Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats

Renin angiotensin system (RAS) worsens diabetic nephropathy (DN) by increasing oxidative stress. We compared the effect of three different RAS inhibitors: the angiotensin converting enzyme inhibitor Ramipril, the vasopeptidase inhibitor AVE7688 and the angiotensin receptor (AT1) antagonist Losartan on the formation of oxidative and carbonyl stress derived protein modifications in kidney from Zucker obese hyperglycemic rats (ZDFn Gm-fa/fa). Gas chromatography-mass spectrometry was used to measure representative markers of several protein oxidative pathways: direct oxidation [dinitrophenylhydrazine reactive carbonyls (DNP), glutamic (GSA), and aminoadipic (AASA) semialdehydes], mixed glyco- and lipoxidation [N^ε-carboxyethyl-lysine (CEL) and N^ε-(carboxymethyl)-lysine (CML)] and lipoxidation-[N^ε-(malondialdehyde)-lysine-(MDAL)], as well as renal fatty acid composition. Urinary albumin (a marker of DN), DNP, GSA, and MDAL levels, were increased in all obese rats and were dose dependently decreased by AVE7688 whereas Ramipril and Losartan were less efficient. These results show that RAS inhibition improves DN at several levels, independently of its effects on blood pressure and glycemic control, via mechanisms depending of renal oxidative stress.     

Protein adsorption on histidyl-aminohexyl-Sepharose 4B: I. Study of the mechanistic aspects of adsorption for the separation of human serum albumin from its non-enzymatic glycated isoforms (advanced glycosylated end products)

The characteristics of albumin adsorption on histidyl-aminohexyl-Sepharose 4B were investigated. In particular, the adsorption capacity of the gel was studied as a function of conductivity and pH of the running buffer. The adsorption was maximum at low salt concentration around neutral pH, involving electrostatic and hydrophobic interactions. Kinetic aspects were also investigated. Dissociation constant (K_D) and maximum capacity (Q_x) were, respectively, estimated to be 4.5×10⁻⁵ M (medium affinity) and 93.3 mg (high capacity) of human serum albumin per ml of adsorbent. According to these preliminary results, separation of HSA and its non-enzymatically glycated isoforms (conventionally named advanced glycated end products: AGEs) was achieved. Chromatographic potential of this separation tool is discussed.     

Sodium—A Functional Plant Nutrient

Plant scientists usually classify plant mineral nutrients based on the concept of “essentiality” defined by Arnon and Stout as those elements necessary to complete the life cycle of a plant. Certain other elements such as Na have a ubiquitous presence in soils and waters and are widely taken up and utilized by plants, but are not considered as plant nutrients because they do not meet the strict definition of “essentiality.” Sodium has a very specific function in the concentration of carbon dioxide in a limited number of C₄ plants and thus is essential to these plants, but this in itself is insufficient to generalize that Na is essential for higher plants. The unique set of roles that Na can play in plant metabolism suggests that the basic concept of what comprises a plant nutrient should be reexamined. We contend that the class of plant mineral nutrients should be comprised not only of those elements necessary for completing the life cycle, but also those elements which promote maximal biomass yield and/or which reduce the requirement (critical level) of an essential element. We suggest that nutrients functioning in this latter manner should be termed “functional nutrients.” Thus plant mineral nutrients would be comprised of two major groups, “essential nutrients” and “functional nutrients.” We present an array of evidence and arguments to support the classification of Na as a “functional nutrient,” including its requirement for maximal biomass growth for many plants and its demonstrated ability to replace K in a number of ways, such as being an osmoticium for cell enlargement and as an accompanying cation for long-distance transport. Although in this paper we have only attempted to make the case for Na being a “functional nutrient,” other elements such as Si and Se may also confirm to the proposed category of “functional nutrients.”     

免疫细胞浸润在非小细胞肺癌诊断与预后中的应用

免疫细胞浸润对癌症的诊断与预后有着重要意义。文中收集TCGA数据库已收录的非小细胞肺癌肿瘤与正常组织基因表达数据,利用CIBERSORT工具得到22种免疫细胞占比来评估免疫细胞浸润情况。以22种免疫细胞占比为特征,用机器学习方法构建了非小细胞肺癌肿瘤与正常组织的分类模型,其中随机森林方法构建的模型分类效果AUC=0.987、敏感性0.98及特异性0.84。并且用随机森林方法构建的肺腺癌和肺鳞癌肿瘤组织分类模型效果AUC=0.827、敏感性0.75及特异性0.77。用LASSO回归筛选22种免疫细胞特征,保留8种强相关特征组成的免疫细胞评分结合临床特征构建了非小细胞肺癌预后模型。经评估及验证,预后模型C-index=0.71并且3年和5年的校准曲线拟合良好,可以对预后风险度进行准确预测。本研究基于免疫细胞浸润所构建的分类模型与预后模型,旨在对非小细胞肺癌的诊断与预后研究提供新的策略。     

华蟾素注射液联合全身化疗治疗中晚期乳腺癌的临床效果分析

目的:探讨华蟾素注射液联合全身化疗治疗中晚期乳腺癌的临床疗效及安全性。方法:选择我科收治的81例中晚期乳腺癌患者并将其随机分为两组,联合组(40例)采用华蟾素注射液联合全身化疗给予治疗,化疗组(41例)单纯给予化疗治疗。治疗后3个月,评价和比较两组的近期和远期疗效,生活质量的改善情况以及不良反应的发生情况。结果:治疗后3个月,联合组治疗有效率明显高于化疗组(P0.05)。截至目前,联合组平均生存期为15个月,化疗组为10个月,两组差异没有统计学意义(P0.05)。联合组的生活质量提高率明显高于化疗组(P0.05)。骨髓抑制和胃肠道反应为两组主要的不良反应,联合组胃肠道反应的发生率明显低于化疗组(P0.05)。结论:华蟾素联合全身化疗对中晚期乳腺癌具有较好的近期治疗效果,并能改善患者的生活质量,且毒副反应较少。     

Reticulocalbin 1 is required for proliferation and migration of non-small cell lung cancer cells regulated by osteoblast-conditioned medium

Reticulocalbin1 (RCN1) is implicated in tumorigenesis and tumour progression. However, whether RCN1-mediated bone metastasis of non-small cell lung cancer (NSCLC) cells was elusive. Here, we assessed the effect of osteoblast-conditioned medium (CM) on proliferation and migration of NSCLC cell line, NCI-H1299 and NCI-H460 cells, and identified the soluble mediators in CMs from osteoblasts and NSCLC cells using MTT, Clonogenicity, Transwell, wound healing, RT-PCR, and Western blotting assays, and LC-MS/MS analysis, respectively. Furthermore, the role of RCN1 was investigated in NSCLC cells cultured with or without osteoblast-CM. Tumour growth and bone resorption were measured in a nude mouse model bearing NCI-H1299 cells transduced with shRNA/RCN1 vector using in vivo imaging technique and micro-CT. The results showed that RCN1 with a higher abundance in osteoblast-CM, which was present in extracellular vesicles (EVs), enhanced RCN1 expression in NSCLC cells. Osteoblast-CM partially offset the inhibitory effect of RCN1 depletion on proliferation and migration of NSCLC cells. RCN1 depletion-induced endoplasmic reticulum (ER) stress caused by increasing GRP78, CHOP, IRE1α, p-IRE1α, p-PERK and p-JNK, which was positively regulated by self-induced autophagy, contributed to suppression of proliferation and migration in NCI-H1299 cells. Therefore, osteoblasts produced RCN1 to transfer into NSCLC cells partially through EVs, facilitating proliferation and migration of NSCLC cells via blocking ER stress. RCN1 could be required for proliferation and migration of NSCLC cells regulated by osteoblast-CM.     

The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC

A series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFR^T790M/L858R inhibitors among which 9c (IC₅₀?=?0.5872?nM), 9d (IC₅₀?=?2.213?nM), or 9h (IC₅₀?=?12.57?nM) showed more potent anti-EGFR^T790M/L858R activity compared with AZD–9291 (IC₅₀?=?20.80?nM) and possessed high SI displaying 307.6, 56.5, or 12.5 for EGFR^T790M/L858R over the wild-type respectively. 9h also showed pretty good activity against H 1975 cells with an IC₅₀ of 1.664?μM and exhibited low toxicity against the normal HBE cells (IC₅₀?>?20?μΜ). 9h had moderate selectivity for H 1975 over A 431 (SI?=?7.0) and the other selected cell lines. Morphological staining results further indicated that 9h could promote apoptosis. Hence, 9h was a promising compound for further investigation as a potential EGFR^T790M/L858R inhibitor for the treatment of NSCLC.     

Cancer stem cell-like population is preferentially suppressed by EGFR-TKIs in EGFR-mutated PC-9 tumor models

Aims

Although the epidermal growth factor receptor (EGFR) and Wnt/β-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the β-catenin signal.

Design,synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer

A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC₅₀ values for the compound C9 were 1.36?±?0.27?µM, 1.25?±?0. 23?µM, 2.31?±?0.41?µM, 2.14?±?0.36?µM and 1.85?±?0.32?µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1.     

Serum circulating cell free DNA as potential diagnostic and prognostic biomarker in non small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) is leading cause of cancer related death and the survival rate for patients with NSCLC remain poor so early diagnosis of NSCLC represents the best opportunity for cure. Cell-free DNA (cf-DNA) is extracellular nucleic acids found in cell-free plasma/serum of humans, given the recent approval of a liquid biopsy in lung cancer, the use of circulating tumor DNA as a novel non-invasive diagnostic and prognostic biomarker is promising.ObjectivesStudying whether the concentrations of circulating Cell Free DNA in serum can be used as a diagnostic and prognostic biomarker for NSCLC patients.MethodThis study was carried out on 140 subjects included 60 patients with non small cell lung cancer,40 patients with Chronic Obstructive Pulmonary Disease (COPD) and 40 healthy controls. Quantitative analysis of serum circulating cf-DNA was done b y AlU-based quantitative real time PCR. Serum level of CEA was measured by ELISA.ResultsNSCLC patients demonstrated significantly higher values of each of ALU 215, ALU 247, and DNA integrity than both COPD patients and controls. On ROC curve analysis, the total accuracy of ALU 247, ALU 115, DNA integrity (92.1%, 83.6%, 56.4%) at cutoff points (325, 565 & 0.48) respectively. On combining both DNA integrity and CEA, improved sensitivity to 93.3% was noted. For NSCLC patients, ALU 115 & ALU 247 increased significantly with more advanced stage and highest level was noticed in metastatic patients. Regarding survival there was better overall survival among patients with low DNA integrity.ConclusionSerum cf-DNA concentrations and integrity index may be valuable tool in early diagnosis of NSCLC and prediction of prognosis of those patients.