Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1s/sα2s/s Mouse Model of High Affinity for Cardiotonic Steroids

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1^r/rα2^s/s mouse failed to do so in the α1^s/sα2^s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.     

The Pharmacology and Therapeutic Utility of Sodium Hydroselenide

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe⁻/H₂Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O₂ consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H₂O₂), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed.     

Thrombospondin-1 CD47 Signalling: From Mechanisms to Medicine

Recent advances provide evidence that the cellular signalling pathway comprising the ligand-receptor duo of thrombospondin-1 (TSP1) and CD47 is involved in mediating a range of diseases affecting renal, vascular, and metabolic function, as well as cancer. In several instances, research has barely progressed past pre-clinical animal models of disease and early phase 1 clinical trials, while for cancers, anti-CD47 therapy has emerged from phase 2 clinical trials in humans as a crucial adjuvant therapeutic agent. This has important implications for interventions that seek to capitalize on targeting this pathway in diseases where TSP1 and/or CD47 play a role. Despite substantial progress made in our understanding of this pathway in malignant and cardiovascular disease, knowledge and translational gaps remain regarding the role of this pathway in kidney and metabolic diseases, limiting identification of putative drug targets and development of effective treatments. This review considers recent advances reported in the field of TSP1-CD47 signalling, focusing on several aspects including enzymatic production, receptor function, interacting partners, localization of signalling, matrix-cellular and cell-to-cell cross talk. The potential impact that these newly described mechanisms have on health, with a particular focus on renal and metabolic disease, is also discussed.     

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.     

Intraspecific variation and interspecific differences in sex pheromones of sibling species inCtenopseustis obliquana complex

The specific status ofCtenopseustis obliquana pheromone-types I, II, and III has been more fully examined. Females of types I and III produce a mixture of (Z)-8- and (Z)-5-tetradecenyl acetates (Z8-14:Ac, Z5-14: Ac). The previously reported different ratios of these two components in females of the two types (type I=8020, III=9010) have been reinvestigated. The median ratios of each type differed significantly, although there was some overlap in the ranges of these ratios. A field cage trial showed that males of type III are attracted to females of type I, so the observed differences may be ascribed to intraspecific variation. In contrast to females of types I or III, females of type II produce Z5-14Ac but no Z8-14Ac. The electroantennogram (EAG) profile of antennae of type II males shows a maximum response to Z5-14Ac, while the EAG profiles of types I and III show a strong response to Z8-14Ac. In wind tunnel tests using mixtures of these two compounds, type II males prefer blends consisting of all or mostly Z5-14: Ac, while type I males showed a preference to a mix of 70% Z8-14Ac plus 30% Z5-14Ac. We found that type I males are attracted to type I females when offered a choice between type I and type II females in a field cage test and that type II males similarly prefer type II females. Males of types I and II have specialist cells for Z8-14Ac and Z5-14Ac but differ with respect to relative densities of these cells and to further cell types responsive to other alkenyl acetates. Type IIC. obliquana is considered therefore a sibling species of types I and III. In addition, the amount of Z5-14Ac produced by type II females varied geographically. Females from the North Island produced significantly less (median=1.2 ng) Z5-14Ac than females from the South Island (median=2.2 ng). Type II populations in the North Island morphologically resembled sympatric type I, rather than type II from the South Island and are designated as type II (North Island). Type II (North Island) populations have so far been found only at Rukuhia (near Hamilton) and from Kerikeri. In contrast, type II populations are sympatric with type III populations over much of the South Island. In a field cage trial, males of types II and II (North Island) were attracted to females of both II and II (North Island). We tentatively ascribe the differences between type II and type II (North Island) to intraspecific variation.     

明胶复合Co-Fe-O体纳米微粉的合成和特性

用微乳液法制备了明胶复合的纳米Co Fe O体。将明胶和亚铁盐以及钴盐制成凝胶,使该凝胶状反应物在微乳液的胶束中反应,再被还原-化合-成核长大。用XRD、TEM、SEM、EDS、IR等测试表明:微粉为明胶包裹的球形纳米微球。生成的微粒处于明胶蛋白分子的包裹之中,单个微粒的粒径3 3～4 6nm,每个复合微球中约有3～22个Co Fe O体粒子组成,微球的平均粒径为10～100nm,Co-Fe-O体复合微粉的比饱和磁化强度σs=1 532kAm-1·g-1;矫顽力Hc=18 4kAm-1;剩磁σr=322 5Am-1·g-1。     

Electrochemical characteristics for redox systems at nano-honeycomb diamond

Electrochemical characteristics for several redox systems at diamond films with highly ordered nanometer-scale cylindrical pores (‘nano-honeycombs’) were examined with cyclic voltammetry (CV) and electrochemical impedance measurements. The cyclic voltammetric anodic-cathodic peak separations for these nano-honeycomb electrodes were in the same range as those for polished polycrystalline diamond films, indicating that the involvement of the oxygen-terminated surface of the nano-pore walls, which should give rise to large peak separations for certain redox couples was only slight. Moreover, the peak currents in the CV were not enhanced to the extent expected on the basis of the roughness factors of the nano-honeycomb films. Ac impedance plots results indicated the existence of a concentration gradient of the reactant in the nano-pores, which is in agreement with theoretical predictions for charge transfer reactions in porous electrodes. The average concentration of the reactant (Fe^2+/3+) inside the nano-pores was a factor of ca. 80 lower than that in the bulk electrolyte. The results of the impedance analysis also indicated an increase in the reaction resistances with decreasing pore diameters.     

Molecular weight averages as criteria for quality assessment of heated oils and fats

A simple method for quality assessment of heated oils and fats is described. The proposed method involves precise determination of molecular weight averages (MWA)viz., the weight average molecular weight ( ), the number average molecular weight ( ) and the Z-average molecular weight ( ) by high performance size exclusion chromatography (HPSEC) and their quantitative correlation to percent polar material obtained by column chromatography (CC). Change in MWA on heat treatment of fourteen different edible oils and fats at 180° ± 2°C for eight 8-hr days is studied. Relative standard deviations and regression coefficients of correlation between MWA and their ratios ( , { }, { }, { }, { } and { )vs percent polar material have been reported. Probable discard time was predicted for all the oils based on the above-mentioned correlations and also from the percent of high molecular weight (H. Mwt) species formed. It was observed that the oils which are generally recommended for coronary patients deteriorated faster. A possibility of extending this methodology to the frying oils is suggested. Part of the work was presented at “40th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy” at Georgia World Congress Centre, USA, 1989. IICT Communication No. 2630.     

江苏省耐盐生物质能源植物选育和生物柴油制备研究

江苏省有近67万公顷沿海盐土滩涂资源,发展适应这些土地资源的油料植物对促进江苏省生物质能的产业化具有极大的促进作用.本研究针对江苏省土地资源的特点,自2001年,从江苏盐城种植了近10年的美国耐盐油料植物海滨锦葵6万株自然群体中筛选了40个优良单株,并进行了子代测定.目前已经初步选育出了海滨锦葵优良无性系,含油量从原群体平均的18 %提高到23 %.2005年首次从耐盐油料植物海滨锦葵中成功获得生物柴油实验室样品,并已经得到中石化权威机构检测数据.