TNF-α, IL-1ß, IL-6, and MCP-1 in the supernatant of LPS-stimulated BV2 cells. Further research indicated that TLR4-IN-C34 suppressed the expression or phosphorylation levels of inflammatory proteins regarding TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In addition, TLR4-IN-C34 reduced ROS production in BV2 cells after LPS treatment. In conclusion, our findings suggest that anti-neuroinflammatory activity of TLR4-IN-C34 may be interrelated to the inhibition of TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reduction of ROS generation.

Starch phosphate carbamate hydrogel based slow-release urea formulation with good water retentivity.

In this work, a novel starch phosphate carbamate hydrogel (SPC-Hydrogel) and its corresponding urea hydrogel (SPCU-Hydrogel) slow-release fertilizer (SRF) were prepared by one-step free radical copolymerization of SPC and acrylamide (AM) without and with urea addition. A series of characterization measurements including FTIR, XRD, EDS, XPS are utilized to confirm the successful formation of the SPC-Hydrogel. The SEM shows SPC-Hydrogel has a porous three-dimensional network architecture. Furthermore, SPC-Hydrogel matrix exhibits superior water absorbency achieving 80.2 g/g than that (70.5 g/g) of the native starch hydrogel (NS-Hydrogel) and desirable water retention capacity in soil with a weight loss of only 48% for 13 days. Compared with pure urea and NS based urea hydrogel (NSU-Hydrogel), the SPCU-Hydrogel releases 50.3% for 15 h, achieving an almost complete release more than 25 h in aqueous phase. While only 46.6% of urea is released in 20 days which extends about 30 days in soil column assays. The maize seedlings growth assays also present an intuitive evaluation on the prominent soil water holding and plant growth promotion role of SPCU-Hydrogel. In conclusion, the present work has demonstrated a novel strategy via preparing biomass hydrogel SRF to enhance the utilization effectiveness of fertilizer and retain soil humidity.

RKC-B1 Blocks Activation of NF-κB and NLRP3 Signaling Pathways to Suppress Neuroinflammation in LPS-Stimulated Mice.

RKC-B1 is a novel fermentation product obtained from the marine micromonospora FIM02-523A. Thus far, there have been few reports about the pharmacological activity of RKC-B1. In our present study, we investigated the anti-neuroinflammatory effects and the possible mechanism of RKC-B1 in LPS-stimulated mice. After treatment with RKC-B1, RNA-seq transcriptome of the cerebral cortex tissue was conducted to find the differentially expressed genes (DEGs). Inflammatory cytokines and proteins were evaluated by ELISA and WB. In RNA-seq analysis, there were 193 genes screened as core genes of RKC-B1 for treatment with neuroinflammation. The significant KEGG enrichment signaling pathways of these core genes were mainly included TNF signaling pathway, IL-17 signaling pathway, NOD-like receptor signaling pathway, NF-κB signaling pathway and others. The corresponding top five KEGG enrichment pathways of three main clusters in PPI network of core genes were closely related to human immune system and immune disease. The results showed that RKC-B1 reduced the levels of pro-inflammatory factors (IL-6, IL-1ß, MCP-1, and ICAM-1) and the expression of COX2 in cerebral cortex tissue. Additionally, we found that the anti-neuroinflammation activity of RKC-B1 might be related to suppress activating of NF-κB and NLRP3/cleaved caspase-1 signaling pathways. The current findings suggested that RKC-B1 might be a promising anti-neuroinflammatory agent.

Chrysomycin A Attenuates Neuroinflammation by Down-Regulating NLRP3/Cleaved Caspase-1 Signaling Pathway in LPS-Stimulated Mice and BV2 Cells.

Chrysomycin A (Chr-A), an antibiotic chrysomycin, was discovered in 1955 and is used to treat cancer and tuberculosis. In the present study, the anti-neuroinflammatory effects and possible mechanism of Chr-A in BALB/c mice and in BV2 microglia cells stimulated by lipopolysaccharide (LPS) were investigated. Firstly, the cortex tissues of mice were analyzed by RNA-seq transcriptome to identify differentially expressed genes (DEGs) regulated by Chr-A in LPS-stimulated mice. Inflammatory cytokines and inflammatory proteins were detected by enzyme-linked immunosorbent assay and Western blot. In RNAseq detection, 639 differential up-regulated genes between the control group and LPS model group and 113 differential down-regulated genes between the LPS model group and Chr-A treatment group were found, and 70 overlapping genes were identified as key genes for Chr-A against neuroinflammation. Subsequent GO biological process enrichment analysis showed that the anti-neuroinflammatory effect of Chr-A might be related to the response to cytokine, cellular response to cytokine stimulus, and regulation of immune system process. The significant signaling pathways of KEGG enrichment analysis were mainly involved in TNF signaling pathway, cytokine-cytokine receptor interaction, NF-κB signaling pathway, IL-17 signaling pathway and NOD-like receptor signaling pathway. Our results of in vivo or in vitro experiments showed that the levels of pro-inflammatory factors including NO, IL-6, IL-1ß, IL-17, TNF-α, MCP-1, CXCL12, GM-CSF and COX2 in the LPS-stimulated group were higher than those in the control group, while Chr-A reversed those conditions. Furthermore, the Western blot analysis showed that its anti-neuroinflammation appeared to be related to the down-regulation of NLRP3/cleaved caspase-1 signaling pathway. The current findings provide new insights into the activity and molecular mechanisms of Chr-A for the treatment of neuroinflammation.

Surface Engineering of g-C3 N4 by Stacked BiOBr Sheets Rich in Oxygen Vacancies for Boosting Photocatalytic Performance.

BiOBr containing surface oxygen vacancies (OVs) was prepared by a simple solvothermal method and combined with graphitic carbon nitride (g-C3 N4 ) to construct a heterojunction for photocatalytic oxidation of nitric oxide (NO) and reduction of carbon dioxide (CO2 ). The formation of the heterojunction enhanced the transfer and separation efficiency of photogenerated carriers. Furthermore, the surface OVs sufficiently exposed catalytically active sites, and enabled capture of photoexcited electrons at the surface of the catalyst. Internal recombination of photogenerated charges was also limited, which contributed to generation of more active oxygen for NO oxidation. Heterojunction and OVs worked together to form a spatial conductive network framework, which achieved 63 % NO removal, 96 % selectivity for carbonaceous products (that is, CO and CH4 ). The stability of the catalyst was confirmed by cycling experiments and X-ray diffraction and transmission electron microscopy after NO removal.

Near-Infrared Light-Enhanced Protease-Conjugated Gold Nanorods As A Photothermal Antimicrobial Agent For Elimination Of Exotoxin And Biofilms.

PURPOSE: Treatment strategies to eliminate bacterial infections have long emphasized bacterial killing as a goal. However, bacteria secrete toxins that sustain chronic disease and dead cells release DNA that can promote the spread of antibiotic resistance even when viable cells are eradicated. Meanwhile, biofilms regulated by quorum-sensing system, protect bacteria and promote the development of antibiotic resistance. Thus, all of these factors underscore the need for novel antimicrobial therapeutic treatments as alternatives to traditional antibiotics. Here, a smart material was developed that incorporated gold nanorods and an adsorbed protease (protease-conjugated gold nanorods, PGs). When illuminated with near-infrared (NIR) light, PGs functioned to physically damage bacteria, prevent biofilm and exotoxin production, eliminate pre-existing biofilm and exotoxin, and inhibit bacterial quorum-sensing systems. METHODS: PGs were incubated with suspensions of Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria followed by exposure to 808-nm NIR laser irradiation. Bacterial viability was determined using a colony-forming unit assay followed by an exploration of cell-damage mechanisms using transmission electron microscopy, scanning electron microscopy, agarose gel electrophoresis, and SDS-PAGE. Quantification of biofilm mass was performed using crystal violet staining. A commercial enterotoxin ELISA kit was used to test inhibitory and degradative effects of PGs on secreted exotoxin. RESULTS: Use of the remote-controlled antibacterial system reduced surviving bacterial populations to 3.2% and 2.1% of untreated control numbers for E. coli and S. aureus, respectively, and inhibited biofilm formation and exotoxin secretion even in the absence of NIR radiation. However, enhanced degradation of existing biofilm and exotoxin was observed when PGs were used with NIR laser irradiation. CONCLUSION: This promising new strategy achieved both the reduction of viable microorganisms and elimination of biofilm and exotoxin. Thus, this strategy addresses the long-ignored issue of persistence of bacterial residues that perpetuate chronic illness in patients even after viable bacteria have been eradicated.

Using near-infrared enhanced thermozyme and scFv dual-conjugated Au nanorods for detection and targeted photothermal treatment of Alzheimer's disease.

Investigation of targeting inhibitors of Aß aggregation, heme-Aß peroxidase-like activity and efficient detectors of Aß aggregation, are of therapeutic value and diagnostics significance for the treatment of Alzheimer's disease (AD). Due to the complex pathogenesis of AD, theranostics treatment with multiple functions are necessary. Herein we constructed the NIR absorption property of gold nanorods (GNRs) loaded with single chain variable fragment (scFv) 12B4 and thermophilic acylpeptide hydrolase (APH) ST0779 as a smart theranostic complex (GNRs-APH-scFv, GAS), which possesses both rapid detection of Aß aggregates and NIR photothermal treatment that effectively disassembles Aß aggregates and inhibits Aß-mediated toxicity. Methods: We screened targeting anti-Aß scFv 12B4 and thermophilic acylpeptide hydrolase as amyloid-degrading enzyme, synthesized GAS gold nanorods complex. The GAS was evalued by Aß inhibition and disaggregation assays, Aß detection assays, Aß mediated toxicity assays in vitro. In vivo, delaying Aß-induced paralysis in AD model of Caenorhabditis elegans was also tested by GAS. Results: In vitro, GAS has a synergistic effect to inhibit and disassociate Aß aggregates, in addition to decrease heme-Aß peroxidase-like activity. In cultured cells, treatment with GAS reduces Aß-induced cytotoxicity, while also delaying Aß-mediated paralysis in CL4176 C.elegans model of AD. Furthermore, the photothermal effect of the GAS upon NIR laser irradiation not only helps disassociate the Aß aggregates but also boosts APH activity to clear Aß. The GAS, as a targeting detector and inhibitor, allows real-time detection of Aß aggregates. Conclusion: These results firstly highlight the combination of scFv, APH and nanoparticles to be theranostic AD drugs. Taken together, our strategy provides a new thought into the design of smart compounds for use as efficiently therapeutic and preventive agents against AD. Moreover, our design provides broad prospects of biomedical strategy for further theranostics application in those diseases caused by abnormal protein.

ZIF-67-Derived 3D Hollow Mesoporous Crystalline Co3 O4 Wrapped by 2D g-C3 N4 Nanosheets for Photocatalytic Removal of Nitric Oxide.

ZIF-67-derived 3D hollow mesoporous crystalline Co3 O4 wrapped by 2D graphitic carbon nitride (g-C3 N4 ) nanosheets are prepared by low temperature annealing, and are used for the photocatalytic oxidation of nitric oxide (NO) at a concentration of 600 ppb. The p-n heterojunction between Co3 O4 and g-C3 N4 forms a spatial conductive network frame and results in a broad visible light response range. The hollow mesoporous structure of Co3 O4 contributes to the circulation and adsorption of NO, and the large specific surface area exposes abundant active sites for the reaction of active species. A maximum NO degradation efficiency of 57% is achieved by adjusting the mass of the Co3 O4 precursor. Cycling tests and X-ray diffraction indicate the high stability and recyclability of the composite, making it promising in environmental purification applications.

Multiple Antigenic Peptide System Coupled with Amyloid Beta Protein Epitopes As An Immunization Approach to Treat Alzheimer's Disease.

Latest studies suggest that Alzheimer's disease (AD) is one of the "four big killers" that threaten the health of the elderly. AD affects about 46 million people across the world, and there is a critical need for research on new therapies for treating AD. The purpose of the present study was to develop and evaluate immunogens to elicit antibodies against the formation of amyloid beta protein (Aß), a pathological hallmark of AD, as a therapeutic strategy in AD. In this study, serial potential immunogenic epitopes were screened according to the Aß sequence. The screened linear epitopes on the Aß C-terminal fragment were coupled with either the carrier protein keyhole limpet hemocyanin (KLH) or the synthesized 4-branch peptide (MAP4). MAP4 immunogens could effectively elicit immunogenicity against Aß1-42 monomer and fiber in Balb/C mice. Furthermore, MAP4 sera could also effectively inhibit the formation of the Aß1-42 fiber. Interestingly, one of the MAP4 sera was able to depolymerize the Aß1-42 fibers that had aggregated. The monoclonal antibody, 1H7, was shown to inhibit the formation of Aß1-42 fiber. MAP4 carrier may provide benefits over current immunization strategies, as it does not induce inflammation. In conclusion, the MAP4-Aß conjugates offer a promising approach for the development of a safe and effective AD vaccine.

Baicalin exerts antidepressant effects through Akt/FOXG1 pathway promoting neuronal differentiation and survival.

BACKGROUND AND AIMS: Impaired neurogenesis in hippocampus may contribute to a variety of neurological diseases, such as Alzheimer's disease and depression. Baicalin (BA), which is mainly isolated from the root Scutellaria baicalensis Georgi (traditional Chinese herb), which was reported to facilitate neurogenesis, but how to play the role and the underlying molecular mechanisms are still unknown. MAIN METHODS: In this study, we adopted the chronic unpredictable mild stress (CUMS)-induced mouse model of depression, and then explore antidepressant-like effects and possible molecular mechanisms. KEY FINDINGS: We found that BA significantly increased sucrose consumption in sucrose preference test, the number of crossing in open filed test and attenuated immobility time in tail suspension test. Additionally, BA administration notably promoted neuronal differentiation and the number of DCX+ cells. Moreover, BA facilitated immature neurons develop into mature neurons and their survival. FOXG1, a transcription factor gene, which is crucial for mammalian telencephalon development, specifically stimulates dendrite elongation. BA could reverse the decrease of p-Akt, FOXG1 and FGF2 caused by CUMS-induced. Additionally, the expression of FOXG1 and FGF2 significantly decreased when the Akt pathway were inhibited by LY294002 in SH-SY5Y cells. Interestingly, BA failed to counteract the decline. SIGNIFICANCE: These results suggest that BA could promote the differentiation of neurons, which transformation into mature neurons and their survival via the Akt/FOXG1 pathway to exert antidepressant effects.

Effects of insulin on transcriptional response and permeability in an in vitro model of human blood-brain barrier.

Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. Active and passive immune therapies targeting beta amyloid (Aß) have shown very limited evidence in human studies of clinical benefits from these approaches. Epidemiological studies have shown that subjects with type 2 diabetes (T2D) are at higher risk of developing AD. However, whether and how these two conditions are causally linked is unknown. With the purpose of confirming the relationship between T2D and AD, this study specifically focused on effects of insulin in an in vitro model of the human blood-brain barrier (BBB) and on potential mechanisms of action in the treatment of AD. By using a series of assays to establish a BBB model, we demonstrated that insulin treatment alone could induce the increase of brain endothelial barrier properties. The transcriptional response of hCMEC/D3 cells to activation with different concentrations of insulin was determined by RT-PCR, and expression levels of genes involved in the control of barrier permeability, including inter-brain endothelial junctions, integrin-focal adhesions complexes, and transporter system, were found to be altered by the treatment. Notably, the influence of insulin on expression of the ATP-binding cassette (ABC) transporter which contributes to the clearance of Aß was investigated. Insulin up-regulated adherens junction and tight junction transmembrane proteins, as well as the ABC transporter. By treatment with insulin, the models have major advantages: it is fast, it has low cost, it is fit for considerable samples, and its conditions are under control.

A novel antimicrobial peptide derived from membrane-proximal external region of human immunodeficiency virus type 1.

With increasing microbial drug resistance worldwide, antimicrobial peptides (AMPs) are considered promising alternatives to addressing this problem. In this study, a series of synthetic peptides were designed based on the membrane-disrupting properties of the membrane-proximal external region (MPER) of human immunodeficiency virus type 1 (HIV-1) envelope protein. The peptide AP16-A was found to exhibit the most effective antimicrobial activities against both Gram-negative and Gram-positive bacteria. The minimal bactericidal concentration (MBC) of AP16-A ranged from 2 µg/ml to 16 µg/ml. AP16-A had no detectable cytotoxicity in various tissue cultures and a mouse model. Furthermore, results of confocal fluorescence microscopy and the SYTOX Green uptake assay indicated that AP16-A killed Gram-negative bacteria by the combined effects of relatively slow membrane permeabilization and interaction with an intracellular target, while it killed Gram-positive bacteria by a fast membrane permeabilization process, which achieved relatively more rapid bacterial killing kinetics. The results of this study support the potential use of AP16-A as an AMP.

Elicitation of HIV-1 neutralizing antibodies by presentation of 4E10 and 10E8 epitopes on Norovirus P particles.

Eliciting efficient broadly neutralizing antibodies (BnAbs) is a major goal in vaccine development against human immunodeficiency virus type 1 (HIV-1). Conserved epitopes in the membrane-proximal external region (MPER) of HIV-1 are a significant target. In this study, Norovirus P particles (NoV PPs) were used as carriers to display conformational 4E10 and 10E8 epitopes in different patterns with an appropriate linker. Immune responses to the recombinant NoV PPs were characterized in guinea pigs and Balb/c mice and could induce high levels of MPER-binding antibodies. Modest neutralizing activities could be detected in sera of guinea pigs but not of Balb/c mice. The 4E10 or 10E8 epitopes dispersed on three loops on the outermost surface of NoV PPs (4E10-loop123 PP or 10E8-loop123 PP) elicited higher neutralizing activities than the equivalent number of epitopes presented on loop 2 only (4E10-3loop2 PP or 10E8-3loop2 PP). The epitopes on different loops of the PP were well-exposed and likely formed an appropriate conformation to induce neutralizing antibodies. Although sera of immunized guinea pigs could neutralize several HIV envelope-pseudoviruses, a vaccine candidate for efficiently inducing HIV-1 BnAbs remains to be developed.