Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer

Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets.     

BMS Derivatives C7-Linked to β-Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5-HIV-1NLAD8 Isolates and Can Be Deemed Potential Microbicides

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1_NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4^th generation, are reported here for the first time.     

Mechanical properties and wear behavior of Tin+1(Al,A)Cn (A = Ga,In, Sn,n = 1, 2) via quasi-high-entropy of single atomic thick A layer

The strengthening method of multi-element M-site solid solution is a common approach to improve mechanical properties of MAX phase ceramic. However, the research on capability of multi-element A-site solid solution to improve mechanical properties has rarely been reported. Thereupon, quasi-high-entropy MAX phase ceramic bulks of Ti₂(Al_1?xA_x)C and Ti₃(Al_1?xA_x)C₂ (A = Ga, In, Sn, x = 0.2, 0.3, 0.4) were successfully synthesized by in situ vacuum hot pressing via multi-elements solid solution. The multi-elements solid solution in single-atom thick A layer was confirmed by X-ray diffraction and X-ray photoelectron spectroscopy as well as by energy dispersive X-ray spectroscopy mappings. Effects of doped multi-elements contents on the phase, microstructure, mechanical properties, and high temperature tribological behaviors were studied. Results demonstrated that the Vickers hardness, anisotropic flexural strength, fracture toughness, and tribological properties of Ti–Al–C based MAX ceramics could be remarkably improved by constitution of quasi-high-entropy MAX phase in A layers. Moreover, the strengthening and wear mechanisms were also discussed in detail. This method of multi-element solid solution at A-site provides new way to enhance mechanical properties of other MAX phase ceramics.     

Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.     

Microstructural and mechanical properties assessment of transient liquid phase bonding of CoCuFeMnNi high entropy alloy

The transient liquid phase (TLP) bonding of CoCuFeMnNi high entropy alloy (HEA) was studied. The TLP bonding was performed using AWS BNi-2 interlayer at 1050 °C with the TLP bonding time of 20, 60, 180 and 240 min. The effect of bonding time on the joint microstructure was characterized by SEM and EDS. Microstructural results confirmed that complete isothermal solidification occurred approximately at 240 min of bonding time. For samples bonded at 20, 60 and 180 min, athermal solidification zone was formed in the bonding area which included Cr-rich boride and Mn₃Si intermetallic compound. For all samples, the γ solid solution was formed in the isothermal solidification zone of the bonding zone. To evaluate the effect of TLP bonding time on mechanical properties of joints, the shear strength and micro-hardness of joints were measured. The results indicated a decrement of micro-hardness in the bonding zone and an increment of micro-hardness in the adjacent zone of joints. The minimum and maximum values of shear strength were 100 and 180 MPa for joints with the bonding time of 20 and 240 min, respectively.     

A novel approach for bulk micromachining of 4H-SiC by tool-based electrolytic plasma etching in HF-free aqueous solution

Bulk micromachining of single-crystal SiC has been challenging due to its extreme stability both mechanically and chemically. To address this issue, a novel tool-based electrolytic plasma etching method is proposed, with which micropatterns and micro-holes are fabricated in SiC in a hydrofluoric acid-free aqueous solution with no need for masks. The material removal is the result of the combined effects of electrolytic plasma chemistry and physics. The chemistry refers to the reaction of Si with hydroxyl radical to form various SiO_x and with H to form silanes, and the reactions of C to form volatile carbon oxides or hydrocarbons, all of which are accomplished and enhanced under the electrolytic plasma atmosphere. Besides, the local high temperature of plasma thermally promotes the evaporation or dissolution of SiO₂ in NaOH solution. The tool-based electrolytic plasma etching method provides alternative approaches for the fabrication of SiC-based MEMS and devices.     

氮含量及固溶温度对21-6-9奥氏体不锈钢组织和硬度的影响

为了探讨氮含量及固溶温度对21-6-9不锈钢组织和硬度的影响,分别在950、1000、1050和1100 ℃对3种不同氮含量的热轧态21-6-9不锈钢进行1 h固溶处理,通过光学显微镜观察其组织结构,结合Thermo-Calc热力学计算对试验钢的微观组织进行分析,并对其进行硬度测试。结果表明,0.20%~0.28%N的21-6-9不锈钢热轧后沿轧制方向析出铁素体,且钢中铁素体经950~1100 ℃固溶处理可消除,当N含量达到0.34%时,试验钢中不再出现铁素体。随着固溶处理温度的升高,21-6-9不锈钢的晶粒组织长大,硬度降低。N含量的增加可显著提高固溶态21-6-9不锈钢的硬度,其增加程度随固溶处理温度的升高而减弱。     

A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with l-Carnitine Improves Biocompatibility on Human Mesothelial Cells

The main reason why peritoneal dialysis (PD) still has limited use in the management of patients with end-stage renal disease (ESRD) lies in the fact that the currently used glucose-based PD solutions are not completely biocompatible and determine, over time, the degeneration of the peritoneal membrane (PM) and consequent loss of ultrafiltration (UF). Here we evaluated the biocompatibility of a novel formulation of dialytic solutions, in which a substantial amount of glucose is replaced by two osmometabolic agents, xylitol and l-carnitine. The effect of this novel formulation on cell viability, the integrity of the mesothelial barrier and secretion of pro-inflammatory cytokines was evaluated on human mesothelial cells grown on cell culture inserts and exposed to the PD solution only at the apical side, mimicking the condition of a PD dwell. The results were compared to those obtained after exposure to a panel of dialytic solutions commonly used in clinical practice. We report here compelling evidence that this novel formulation shows better performance in terms of higher cell viability, better preservation of the integrity of the mesothelial layer and reduced release of pro-inflammatory cytokines. This new formulation could represent a step forward towards obtaining PD solutions with high biocompatibility.     

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene,a Major Active Metabolite of Bisphenol A,Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.     

冷低压分离器油相系统铵盐垢下腐蚀风险的模拟预测

为探究某加氢装置高压换热器管束腐蚀泄漏原因，利用Aspen Plus工艺模拟软件计算了冷低压分离器油相（简称冷低分油）中水质量分数分别为1%,2%,3%时，冷低分油系统的露点温度、氯化铵结晶温度、氯化铵潮解点温度和相对湿度。结果表明：相较于经验的露点温度预测方法，通过引入潮解点、划分系统“湿环境”温度范围判断氯化铵垢下腐蚀风险区域的方法与实际腐蚀案例更为切合；在3种油相含水条件下，换热器管束存在氯化铵垢下腐蚀的“湿环境”温度范围分别为：50~103 ℃,50~161 ℃,50~176 ℃；随着油相中含水量的提高，“湿环境”腐蚀区域逐渐向高温部位迁移，预计铵盐导致的垢下腐蚀将会愈加严重。