Synthesis of a heparan sulfate mimetic library targeting FGF and VEGF via click chemistry on a monosaccharide template

A disulfated methyl 6-azido-6-deoxy-α-D-mannopyranoside template was used as a core structure for binding to the angiogenic growth factors FGF-1, FGF-2, and VEGF. The core structure was diversified in a rapid, parallel manner by employing the Cu(I)-catalyzed Huisgen azide-alkyne cycloaddition ("click") reaction. The diversity was further extended by incorporating a Swern oxidation-Wittig reaction sequence on a click adduct of propargyl alcohol. Thus, the sulfated core was linked by various spacers to selected hydrophobic or polar motifs, which were designed to probe the protein surface surrounding the cationic heparan sulfate binding sites of the growth factors in order to improve affinity and selectivity. The affinities of the compounds for the growth factors were measured by surface plasmon resonance solution affinity assays. A lead compound was identified with micromolar binding affinity toward both FGF-1 and VEGF (K(d)=84 and 49 μM, respectively) and good selectivity over FGF-2 (29- and 51-fold, respectively).     

Chitosan—A versatile semi-synthetic polymer in biomedical applications

This review outlines the new developments on chitosan-based bioapplications. Over the last decade, functional biomaterials research has developed new drug delivery systems and improved scaffolds for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. The aim is to restore or replace damaged body parts or lost organs by transplanting supportive scaffolds with appropriate cells that in combination with biomolecules generate new tissue. This is a highly interdisciplinary field that encompasses polymer synthesis and modification, cell culturing, gene therapy, stem cell research, therapeutic cloning and tissue engineering. In this regard, chitosan, as a biopolymer derived macromolecular compound, has a major involvement. Chitosan is a polyelectrolyte with reactive functional groups, gel-forming capability, high adsorption capacity and biodegradability. In addition, it is innately biocompatible and non-toxic to living tissues as well as having antibacterial, antifungal and antitumor activity. These features highlight the suitability and extensive applications that chitosan has in medicine. Micro/nanoparticles and hydrogels are widely used in the design of chitosan-based therapeuticsystems. The chemical structure and relevant biological properties of chitosan for regenerative medicine have been summarized as well as the methods for the preparation of controlled drug release devices and their applications.     

境外豁免农药残留名单(三)

为加强食品安全监管,一些国家和地区对部分作为农药登记使用的有效成分批准了豁免制订其在食品中的最大残留限量标准。介绍了欧盟、日本、美国、澳大利亚、新西兰、中国台湾和中国香港等的豁免农药名单。     

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.     

T-钙黏着蛋白与碱性成纤维细胞生长因子在人子宫肌瘤中的表达及其相关性

目的探讨T-钙黏着蛋白(T-cadherin)与碱性成纤维细胞生长因子(basic fibro blast growth factor,bFGF)在人子宫肌瘤中的表达及其相关性,以探讨二者在子宫肌瘤发生、发展过程中的作用。方法收集2011年9～12月间经重庆医科大学附属第一医院诊断为子宫肌瘤并行手术治疗,术后病理报告确诊为子宫肌瘤的患者50例,取其子宫肌瘤组织(A组)及同源正常子宫肌层组织(B组),同期收集经该院诊断为良性疾病并行手术治疗,术后病理报告确诊未患子宫肌瘤的10名患者正常子宫肌层组织作为对照组(C组)。50例子宫肌瘤患者根据术前彩色多普勒血流显像(Color Doppler Flow Imaging,CDFI)和激素水平进一步分组比较。采用SP免疫组化法检测子宫组织中T-cadherin和bFGF蛋白的定位,Western blot和RT-PCR法分别检测子宫组织中T-cadherin和bFGF蛋白的表达水平及基因mRNA转录水平,并分析二者与CDFI分级和激素分期的相关性。结果 A组T-cadherin主要定位于肌瘤细胞膜,bFGF主要定位于肌瘤细胞浆;A组子宫组织中T-cadherin和bFGF基因mRNA的转录水平及蛋白的表达水平均明显高于B组和C组(P<0.05),且二者明显呈正相关(P<0.01);T-cadherin和bFGF基因mRNA的转录水平及蛋白的表达水平均随CDFI等级的升高而增强(P<0.05或P<0.01)。结论 T-cadherin和bFGF在子宫肌瘤组织中高表达,提示二者在子宫肌瘤的发生、发展过程中起促进作用。     

Evaluation of a water-resistant and biocompatible adhesive with potential use in bone fractures

The use of osteosynthesis materials when complex fractures are presented is well known. However, the use of these materials has not achieved a correct fixation and reduction of all bone fragments. Therefore, an adhesive for bones would provide a simple and quick method to fix this kind of fractures. The aim of this work is to propose and to evaluate an adhesive based on chitosan hydrogels that could have a potential use as a bone adhesive underwater and will not develop cytotoxic effects. Ionically and covalently crosslinked hydrogels based on chitosan were used in this study. Butt joint test with bovine cancellous bone specimens were used in order to measure the tensile bond strength (TBS) in ideal (completely dry) and physiological (immersed in water at 37 °C) conditions. Additionally, TBS was estimated as a function of time of bone specimens immersed in water at 37 °C. Cell viability was studied using MTT assay and cell morphology on the adhesive surface was examined by scanning electron microscope. Mechanical studies revealed that only covalently crosslinked hydrogels maintain their TBS at physiological condition with respect to the dry environment. In addition, it was observed that the TBS, using only covalently crosslinked hydrogels adhesives, dramatically changes as a function of time and its behavior increases as calcium carbonate and hydroxyapatite is added. Finally, in vitro cell testing of covalently crosslinked hydrogel with calcium carbonate and hydroxyapatite exhibited excellent biocompatibility. Therefore, this formulation is proposed as a potential candidate for clinical use in orthopedic surgery.     

Effect of Bacterial Infection on Ghrelin Receptor Regulation in Periodontal Cells and Tissues

The effect of bacterial infection on the expression of growth hormone secretagogue receptor (GHS-R) was investigated in periodontal cells and tissues, and the actions of ghrelin were evaluated. GHS-R was assessed in periodontal tissues of rats with and without periodontitis. Human gingival fibroblasts (HGFs) were exposed to Fusobacterium nucleatum in the presence and absence of ghrelin. GHS-R expression was determined by real-time PCR and immunocytochemistry. Furthermore, wound healing, cell viability, proliferation, and migration were evaluated. GHS-R expression was significantly higher at periodontitis sites as compared to healthy sites in rat tissues. F. nucleatum significantly increased the GHS-R expression and protein level in HGFs. Moreover, ghrelin significantly abrogated the stimulatory effects of F. nucleatum on CCL2 and IL-6 expressions in HGFs and did not affect cell viability and proliferation significantly. Ghrelin stimulated while F. nucleatum decreased wound closure, probably due to reduced cell migration. Our results show original evidence that bacterial infection upregulates GHS-R in rat periodontal tissues and HGFs. Moreover, our study shows that ghrelin inhibited the proinflammatory actions of F. nucleatum on HGFs without interfering with cell viability and proliferation, suggesting that ghrelin and its receptor may act as a protective molecule during bacterial infection on periodontal cells.     

Suppression of Cutibacterium acnes-Mediated Inflammatory Reactions by Fibroblast Growth Factor 21 in Skin

Cutibacterium acnes (C. acnes) is a common commensal bacterium that is closely associated with the pathogenesis of acne. Fibroblast growth factor 21 (FGF21), as a favorable regulator of glucose and lipid metabolism and insulin sensitivity, was recently shown to exert anti-inflammatory effects. The role and mechanism of FGF21 in the inflammatory reactions induced by C. acnes, however, have not been determined. The present study shows that FGF21 in the dermis inhibits epidermal C. acnes-induced inflammation in a paracrine manner while it functions on the epidermal layer through a receptor complex consisting of FGF receptor 1 (FGFR1) and β-Klotho (KLB). The effects of FGF21 in heat-killed C. acnes-induced HaCaT cells and living C. acnes-injected mouse ears were examined. In the presence of C. acnes, FGF21 largely counteracted the activation of Toll-like receptor 2 (TLR2), the downstream nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways induced by C. acnes. FGF21 also significantly reduced the expression of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Taken together, these findings indicate that FGF21 suppresses C. acnes-induced inflammation and might be used clinically in the management and treatment of acne.     

重组碱性成纤维细胞生长因子凝胶剂的制备

目的制备重组碱性成纤维细胞生长因子(bFGF)凝胶剂。方法以卡波姆940、甘油、1,2丙二醇为基质,加入复方保护剂(肝素钠、人血白蛋白、甘露醇和HP-β-CD),制成bFGF凝胶剂,观察25和4℃保存的稳定性,并进行家兔局部刺激试验、急性毒性试验、促烧伤创面愈合试验。结果bFGF凝胶剂在25℃保存18个月、4℃保存24个月,效价维持在原效价的80%以上;局部用药未见皮肤刺激反应和急性毒性反应;促家兔烧伤创面愈合的效果明显优于水溶液剂。结论制备的bFGF凝胶剂安全有效,具有缓释作用,稳定性良好,具有广阔的临床应用前景。     

Comparison of fibroblast and nerve cells response on plasma treated poly (L‐lactide) surface

Plasma technique can easily be used to introduce desired functional groups or chains onto the surface of materials, and so it has a special application to improve the cell affinity of polymers surfaces. The purpose of this study is to elucidate the interaction between the cells and the surface of crystalline poly (L ‐lactide) (PLLA) samples, which were modified using a low‐temperature plasma treatment apparatus. The plasma treatments were carried out in the carbon dioxide (CO₂) gas. The results showed that the contact angle of the samples, which was plasma treated in CO₂ gas, decreased compared with that of the untreated samples. The hydrophilicity increased because of the introduction of oxygen‐containing functional groups onto the PLLA surfaces according to the spectroscopy for chemical analysis. High quantities of ? C? O groups, such as hydroxyl and carboxyl could be in corporate into the surface of PLLA. The surface wettability, topography, and chemistry of treated PLLA samples were characterized by contact angle measurement, scanning electron microscope (SEM), and ATR‐FTIR spectroscopy. The origin and plasma‐treated samples were used to investigate the interaction of two different types of cells namely, B65 glial nervous, and L929 fibroblast cells. The nervous cell response on the PLLA plasma treated in the CO₂ gas were significantly superior to that of the L929 fibroblast cells and untreated one. The surface modification technique used in this study may be applicable to tissue engineering for the improvement of nerve tissue compatibility of polymer and scaffold‐type substrates. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009