Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function

Background

Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.

Effects of glucagon-like peptide 1 (7–36 amide) on whole-body protein metabolism in healthy man

The incretin glucagon-like peptide 1 (GLP-1) shows glucose-dependent insulinotropic activity and may exert anabolic effects. Whole-body protein metabolism was assessed by measuring [1-¹³C]-leucine kinetics in 13 healthy volunteers during hyperglycaemic clamping with or without pancreatic clamping (somatostatin infusion) in order to differentiate between insulin-mediated and direct GLP-1 effects. During intact pancreatic secretion leucine flux and leucine oxidation rate as parameters of whole-body protein breakdown decreased markedly after 180 min of synthetic GLP-1 infusion (GLP-1 vs. placebo: P  < 0.003). Indirect calorimetry showed an increase in energy expenditure and CO₂ production during GLP-1 administration ( P  < 0.0005). Plasma insulin increased after 3 h of GLP-1 infusion to 1486 ± 145 pmol L⁻¹ vs. 185 ± 12 pmol L⁻¹ for saline ( P  < 0.0001). When plasma insulin levels were kept constant (GLP-1 vs. saline, NS) during pancreatic clamping, GLP-1 effects on both protein metabolism and energy expenditure were abolished. Thus, GLP-1 infusion in man exerts protein anticatabolic and thermic effects, which are mediated by GLP-1-induced stimulation of insulin secretion.     

Toll样受体2胞外域及其氨基端和羧基端片段的克隆与序列分析

目的：为研究TLR2胞外域在肽聚糖诱导的信号转导中的功能，构建TLR2胞外域及其氨基端和羧基端片段真核表达载体。方法：提取HL－60细胞总RNA，以RT－PCR方法获取了TLR2胞外域cDNA片段，将其与pGEM-T Easy载体连接，转化E.coli JM109,建立了TLR2胞外域的cDNA克隆；籍此，又相继克隆了胞外域的氨基端和羧基端片段，然后将这三个片段克隆到真核表达载体pcDNA3中。结果：序列分析表明，与GenBank中的人TLR2全长cDNA序列比较，仅4个碱基不同，同源性为0．998。结论：成功获得了HL－60细胞TLR2胞外域及其氨基端和羧基端片段的克隆。     

增强子结合蛋白家族的新基因HP8的部分cDNA克隆

探讨人的增强子结合蛋白（Ｃ／ＥＢＰ）相关基因。方法以大鼠Ｃ／ＥＢＰｃＤＮＡ为探针，筛选人胎盘ｃＤＮＡ文库。结果得到一个含有１９７５碱基命名为ＨＰ８的ｃＤＮＡ克隆，其中１～６０４位碱基属编码区。经基因数据库查对未发现同源基因。该基因编码的蛋白Ｃ－末端含有亮氨酸拉链结构（ｌｅｕｃｉｎｅ ｚｉｐｐｅｒ ｓｔｒｕｃｅｕｒｅ）和Ｃ／ＥＢＰ功能区（Ｃ－末端６０个氨基酸）同源性高达９７％，而上游编码区则与Ｃ／ＥＢＰ及其已知家族同源性很低，表明该基因属Ｃ／ＥＢＰ基因家族新成员。基因组Ｓｏｕｔｈｅｒｎ杂交证实该基因为单拷贝基因。在１４种胎儿组织中显示小肠、皮肤高表达，肾上腺中度表达，肝、肺、肾、甲状腺、胆囊低表达。在３例正常成人肝组织中仅１例低表达，而在５对肝癌及癌旁肝组织中显示２例癌组织及１例癌旁组织高表达。结论以上结果提示该基因可能与细胞增殖有关。     

Biochemical characterization of I-Ak proteins from mutant antigen-presenting B-cell--B-lymphoma hybridomas

Chemically induced mutants of an I-Ak,d expressing antigen-presenting B-cell--B-lymphoma hybridoma have recently been generated by immunoselection in vitro and were found to possess alterations in some of their serologically and functionally defined I-Ak region dependent functions. In order to identify at the structural level the origin of the differences in serological and functional properties of these mutants, I-Ak molecules from several of these mutant hybridomas were compared biochemically to wild-type I-Ak polypeptides by two-dimensional gel electrophoresis and high-pressure liquid chromatographic tryptic peptide analyses. Two-dimensional gel electrophoresis indicated that no major structural alterations, resulting in changes in mol. wt or charge, had occurred in the Ak alpha or Ak beta polypeptides from the mutant cells. Likewise, Ak alpha peptide maps of the mutants were indistinguishable from the normal Ak alpha peptide maps. However, two of the three mutants studied did exhibit one additional peptide in their Ak beta peptide maps. These results suggest that the major deficiencies in T-cell-activating functions of these mutants are a result of a limited alteration in the Ak beta polypeptide primary structure.     

Dual leucine zipper kinase (MAP3K12) modulators: a patent review (2010–2015)

Introduction: The dual leucine zipper kinase (DLK, MAP3K12) is essential for neuronal development and has been shown to mediate axon regeneration. On the other hand, DLK is involved in the pathogenesis of neurodegenerative disease and diabetes mellitus. Several patents have been published claiming to modulate or inhibit DLK by various approaches including ATP competitive inhibitors. In addition, two publications describe SAR of highly selective DLK inhibitors with efficacy in distinct mouse models of neurodegeneration.

Areas covered: This review summarized patents claiming to modulate DLK activity published between 2010 and 2015. Peer-reviewed publications related to the patents and additional peer-reviewed publications are included. This article describes 18 patents from three pharmaceutical companies and three academic research groups.

Expert opinion: Several methods are proposed to modulate DLK activity, some of them very experimental and not suitable for easy application in patients. ATP competitive kinase inhibitors exert high affinity, but for the majority, no information about their selectivity is available. To date, two inhibitors have been tested in mice. Given the controversial findings that DLK is required for neurodegeneration and for axon regeneration, more research is needed to further elucidate the regulation and the function of this kinase in diverse organs/tissues and under physiological and pathological conditions.     

Association between Excessive Dietary Branched-Chain Amino Acids Intake and Hypertension Risk in Chinese Population

The dietary intake of branched-chain amino acids (BCAAs) has been reported to be associated with both elevated blood pressure (BP) and hypertension risk, while published findings were inconsistent, and the causality has never been well disclosed. We performed this prospective study aiming to find out the relationship between dietary BCAAs intake and hypertension risk in the Chinese population. A total of 8491 participants (40,285 person-years) were selected. The levels of dietary BCAAs intake were estimated using the 24-h Food Frequency Questionnaire. Associations of both BP values and hypertension risk with per standard deviation increase of BCAAs were estimated using linear and COX regression analysis, respectively. The hazard ratios and 95% confidence interval were given. Restricted cubic spline analysis (RCS) was used to estimate the nonlinearity. Both systolic and diastolic BP values at the end points of follow-up were positively associated with dietary BCAAs intake. Positive associations between BCAAs intake and hypertension risk were shown in both men and women. By performing a RCS analysis, the nonlinear relationship between BCAAs intake and hypertension was shown. As the intake levels of Ile, Leu, and Val, respectively, exceeded 2.49 g/day, 4.91 g/day, and 2.88 g/day in men (2.16 g/day, 3.84 g/day, and 2.56 g/day in women), the hypertension risk increased. Our findings could provide some concrete evidence in the primary prevention of hypertension based on dietary interventions.     

Active site of trichosanthin acting as a ribosome-inactivating protein

天花粉蛋白核糖体灭活活性部位的定位方法：羟胺特异裂解天花粉蛋白唯一ＡｓｎＧｌｙ肽键．制备性凝胶电泳获ＨＡＴｆ１和ＨＡＴｆ２二片段．免疫印迹确定天花粉蛋白上不同表位并筛选抗体．兔网织红无细胞系统测定天花粉蛋白及片段对蛋白合成的抑制活性．结果：ＨＡＴｆ１和ＨＡＴｆ２纯度各达９６６％和８０５％．ＨＡＴｆ１保留完整天花粉蛋白的抑制活性．第１４号和第１６号抗天花粉蛋白单抗与二片段显示不同免疫反应性，并用于封闭试验．第１４号单抗能封闭天花粉蛋白及ＨＡＴｆ１活性，而第１６号单抗则否．结论：天花粉蛋白抑制蛋白质生物合成的活性部位位于ＨＡＴｆ１侧，近二部分交界．