Hydrogen‐Bonded Shape‐Persistent Aryl Hydrazide Polymers: Side‐Chain‐Tuned Formation of Vesicles and Organogels

A new class of aromatic, hydrazide‐based, zigzag polymer has been synthesized using the Yamazaki polymerization conditions. Hydrophobic, hydrophilic or amphiphilic side chains are introduced to the backbones to tune their solubility in organic solvents of different polarities. The side chains form successive, intramolecular, six‐membered RO···HN hydrogen bonds, which increase the planarity of the backbones. The new shape‐persistent polymers are revealed to self‐assemble into vesicles or fibers to gelate organic solvents of different polarities. The polymeric backbones may be regarded as a conceptual extension of the emerging foldamers, which are usually constructed from oligomeric backbones.

     

Melatonin prevents H2O2-induced activation of rat hepatic stellate cells

Considerable evidence shows therapeutic effects of melatonin on liver injury and the involvement of hepatic stellate cells (HSCs) in vivo. In the present studies, we investigate the protective effect of melatonin on H2O2-induced activation of HSCs in vitro. Compared with that in control HSCs, synthesis of collagen type I was increased in H2O2-treated cells. Melatonin pretreatment significantly inhibited the above effects of H2O2 in HSCs. CCAAT/enhancer-binding protein alpha (C/EBP-alpha), which could partially reverse the phenotype of activated HSCs, augmented in HSCs pretreated with melatonin. Moreover, secretion of the most important fibrotic cytokine transforming growth factor beta 1 (TGF-beta1) diminished in melatonin-pretreated HSCs. These results suggest that melatonin prevents H2O2-induced activation of HSCs and that the mechanism involves, at least in part, differential regulation of TGF-beta1 and C/EBP-alpha gene expression.     

Changes in steroid receptors and proteoglycan expression in the guinea pig prostate stroma during puberty and hormone manipulation

BACKGROUND: Proteoglycans are structural and informational molecules important during embryogenesis and organ maturation. Maturation of the prostate is influenced by androgens and estrogens, but changes in the relative spatiotemporal expression of steroid receptors and proteoglycans during hormonal change are unexplored. METHODS: Guinea pig prostate was used to define hormone-induced changes in the expression of androgen (AR) and estrogen (ER(alpha)) receptors, chondroitin sulfate (CS) glycosaminoglycan and core proteins of versican and syndecan-1. Tissue locations of AR, ER(alpha), CS and the proteoglycans versican and syndecan-1 were determined by immunohistochemistry. Cellular content of ER(alpha) and syndecan-1 was assessed visually. Versican, CS56 epitope, and AR were quantified by image analysis. RESULTS: AR expression within prostate epithelial and stromal cell nuclei decreased following castration and increased following treatment of castrate animals with dihydrotestosterone (DHT). ER(alpha) expression was restricted to prostate stromal cell nuclei and decreased during puberty, and following treatment of castrate animals with DHT. Versican was present in periacinar stroma immediately peripheral to basal epithelial cells, fibromuscular stromal tissue bands surrounding acinar units, and loose fibrovascular connective tissue interspersed between individual acini. Versican and native CS expression decreased (>10-fold) in periacinar stroma during puberty and following administration of DHT to castrated animals. Expression of syndecan-1 was restricted to fibromuscular cells of prostate stroma, and remained constant during puberty and hormone manipulation. CONCLUSIONS: ER(alpha), versican core protein and CS side chain epitopes are negatively regulated in prostate stromal tissue by DHT, whilst AR levels are positively regulated.     

整合素β1在心房颤动心房结构重构中的作用

目的探讨整合素β1在慢性心房颤动(房颤)心房结构重构中的作用。方法选择30例经心外科手术患者的右心耳肌组织,按有无房颤病史分为房颤组(15例)和无房颤组(15例)。Masson染色测定两组心房组织胶原容积分数(CVF);RT-PCR方法检测整合素β1 mRNA的表达;Western blot检测整合素β1蛋白的表达。结果与无房颤组比较,房颤组患者左心房直径增大[(4.96±0.50)mm vs (4.15±1.04)mm.P<0.05];房颤组患者CVF较无房颤组明显升高(42.38±9.79 vs 11.67±3.35,P<0.01);与无房颤组比较,房颤组患者整合素β1 mRNA及蛋白表达上调(0.43±0.03 vs 0.36±0.02,P<0.05;1 724.33±91.07 vs 853.13±30.34,P<0.01)。整合素β1蛋白与左心房直径(r=0.879,P<0.01)、房颤持续时间(r=0.830,P<0.01)及CVF(r=0.770,P<0.05)呈正相关。结论慢性房颤时,整合素β1基因及蛋白表达上调;整合素β1可能参与房颤时心房的结构重构。     

Cell Guidance by 3D-Gradients in Hydrogel Matrices: Importance for Biomedical Applications

Concentration gradients of soluble and matrix-bound guidance cues in the extracellular matrix direct cell growth in native tissues and are of great interest for design of biomedical scaffolds and on implant surfaces. The focus of this review is to demonstrate the importance of gradient guidance for cells as it would be desirable to direct cell growth onto/into biomedical devices. Many studies have been described that illustrate the production and characterization of surface gradients, but three dimensional (3D)-gradients that direct cellular behavior are not well investigated. Hydrogels are considered as synthetic replacements for native extracellular matrices as they share key functions such as 2D- or 3D-solid support, fibrous structure, gas- and nutrition permeability and allow storage and release of biologically active molecules. Therefore this review focuses on current studies that try to implement soluble or covalently-attached gradients of growth factors, cytokines or adhesion sequences into 3D-hydrogel matrices in order to control cell growth, orientation and migration towards a target. Such gradient architectures are especially desirable for wound healing purposes, where defined cell populations need to be recruited from the blood stream and out of the adjacent tissue, in critical bone defects, for vascular implants or neuronal guidance structures where defined cell populations should be guided by appropriate signals to reach their proper positions or target tissues in order to accomplish functional repair.     

The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation

The pericarp of Sapindus mukorossi Gaertn is traditionally used as an expectorant in Japan, China, and Taiwan. Activated neutrophils produce high concentrations of the superoxide anion (O₂⁻) and elastase known to be involved in airway mucus hypersecretion. In the present study, the anti-inflammatory functions of hederagenin 3-O-(3,4-O-di-acetyl-α-l-arabinopyranoside)-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (SMG-1), a saponin isolated from S. mukorossi, and its underlying mechanisms were investigated in human neutrophils. SMG-1 potently and concentration-dependently inhibited O₂⁻ generation and elastase release in N-Formyl-Met-Leu-Phe (FMLP)-activated human neutrophils. Furthermore, SMG-1 reduced membrane-associated p47^phox expression in FMLP-induced intact neutrophils, but did not alter subcellular NADPH oxidase activity in reconstituted systems. SMG-1 attenuated FMLP-induced increase of cytosolic calcium concentration and phosphorylation of p38 MAPK, ERK, JNK, and AKT. However, SMG-1 displayed no effect on cellular cAMP levels and activity of adenylate cyclase and phosphodiesterase. Significantly, receptor-binding analysis showed that SMG-1 inhibited FMLP binding to its receptor in a concentration-dependent manner. In contrast, neither phorbol myristate acetate-induced O₂⁻ generation and MAPKs activation nor thapsigargin-caused calcium mobilization was altered by SMG-1. Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases.     

Modulation of cell sensitivity to antitumor agents by targeting survival pathways

The advent of drugs targeting tumor-associated prosurvival alterations of cancer cells has changed the interest of antitumor drug development from cytotoxic drugs to target-specific agents. Although single-agent therapy with molecularly targeted agents has shown limited success in tumor growth control, a promising strategy is represented by the development of rational combinations of target-specific agents and conventional antitumor drugs. Activation of survival/antiapoptotic pathways is a common feature of cancer cells that converge in the development of cellular resistance to cytotoxic agents. The survival pathways implicated in cellular response to drug treatment are primarily PI3K/Akt and Ras/MAPK, which also mediate the signalling activated by growth factors and play a role in the regulation of critical processes including cell proliferation, metabolism, apoptosis and angiogenesis. Inhibitors of PI3K, Akt and mTOR have been shown to sensitize selected tumor cells to cytotoxic drugs through multiple downstream effects. Moreover, the MAPK pathway, also implicated in the regulation of gene expression in response to stress stimuli, can interfere with the chemotherapy-induced proapoptotic signals. Targeting Hsp90, which acts as a molecular chaperone for survival factors including Akt, may have the potential advantage to simultaneously block multiple oncogenic pathways. Overall, the available evidence supports the interest of rationally designed approaches to enhance the efficacy of conventional antitumor treatments through the inhibition of survival pathways and the notion that the concomitant targeting of multiple pathways may be a successful strategy to deal with tumor heterogeneity and to overcome drug resistance of tumor cells.