Gα13 Mediates Transendothelial Migration of Neutrophils by Promoting Integrin-Dependent Motility without Affecting Directionality.

Neutrophil migration requires ß2 integrins and chemoattractant receptor signaling for motility and directionality. G protein subunit Gα13 can facilitate cell migration by mediating RhoA activation induced by G protein-coupled receptors. However, the possible role of Gα13-integrin interaction in migration is unclear. In this study, we show that Gα13 -/- neutrophils are deficient in transendothelial migration and migration on ß2 integrin ligand ICAM-1. However, unlike G protein-coupled receptors and integrin inside-out signaling pathways, Gα13 is important in migration velocity and neutrophil spreading but not in directionality nor cell adhesion. Importantly, neutrophil recruitment in vivo was also inhibited in Gα13 -/- mice, suggesting the importance of Gα13 in transendothelial migration of neutrophils in vitro and in vivo. Furthermore, a synthetic peptide (MB2mP6) derived from the Gα13 binding site of ß2 inhibited Gα13-ß2 interaction and Gα13-mediated transient RhoA inhibition in neutrophils, suggesting that this peptide inhibited integrin outside-in signaling. MB2mP6 inhibited migration of control neutrophils through endothelial cell monolayers or ICAM-1-coated filters, but was without further effect on Gα13 -/- neutrophils. It also inhibited integrin-dependent neutrophil migration velocity without affecting directionality. In vivo, MB2mP6 markedly inhibited neutrophil infiltration into the cardiac tissues induced by ischemia/reperfusion injury. Thus, Gα13-dependent outside-in signaling enables integrin-dependent neutrophil motility without affecting directionality and may be a new therapeutic target for inhibiting neutrophil trafficking but not adhesion.

Shear and Integrin Outside-In Signaling Activate NADPH-Oxidase 2 to Promote Platelet Activation.

[Figure: see text].

MicroRNA-762 Modulates Lipopolysaccharide-induced Acute Lung Injury via SIRT7.

BACKGROUND: Inflammation and oxidative stress contribute to the pathogenesis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). MicroRNA-762 (miR-762) has been implicated in the progression of inflammation and oxidative stress; however, its role in ALI remains unclear. In this study, we aim to investigate the role and underlying mechanisms of miR-762 in LPS-induced ALI. METHODS: Mice were intravenously injected with miR-762 antagomir, agomir or the negative controls for 3 consecutive days and then received a single intratracheal instillation of LPS (5 mg/kg) for 12 h to establish ALI model. Adenoviral vectors were used to knock down the endogenous SIRT7 expression. RESULTS: An increased miR-762 expression was detected in LPS-treated lungs. miR-762 antagomir significantly reduced inflammation, oxidative stress and ALI in mice, while the mice with miR-762 agomir treatment exhibited a deleterious phenotype. Besides, we found that SIRT7 upregulation was essential for the pulmonoprotective effects of miR-762 antagomir, and that SIRT7 silence completely abolished the anti-inflammatory and anti-oxidant capacities of miR-762 antagomir. CONCLUSION: miR-762 is implicated in the pathogenesis of LPS-induced ALI via modulating inflammation and oxidative stress, which depends on its regulation of SIRT7 expression. It might be a valuable therapeutic target for the treatment of ALI.

The function and mechanism of microRNA-92a-3p in lipopolysaccharide-induced acute lung injury.

OBJECTIVES: Sepsis-associated acute lung injury (ALI) is a clinically severe respiratory disorder and remains the leading cause of multiple organ failure and mortality. Herein, we used lipopolysaccharide (LPS) to generate sepsis-induced ALI and try to explore the role and mechanism of microRNA-92a-3p (miR-92a-3p) in this process. METHODS: Mice were intravenously injected with miR-92a-3p agomir, antagomir and negative controls for 3 consecutive days and then were intratracheally instillated by LPS (5 mg/kg) for 12 h. To knock down the endogenous A-kinase anchoring protein 1 (AKAP1), mice were intratracheally injected with recombinant adenovirus carrying the short hairpin RNA targeting AKAP1 (shAkap1) at 1 week before LPS administration. RESULTS: miR-92a-3p level was significantly upregulated in the lungs by LPS injection. miR-92a-3p antagomir reduced LPS-induced intrapulmonary inflammation and oxidative stress, thereby preventing pulmonary injury and dysfunction. In contrast, miR-92a-3p agomir aggravated LPS-induced intrapulmonary inflammation, oxidative stress, pulmonary injury and dysfunction. Moreover, we reported that AKAP1 upregulation was required for the beneficial effects of miR-92a-3p antagomir, and that AKAP1 knockdown completely abolished the anti-inflammatory and antioxidant capacities of miR-92a-3p antagomir. CONCLUSION: Our data identify that miR-92a-3p modulates LPS-induced intrapulmonary inflammation, oxidative stress and ALI via AKAP1 in mice.

The Kinesin Light Chain-Related Protein PAT1 Promotes Superoxide Anion Production in Human Phagocytes.

Superoxide anion production by the phagocyte NADPH oxidase plays a crucial role in host defenses and inflammatory reaction. The phagocyte NADPH oxidase is composed of cytosolic components (p40phox, p47phox, p67phox, and Rac1/2) and the membrane flavocytochrome b558, which is composed of two proteins: p22phox and gp91phox/NOX2. p22phox plays a crucial role in the stabilization of gp91phox in phagocytes and is also a docking site for p47phox during activation. In the current study, we have used a yeast two-hybrid approach to identify unknown partners of p22phox. Using the cytosolic C-terminal region of p22phox as bait to screen a human spleen cDNA library, we identified the protein interacting with amyloid precursor protein tail 1 (PAT1) as a potential partner of p22phox. The interaction between p22phox and PAT1 was further confirmed by in vitro GST pulldown and overlay assays and in intact neutrophils and COSphox cells by coimmunoprecipitation. We demonstrated that PAT1 is expressed in human neutrophils and monocytes and colocalizes with p22phox, as shown by confocal microscopy. Overexpression of PAT1 in human monocytes and in COSphox cells increased superoxide anion production and depletion of PAT1 by specific small interfering RNA inhibited this process. These data clearly identify PAT1 as a novel regulator of NADPH oxidase activation and superoxide anion production, a key phagocyte function.

Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation.

It is currently unclear why agonist-stimulated platelets require shear force to efficiently externalize the procoagulant phospholipid phosphatidylserine (PS) and release PS-exposed microvesicles (MVs). We reveal that integrin outside-in signaling is an important mechanism for this requirement. PS exposure and MV release were inhibited in ß3-/- platelets or by integrin antagonists. The impaired MV release and PS exposure in ß3-/- platelets were rescued by expression of wild-type ß3 but not a Gα13 binding-deficient ß3 mutant (E733EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of Gα13 or Src also diminished agonist/shear-dependent PS exposure and MV release, further indicating a role for integrin outside-in signaling. PS exposure in activated platelets was induced by application of pulling force via an integrin ligand, which was abolished by inhibiting Gα13-integrin interaction, suggesting that Gα13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of Gα13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of Gα13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, ß3 integrins serve as a shear sensor activating the Gα13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of Gα13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation.

Serum amyloid A promotes LPS clearance and suppresses LPS-induced inflammation and tissue injury.

Lipopolysaccharide (LPS) is a major microbial mediator for tissue injury and sepsis resulting from Gram-negative bacterial infection. LPS is an external factor that induces robust expression of serum amyloid A (SAA), a major constituent of the acute-phase proteins, but the relationship between SAA expression and LPS-induced tissue injury remains unclear. Here, we report that mice with inducible transgenic expression of human SAA1 are partially protected against inflammatory response and lung injury caused by LPS and cecal ligation and puncture (CLP). In comparison, transgenic SAA1 does not attenuate TNFα-induced lung inflammation and injury. The SAA1 expression level correlates inversely with the endotoxin concentrations in serum and lung tissues since SAA1 binds directly to LPS to form a complex that promotes LPS uptake by macrophages. Disruption of the SAA1-LPS interaction with a SAA1-derived peptide partially reduces the protective effect and exacerbates inflammation. These findings demonstrate that acute-phase SAA provides innate feedback protection against LPS-induced inflammation and tissue injury.

Effects of milk fat, casein, and serum protein concentrations on sensory properties of milk-based beverages.

Our goal was to determine the effect of systematically controlled variation in milk fat, true protein, casein, and serum protein concentrations on the sensory color, flavor and texture properties, instrumental color and viscosity, and milk fat globule size distribution of milk-based beverages. Beverage formulations were based on a complete balanced 3-factor (fat, true protein, and casein as a percentage of true protein) design with 3 fat levels (0.2, 1.0, and 2.0%), 4 true protein (TP) levels (3.00, 3.67, 4.34, and 5.00%) within each fat level, and 5 casein as a percentage of true protein (CN%TP) levels (5, 25, 50, 75, and 80%) within each protein level (for a total of 60 formulations within each of 2 replicates). Instrumental measures of Hunter L and a values and Commission Internationale de l'Éclairage (CIE) b* values, instrumental viscosity, particle size, flavor, sensory texture and sensory appearance evaluations were done on each pasteurized/homogenized beverage formulation. Within each of the 3 fat levels, higher serum protein concentration drove higher aroma intensity, sweet aromatic, cooked/sulfur, cardboard/doughy flavors, and sensory yellowness scores, whereas higher casein concentration drove higher instrumental viscosity in milk protein beverages. Increasing serum protein concentration increased yellowness, sweet aromatic, aroma intensity, cooked/sulfur, and cardboard/doughy flavors across all fat levels and also had the largest effect on L, a, and b* values, sensory whiteness, and opacity within each fat level. Increases in true protein increased throat cling and astringency intensities. Increases in fat concentration were correlated with higher L, a, and b* values, larger particle size, and increased sensory whiteness, mouth coating, cooked/milky, and milkfat flavors. Multiple linear regression of L, a, and b* values produced better predictions of sensory whiteness and yellowness of pasteurized milk protein beverages than simple linear regression of L or b* values, respectively. Formulating milk protein beverages to a higher true protein level increased astringency regardless of fat level. When formulating milk protein beverages, a product developer has a wide range of milk-based protein ingredient choices that differ in price and change price relationship across time. Understanding the expected relative effect of different milk protein ingredients on the textural and flavor characteristics of milk-based beverages could be used to help guide product reformulation decisions and ingredient choices to achieve a specific sensory profile while controlling total beverage ingredient cost.

Effect of pasteurization and fat, protein, casein to serum protein ratio, and milk temperature on milk beverage color and viscosity.

Our goal was to determine the effect of pasteurization-homogenization, fat and protein concentration, proportion of milk protein that is casein and serum protein, and temperature on sensory and instrumental measures of viscosity and color of milk-based beverages. A second goal was to use instrumental measures of whiteness and yellowness to predict sensory measures of whiteness and yellowness. A complete balanced 3 factor (fat, true protein, and casein as a percentage of true protein) design was applied with 3 levels of fat (0.2, 1.0 and 2.0%), 4 levels of true protein (3.00, 3.67, 4.34, and 5.00%) within each fat level, and 5 levels of casein as a percentage of true protein (CN%TP; 5, 25, 50, 75, and 80%) within each protein level for beverage formulation. Instrumental color and viscosity, and visual sensory color analyses were done on each beverage formulation. For unpasteurized beverages across 3 fat levels (0.2, 1, and 2%), changes in CN%TP had the largest effect on L values, sensory whiteness, opacity, color intensity, and yellowness, whereas changes in fat concentration had a stronger influence on a and b* values. Increasing CN%TP from 5 to 80% increased L values, sensory whiteness, and opacity, and decreased sensory color intensity and yellowness. The a and b* values increased with increasing fat concentration. For unpasteurized milk protein beverages within each fat level, variation in CN%TP dominated the changes in L values, sensory whiteness, and opacity, and decreased a and b* values, sensory color intensity, and yellowness. The effect of heat (pasteurization and homogenization) and its interaction terms had the second largest effect on color of milk protein beverages with respect to instrumental color data and sensory appearance attributes. Heat increased L values, sensory whiteness, and opacity, and decreased a and b* values, sensory color intensity, and yellowness. Increases in temperature decreased instrumental viscosity and changes in protein concentration and CN%TP had a greater effect on instrument viscosity data within each temperature (4, 20, and 50°C) than fat. Sensory perception of yellowness was not highly correlated with b* values. Multiple linear regressions of L, a, and b* values produced more robust predictions for both sensory whiteness and yellowness than simple linear regression with L and b* values alone, and may be a useful instrumental approach for quality control of sensory whiteness and yellowness of milk protein beverages.

Propylene Polymerization Catalyzed by Metallocene /Methylaluminoxane Systems on Rice Husk Ash.

Silica generated from agricultural waste is more cost effective and environmentally friendly than silica from traditional commercial processes. In this study, spherical silica particles with a diameter of around 120 nm were fabricated from rice husk ash (RHA), and were used to support two bridged zirconcene complexes ((I) Me2Si(Ind)2ZrCl2 and (II) C2H4(Ind)2ZrCl2 ) for catalyzing propylene polymerization to produce polypropylene (PP) in a temperature range of 40-70 C and in a solution methylaluminoxane (MAO) range of 0.1-0.6 wt%. Due to its small particle size, RHA-supported catalyst exhibited much higher activity than micro-sized commercial silica-supported catalyst. At the optimum polymerization temperature of 55 C and with increasing MAO concentration, polymer yield increased proportionally with the increase of number average molecular weight. Compared to (I), (II) produced more polymer molecules but with much shorter chain length, ascribed to the differences of Zr loading and bridge structure. With increasing polymerization temperature, polymer molecular weight decreased rapidly and resulted in a significant change of PP assembly morphology (shape and size). At 55 C, (I) produced uniform PP assemblies which had dumbbell-like structure with a smooth middle section and two fibrillar ends, while (II) produced spherical PP particles. The dumbbell middle part width was essentially identical to the Batchelor microscale proposed in turbulent mixing theory.

Discrimination of Natural Mature Acacia Honey Based on Multi-Physicochemical Parameters Combined with Chemometric Analysis.

Honey maturity is an important factor in evaluating the quality of honey. We established a method for the identification of natural mature acacia honey with eighteen physicochemical parameters combined with chemometric analysis. The analysis of variance showed significant differences between mature and immature acacia honey in physicochemical parameters. The principal component analysis explained 82.64% of the variance among samples, and indicated that total phenolic content, total protein content, and total sugar (glucose, fructose, sucrose) were the major variables. The cluster analysis and orthogonal partial least squares-discriminant analysis demonstrated that samples were grouped in relation to the maturity coinciding with the results of the principal component analysis. Meanwhile, the 35 test samples were classified with 100% accuracy with the method of multi-physicochemical parameters combined with chemometric analysis. All the results presented above proved the possibility of identifying mature acacia honey and immature acacia honey according to the chemometric analysis based on the multi-physicochemical parameters.

Enhanced DNA Binding and Photocleavage Abilities of ß-Cyclodextrin Appended Ru(II) Complex through Supramolecular Strategy.

Photosensitizers with high photocleavage ability are urgently needed to improve photodynamic therapy efficacy. Herein, a supramolecular complex was constructed through host-guest self-assembly using hexa-ß-CD-appended ruthenium polypyridyl (6CD-Ru) and adamantane-modified anthracene (ADA-AN) in water. The targeted DNA-intercalation of peripheral anthracenes can remarkably enhance photocleavage ability and antitumor activity of the complex irradiated with visible light.

Hunter versus CIE color measurement systems for analysis of milk-based beverages.

The objective of our work was to determine the differences in sensitivity of Hunter and International Commission on Illumination (CIE) methods at 2 different viewer angles (2 and 10°) for measurement of whiteness, red/green, and blue/yellow color of milk-based beverages over a range of composition. Sixty combinations of milk-based beverages were formulated (2 replicates) with a range of fat level from 0.2 to 2%, true protein level from 3 to 5%, and casein as a percent of true protein from 5 to 80% to provide a wide range of milk-based beverage color. In addition, commercial skim, 1 and 2% fat high-temperature, short-time pasteurized fluid milks were analyzed. All beverage formulations were HTST pasteurized and cooled to 4°C before analysis. Color measurement viewer angle (2 vs. 10°) had very little effect on objective color measures of milk-based beverages with a wide range of composition for either the Hunter or CIE color measurement system. Temperature (4, 20, and 50°C) of color measurement had a large effect on the results of color measurement in both the Hunter and CIE measurement systems. The effect of milk beverage temperature on color measurement results was the largest for skim milk and the least for 2% fat milk. This highlights the need for proper control of beverage serving temperature for sensory panel analysis of milk-based beverages with very low fat content and for control of milk temperature when doing objective color analysis for quality control in manufacture of milk-based beverages. The Hunter system of color measurement was more sensitive to differences in whiteness among milk-based beverages than the CIE system, whereas the CIE system was much more sensitive to differences in yellowness among milk-based beverages. There was little difference between the Hunter and CIE system in sensitivity to green/red color of milk-based beverages. In defining milk-based beverage product specifications for objective color measures for dairy product manufacturers, the viewer angle, color measurement system (CIE vs. Hunter), and sample measurement temperature should be specified along with type of illuminant.

The Protective Effect of Whole Honey and Phenolic Extract on Oxidative DNA Damage in Mice Lymphocytes Using Comet Assay.

In this study, the antioxidant activity and the protective effect against hydrogen peroxide-induced DNA damage were assessed for five honeys of different botanical origin. Seven phenolic acids were detected in the honey samples. Ferulic acid was the most abundant phenolic acid detected in longan honey, jujube honey and buckwheat honey. Ellagic acid, p-hydroxybenzoic acid and protocatechuic acid were the main phenolic acids detected in vitex honey. Of all honey samples tested, the highest total phenolic content and antioxidant activity were found in buckwheat honey, whereas the lowest total phenolic content and antioxidant activity were found in locust honey. Treatment with hydrogen peroxide induced a 62% increase in tail DNA in mice lymphocytes, and all studied honeys significantly inhibited this effect (P < 0.05). The buckwheat honey with higher antioxidant capability also exhibited super protective effect than others. Phenolic extracts of honey displayed greater protective effects than whole honey in comet assay. The hydrogen peroxide-generated increase in 8-hydroxy-2-deoxyguanosine (8-OHdG) was effectively inhibited by the honeys studied (P < 0.05). Moreover, a dose-effect relationship between honey concentration and its protective effect was clearly observed in this study. It can be deduced that phenolic acids of honey can penetrate into lymphocytes and protect DNA from oxidative damage by scavenging hydrogen peroxide and/or chelating ferrous ions.

The protective role of autophagy in experimental osteoarthritis, and the therapeutic effects of Torin 1 on osteoarthritis by activating autophagy.

BACKGROUND: Recent studies have shown that autophagy was associated with the development of osteoarthritis (OA), the purpose of this research was to determine the exact role of autophagy in OA and investigate effective therapeutic drugs to inhibit the pathological progression of OA. METHODS: In this study, a cellular OA model was generated by stimulating SW1353 cells with IL-1ß and a rabbit OA model was established by intra-articular injection of collagenase, followed by treatment with Torin 1 or 3-Methyladenine (3-MA). The mRNA expression levels of VEGF, MMP-13 and TIMP-1 were determined by quantitative real-time PCR. The caitilage degeneration was examined by histological evaluation, chondrocytes degeneration and autophagosomes were observed by transmission electron microscopy. Expression levels of Beclin-1 and LC3 were evaluated by western blotting and immunofluorescence. RESULTS: The degeneration of SW 1353 cells, cartilage and chondrocytes was related to the loss of autophagy in experimental OA. 3-MA increased the severity of degeneration of cells and cartilage by autophagy inhibition, while Torin 1 reduced that by autophagy activation. CONCLUSIONS: The loss of autophagy is linked with the experimental OA and autophagy may play a protective role in the pathogenesis of OA. Treatment of Torin 1 can inhibit the degenerative changes of experimental OA by activating autophagy and it may be a useful therapeutic drug for OA.

Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway.

Interleukin-33 (IL-33), an IL-1 family cytokine and nuclear alarmin, is constitutively expressed in epithelial barrier tissues and human blood vessels. However, little is known about the induced expression of IL-33 in monocytes and macrophages, which are major cytokine-producing cells of the innate immune system. Here, we report the induction of IL33 expression in both human monocytes and mouse macrophages from C57BL/6 mice by the acute-phase protein serum amyloid A (SAA). SAA-induced transcriptional activation of the Il33 gene, resulting in nuclear accumulation of the IL-33 protein. TLR2, one of the SAA receptors, was primarily responsible for the induction of IL-33. Progressive deletion of the human IL-33 promoter led to the identification of two potential binding sites for interferon regulatory factor 7 (IRF7), one of which (-277/-257) was found to be important for SAA-stimulated IL-33 promoter activity. IRF7 was recruited to the IL-33 promoter upon SAA stimulation, and silencing IRF7 expression in THP-1 cells abrogated SAA-induced Il33 expression. SAA also promoted an interaction between TNF receptor-associated factor 6 and IRF7. Taken together, these results identify IRF7 as a critical transcription factor for SAA-induced Il33 expression in monocytes and macrophages.

Experimental and DFT studies on the aggregation behavior of imidazolium-based surface-active ionic liquids with aromatic counterions in aqueous solution.

Two imidazolium-based surface-active ionic liquids with aromatic counterions, namely, 1-dodecyl-3-methylimidazolium salicylate (C12mimSal) and 1-dodecyl-3-methylimidazolium 3-hydroxy-2-naphthoate (C12mimHNC), were synthesized, and their aggregate behavior in aqueous solutions was systematically explored. Surface tension and conductivity measurements indicate that both C12mimSal and C12mimHNC show superior surface activity compared to the common imidazolium-based SAIL with the same hydrocarbon chain length, 1-dodecyl-3-methylimidazolium bromide (C12mimBr). This result demonstrates that the incorporation of aromatic counterions favors the formation of micelles. C12mimHNC displays a higher surface activity than C12mimSal, resulting from the different hydrophobicities of the counterions. In comparison with C12mimBr, C12mimSal not only can form hexagonal liquid-crystalline phase (H1) in aqueous solution, but also exhibits a broad region of cubic liquid-crystalline phase (V2) at higher concentration. As for the C12mimHNC/H2O system, a lamellar liquid-crystalline (L(α)) phase was observed. These lyotropic liquid crystals (LLCs) were characterized by polarized optical microscopy (POM) and small-angle X-ray scattering (SAXS). Structural parameters calculated from SAXS patterns suggest that a higher concentration of the SAIL leads to a denser arrangement whereas a higher temperature results in the opposite effect. The rheological results manifest that the formed H1 phase in the C12mimSal/H2O system exhibits an impressive viscoelastic behavior, indicated by a modulus (G' and G″) that is 1 order of magnitude higher than that of C12mimBr. Density functional theory (DFT) calculations reveal that C12mimSal has a more negative interaction energy with a water molecule and the Sal(-) counterion presents a stronger electronegativity than the HNC(-) counterion. The specific phase behavior of the C12mimSal/H2O and C12mimHNC/H2O systems can be attributed to the strong synergic interaction between the imidazolium cation and the aromatic counterion, including electrostatic attraction, hydrophobic interaction, and especially π-π interaction.

Effect of 24-epibrassinolide treatment on the metabolism of eggplant fruits in relation to development of pulp browning under chilling stress.

This study aims to investigate the effect of 24-epibrassinolide (EBR) on the metabolism in relation to development of chilling injury-induced pulp browning of eggplant fruit. The fruits were dipped for 10 min in solutions containing 10 µmM EBR and then stored at 1 °C for 15 days. Chilling injury index, weight loss, electrolyte leakage and malondialdehyde (MDA) content of control fruit increased during storage. Chilling injury improved phenylalanine ammonia-lyase (PAL), polyphenol oxidase (PPO), and peroxidase (POD) activities, which are correlated with the increase of total phenolic content and pulp browning of eggplant fruit. The inhibition of pulp browning by EBR treatment was possibly attributed to preserving the cell membrane integrity, reducing total phenolic content, and decreasing PAL, PPO, and POD activities. These results suggest that EBR may inhibit chilling injury and pulp browning in eggplant fruit during cold storage.

Design, synthesis and characterization of fMLF-mimicking AApeptides.

The tripeptide N-formyl-Met-Leu-Phe (fMLF) is a potent neutrophil chemoattractant and the reference agonist for the G protein-coupled N-formylpeptide receptor (FPR). As it plays a very important role in host defense and inflammation, there has been considerable interest in the development of fMLF analogues in the hope of identifying potential therapeutic agents. Herein we report the design, synthesis, and evaluation of AApeptides that mimic the structure and function of fMLF. The lead AApeptides induced calcium mobilization and mitogen-activated protein kinase (MAPK) signal transduction pathways in FPR-transfected rat basophilic leukemic (RBL) cells. More intriguingly, at high concentrations, certain AApeptides were more effective than fMLF in the induction of calcium mobilization. Their agonistic activity is further supported by their ability to stimulate chemotaxis and the production of superoxide in HL-60 cells. Similarly to fMLF, these AApeptides are much more selective towards FPR1 than FPR2. These results suggest that the fMLF-mimicking AApeptides might emerge as a new class of therapeutic agents that target FPRs.

Gels and lyotropic liquid crystals: using an imidazolium-based catanionic surfactant in binary solvents.

The self-assembly behavior of an imidazolium-based catanionic surfactant, 1-butyl-3-methylimidazolium dodecylsulfate ([C4mim][C12H25SO4]), was investigated in water-ethylammonium nitrate (EAN) mixed solvents with different volume ratios. It is particular interesting that this simple surfactant could not only form lyotropic liquid crystals (LLC) with multimesophases, i.e., normal hexagonal (H1), lamellar liquid crystal (Lα), and reverse bicontinuous cubic phase (V2), in the water-rich environment but also act as an efficient low-molecular-weight gelator (LMWG) which gelated EAN-abundant binary media in a broad concentration range. The peculiar nanodisk cluster morphology of gels composed of similar bilayer units was first observed. FT-IR spectra and density functional theory (DFT) calculations reveal that strong H bonding and electrostatic interactions between EAN and the headgroups of [C4mim][C12H25SO4] are primarily responsible for gelation. The self-assembled gels displayed excellent mechanical strength and a thermoreversible sol-gel transition. It is for the first time that a rich variety of controllable ordered aggregates could be observed only by simply modulating the concentration of a single imidazolium-based catanionic surfactant or the ratio of mixed solvents. This environmentally friendly system is expected to have broad applications in various fields, such as materials science, drug delivery systems, and supramolecular chemistry.