Dianthiamides A–E,Proline-Containing Orbitides from Dianthus chinensis

Orbitides are plant-derived small cyclic peptides with a wide range of biological activities. Phytochemical investigation of the whole plants of Dianthus chinensis was performed with the aim to discover new bioactive orbitides. Five undescribed proline-containing orbitides, dianthiamides A–E (1–5), were isolated from a methanolic extract of Dianthus chinensis. Their structures were elucidated by extensive analysis of 1D and 2D NMR and HRESI–TOF–MS as well as ESI–MS/MS fragmentation data. The absolute configuration of the amino acid residues of compounds 1–5 was determined by Marfey’s method. All compounds were tested for their cytotoxic activity, and dianthiamide A (1) exhibited weak activity against A549 cell line with IC₅₀ value of 47.9 μM.     

ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses

Zinc is a trace element that is essential for immune responses. Therefore, changes in cellular zinc levels in specific immune cells may influence inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). However, the regulation of zinc mobilization in immune cells and its role in the pathogenesis of RA are not fully understood. Thus, we investigated the roles of zinc transporters in RA pathogenesis. We demonstrated that ZIP8 was specifically upregulated in CD4⁺ T cells that infiltrated the inflamed joint and that ZIP8 deficiency in CD4⁺ T cells abrogated collagen-induced arthritis. ZIP8 deficiency dramatically affected zinc influx in effector T cells and profoundly reduced T cell receptor (TCR)-mediated signaling, including NF-κB and MAPK signaling, which are pathways that are involved in T helper (Th) 17 cell differentiation. Taken together, our findings suggest that ZIP8 depletion in CD4⁺ T cells attenuates TCR signaling due to insufficient cellular zinc, thereby reducing the function of effector CD4⁺ T cells, including Th17 cells. Our results also suggest that targeting ZIP8 may be a useful strategy to inhibit RA development and pathogenesis.Subject terms: Autoimmunity, Immunological disorders     

Factors affecting the catalytic epoxidation of olefins by iron porphyrin complexes and H2O2 in protic solvents

The catalytic epoxidation of cyclohexene by iron(III) porphyrin complexes and H2O2 has been investigated in alcohol solvents to understand factors affecting the catalyst activity in protic solvents. The yields of cyclohexene oxide and the Fe(III/II) reduction potentials of iron porphyrin complexes were significantly affected by the protic solvents, and there was a close correlation between the product yields and the reduction potentials of the iron porphyrin catalysts. The role of alcohol solvents was proposed to control the electronic nature of iron porphyrin complexes that determines the catalyst activity in the epoxidation of olefins by H2O2. We have also demonstrated that an electron-deficient iron porphyrin complex can catalyze the epoxidation of olefins by H2O2 under conditions of limiting substrate with high conversion efficiency in a solvent mixture of CH3OH and CH2Cl2.     

Crucial role of three-center hydrogen bonding in a challenging chiral molecular recognition

The enantio-discrimination of beta-chiral primary ammonium ions is achieved by a rational approach that utilizes three-center (bifurcated) hydrogen bonding. The extraction experiments on various selected guests reveal that the bifurcated H-bonding plays a crucial role for the chiral discrimination. The X-ray data obtained for an inclusion complex substantiate such interactions. Using the bifurcated H-bonding, the chiral molecular recognition with our C(3)-symmetric tripodal oxazoline receptors is extended generally toward ammonium ions of alpha-, beta-, and alpha,beta-chiral amines. Simple molecular models, evoking the bifurcated H-bonding, explain the chiral discrimination modes.     

Differential effects of Fas cross-linking on phospholipase D activation and related lipid metabolism in Fas-resistant A20 cells

A20 murine lymphoma cells undergoing Fas-mediated apoptosis showed increase in the activity of phospholipase D (PLD), which is involved in proliferative or mitogenic cellular responses. Using A20 cell lines that were resistant to Fas-induced apoptosis, we investigated the differential effects of Fas cross-linking on PLD activity and sphingolipid metabolism. The basal PLD activities in all of the selected three Fas-resistant clones (#5, #8, and #11) were about 2~4 folds higher than that of wild type A20 cells. Among the PLD isoforms, PLD2 expression was increased in all of the selected Fas-resistant clones. The Fas downstream signaling events triggered by Fas cross-linking, including the activations of PLD, phosphatidylcholine-specific phospholipase C (PC-PLC), sphingomyelinase (SMase), the increase in diacylglycerol (DAG) and protein phosphorylation levels, and the translocation of protein kinase C to membrane were not changed in both of Fas-resistant clone #5 and #8. In contrast, Fas cross-linking stimulated the activity of PLD, PC-PLC, and SMase, translocation of PKC, and protein phosphorylation in Fas-resistant clone #11, similar to that of wild type cells. We also found that clone #11 had a different Fas sequence encoding Fas B which has been known to inhibit Fas-induced apoptosis. These findings suggest that increased PLD2 expression resulting in increased basal PLD activity and the blockade of Fas downstream signaling cascades may be involved to limit apoptosis induced by Fas cross-linking.     

Synthesis and properties of organosoluble poly(amide imide imide)s based on tetraimide dicarboxylic acid condensed from 4,4′‐(hexafluoroisopropylidene)diphthalic anhydride, 4,4′‐oxydianiline,and trimellitic anhydride and various aromatic diamines

A novel tetraimide dicarboxylic acid was synthesized with the ring‐opening addition of 4,4′‐(hexafluoroisopropylidene)diphthalic anhydride, 4,4′‐oxydianiline, and trimellitic anhydride in a 1/2/2 molar ratio in N‐methyl‐2‐pyrrolidone followed by azeotropic condensation to tetraimide dicarboxylic acid. A series of poly(amide imide imide)s (PAIIs) with inherent viscosities of 0.8–1.1 dL/g were prepared from tetraimide dicarboxylic acid with various aromatic diamines by direct polycondensation. Most of the PAIIs were readily soluble in a variety of amide polar solvents and even in less polar m‐cresol and pyridine. Solvent‐cast films had tensile strengths ranging from 99 to 106 MPa, elongations at break ranging from 8 to 13%, and initial moduli ranging from 2.0 to 2.3 GPa. The glass‐transition temperatures of these PAIIs were recorded at 244–276 °C. They had 10% weight losses at temperatures above 520 °C in air or nitrogen atmospheres. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1092–1102, 2002     

Skin‐worn Soft Microfluidic Potentiometric Detection System

A flexible skin‐mounted microfluidic potentiometric device for simultaneous electrochemical monitoring of sodium and potassium in sweat is presented. The wearable device allows efficient natural sweat pumping to the potentiometric detection chamber, containing solid‐contact ion‐selective Na⁺ and K⁺ electrodes, during exercise activity. The fabricated microchip electrolyte‐sensing device displays good analytical performance and addresses sweat mixing and carry‐over issues of early epidermal potentiometric sensors. Such soft skin‐worn microchip platform integrates potentiometric measurement, microfluidic technologies with flexible electronics for real‐time wireless data transmission to mobile devices. The new fully integrated microfluidic electrolyte‐detection device paves the way for practical fitness and health monitoring applications.     

An Unprecedented Cyclization Mechanism in the Biosynthesis of Carbazole Alkaloids in Streptomyces

Carquinostatin A (CQS), a potent neuroprotective substance, is a unique carbazole alkaloid with both an ortho‐quinone function and an isoprenoid moiety. We identified the entire gene cluster responsible for CQS biosynthesis in Streptomyces exfoliatus through heterologous production of CQS and gene deletion. Biochemical characterization of seven CQS biosynthetic gene products (CqsB1–7) established the total biosynthetic pathway of CQS. Reconstitution of CqsB1 and CqsB2 showed that the synthesis of the carbazole skeleton involves CqsB1‐catalyzed decarboxylative condensation of an α‐hydroxyl‐β‐keto acid intermediate with 3‐hydroxybutyryl‐ACP followed by CqsB2‐catalyzed oxidative cyclization. Based on crystal structures and mutagenesis‐based biochemical assays, a detailed mechanism for the unique deprotonation‐initiated cyclization catalyzed by CqsB2 is proposed. Finally, analysis of the substrate specificity of the biosynthetic enzymes led to the production of novel carbazoles.     

Antiadhesive Nanosomes Facilitate Targeting of the Lysosomal GlcNAc Salvage Pathway through Derailed Cancer Endocytosis

Activated endocytosis of extracellular macromolecules and their intracellular trafficking to lysosomes is an essential metabolic mechanism in cancer cells during their rapid proliferation. Cancer cells reuse a vast amount of N‐acetylglucosamine (GlcNAc) supplied from the GlcNAc salvage pathway for the accelerated synthesis of a pivotal uridine diphosphate (UDP)‐GlcNAc. A method to inactivate key glycosidases in lysosomes could critically contribute to the development of potent anticancer therapy. Here we demonstrate that “nanosomes” made of core metals covered by an antiadhesive mixed self‐assembled monolayer allow for avoiding nonspecific surface protein corona and targeted molecular delivery through activated endocytosis. Nanosomes carrying suicide substrates showed that lysosomal glycosidases such as β‐hexosaminidase and β‐galactosidase in cancer cells are promising targets for novel anticancer therapeutic nanomedicine that induce apoptotic cell death through lysosomal membrane permeabilization. The advantage of this method is evident because multivalent surface loading by antiadhesive nanosomes makes it possible to highlight “weak interactions” such as carbohydrate–lectin interactions independent of surface protein corona.