GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.     

Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-β oligomers

The production of amyloid-β (Aβ) is the key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of Aβ within the brain cause synapse degeneration and the dementia that is characteristic of AD. Here the factors that affect the release of disease-relevant forms Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released soluble Aβ oligomers that caused synapse damage in cultured neurons. Supernatants from 7PA2 cells treated with the cholesterol synthesis inhibitor squalestatin contained similar concentrations of Aβ₄₂ to control cells but did not cause synapse damage in neuronal cultures. These supernatants contained reduced concentrations of Aβ₄₂ oligomers and increased concentrations of Aβ₄₂ monomers. Treatment of 7PA2 cells with platelet-activating factor (PAF) antagonists had similar effects; it reduced concentrations of Aβ₄₂ oligomers and increased concentrations of Aβ₄₂ monomers in cell supernatants. PAF activated cholesterol ester hydrolases (CEH), enzymes that released cholesterol from stores of cholesterol esters. Inhibition of CEH also reduced concentrations of Aβ₄₂ oligomers and increased concentrations of Aβ₄₂ monomers in cell supernatants. The Aβ monomers produced by treated cells protected neurons against Aβ oligomer-induced synapse damage. These studies indicate that pharmacological manipulation of cells can alter the ratio of Aβ monomer:oligomer released and consequently their effects on synapses.     

光通过散射介质聚焦的空间位相逐个单元调节方法

本研究在分析现有散射介质聚焦方法的基础上,提出一种利用单元裂解进行波前位相调制,将经过强散射介质的散射光聚焦的快速收敛方法.文中详细地描述了这一新方法的原理,并同现有逐个单元调节方法进行运行对比.单元裂解方法的物理本质,即为实现空间光调制器的调制各单元光波之间同位相干涉.本方法具有更高的信噪比,并且聚焦收敛的速度快.这一新方法为进一步开展生物成像的光学理论研究提供了新思路.     

鼓室内注射地塞米松联合盐酸氨溴索对分泌性中耳炎患者听力水平及免疫功能的影响

目的:探讨鼓室内注射地塞米松联合盐酸氨溴索对分泌性中耳炎(SOM)患者听力水平及免疫功能的影响。方法:选取2017年5月-2017年11月期间我院收治的SOM患者240例为研究对象。根据随机数字表法将患者分为对照组(n=120)与研究组(n=120),对照组给予鼓室内注入地塞米松治疗,研究组在此基础上联合盐酸氨溴索治疗。比较两组患者临床疗效,比较两组患者治疗前后0.5KHz、1.0KHz、2.0KHz频率下的气导听力水平、鼓室压及CD4+、CD8+、CD4+/CD8+水平,同时观察两组不良反应发生情况。结果:治疗后研究组患者总有效率为86.67%(104/120),高于对照组的70.83%(85/120)(P0.05)。两组患者治疗后0.5KHz、1.0KHz、2.0KHz的气导听力水平以及鼓室压均较治疗前升高,且研究组高于对照组(P0.05)。两组患者治疗后CD4+、CD4+/CD8+均较治疗前升高,且研究组高于对照组(P0.05);两组患者治疗后CD8+较治疗前降低(P0.05),但研究组与对照组比较无差异(P0.05)。两组患者在治疗期间均未发生严重的不良反应。结论:地塞米松联合盐酸氨溴索治疗SOM患者疗效确切,对患者的免疫功能及听力水平均有一定的改善作用,安全性好,具有一定的临床应用价值。     

The secretion of urokinase-like plasminogen activator is inhibited by microtubule-interacting drugs

The secretion of proteinases into the extracellular matrix is one of the main features of tumour cells, as related to their invasive behaviour. Considering the role of the microtubule cytoskeleton, and particularly the action of microtubule-associated protein (MAPs) in mediating protein secretion, the effects of the anti-microtubule drugs estramustine and taxol, on the secretion of urokinase-type plasminogen activator (u-PA) and the 72 kDa gelatinase were investigated. Treatment of 5637 bladder carcinoma cells with estramustine and taxol inhibited u-PA secretion into the conditioned medium in a drug concentration-dependent fashion. This inhibition was confirmed by determinations of u-PA enzymatic activities and by measurements of the levels of immunoreactive activator. Studies using gelatin zymograms also showed an inhibition of another tumoural proteinase namely the 72 kDa gelatinase. Time-course uptake experiments showed that estramustine was incorporated into the cells, a process which depended on temperature. On the other hand, immunofluorescence studies indicated that the microtubule network was affected by taxol with the formation of bundles of microtubules at different cell domains. Minor effects were visualized after treatment of the cells with estramustine-phosphate, a drug that blocks primarily the action of microtubule-associated proteins. The studies provide a way to analyse the relationships between u-PA secretion and the integrity of the cytoskeletal network.     

Feruloyl esterase production by Aspergillus terreus CECT 2808 and subsequent application to enzymatic hydrolysis

Ferulic acid esterases (FAE) were produced by Aspergillus terreus CECT 2808 from vine trimming shoots (VTS) and corn cob. Later, the fungal extracts thus obtained were used to enzymatically release ferulic acid (FA) from both substrates. Our findings showed a higher FAE activity in the enzymatic extracts produced on corn cob (0.070 ± 0.004 U/mL). Nevertheless, the enzymatic extracts produced on VTS demonstrated a better performance for FA release from both corn cob (2.05 ± 0.01 mg/g) and VTS (0.19 ± 0.003 mg/g). This result was probably because of the higher xylanase/FAE ratio determined in VTS extract. Therefore, an additional assay was carried out by supplementing corn cob extract with a commercial xylanase to test the influence of FAE/xylanase ratio in FA release. The results revealed the relevance of the FAE/xylanase ratio for an optimal FA release.     

Optimization of Nutrient and Fermentation Parameters for Antifungal Activity by Streptomyces lavendulae Xjy and Its Biocontrol Efficacies against Fulvia fulva and Botryosphaeria dothidea

This study has been proved that statistical experimental designs offer efficient and feasible approaches for determination of culture medium and fermentation conditions of Streptomyces lavendulae Xjy. Nutrition and cultural conditions have high influence on the antibiotic production of S. lavendulae Xjy. Soya bean meal, NaCl and (NH₄)₂SO₄ were identified as the best ingredients for high antifungal activity of Xjy based on single variable experiments. Using response surface methodology, the best concentrations of medium ingredients were 1.46% soya bean meal, 2.25% NaCl and 1.26% (NH₄)₂SO₄. The potential components were reduced from seven to three, and the antibiotic activity was increased by 10%. The optimized conditions for Xjy in a 250‐ml Erlenmeyer flask were initial pH 5, medium volume 25 ml/250 ml and inoculation volume 10% at 30°C with 200 rpm by response surface methodology. Validation experiments carried out to check the accuracy of the models indicated that the predicted values agreed with the experimental values. The extension of necrosis lesion of Botryosphaeria dothidea was impeded by the application of Xjy in apple fruit. In tomato plants, Xjy showed the 43.7–51.7% curative and protective effects against Fulvia fulva. The optimal medium not only gave a 20% increase in antifungal activity, but it provided a simpler formulation. The results will set a basis for further study on large‐scale fermentation volumes using S. lavendulae Xjy and be useful for the development of more advanced control strategies on plant diseases.     

Accuracy of dose calculation algorithms for static and rotational IMRT of lung cancer: A phantom study

PurposeTo evaluate the dosimetric accuracy of Pencil beam (PB), Anisotropic Analytical Algorithm (AAA) and Collapsed Cone Convolution Superposition (CCCS) in thoracic tumours for various IMRT techniques.MethodsStep-and-shoot Linac IMRT (IMRT), arc volumetric RapidArc (RA) and Helical Tomotherapy (HT) lung treatments for different clinical situations (mediastinum tumour, single metastasis and multiple metastases) were simulated and calculated with PB/AAA, AAA, CCCS, respectively. Delivery quality assurance plans were first verified in homogeneous media (Cheese phantom and ArcCHECK); then several low-density inhomogeneous phantoms were used: the Multiplug ArcCHECK, the commercial ArcCHECK slightly modified with a low density lung–shape insert and a custom-made slab heterogeneous phantom simulating the thorax region. Absolute doses and planar dose maps were checked to assess the agreement between measured and calculated dose distributions.ResultsIn total, data referred to 195 point dose measurements and 189 planar measurements were considered. Average point absolute deviations <3% were found for all the delivery techniques/dose algorithms. In small targets completely embedded in very low density media, deviations up to 7–10% and 4–5% were found for PB and AAA/CCCS respectively. Excellent results were found for planar measurements in ArcCHECK configurations, where ≥95% of points satisfy the 3%/3 mm acceptance criteria for all the algorithms.ConclusionsA satisfactory agreement (<2%) between planned and measured doses was generally found for CCCS and AAA, excepting the very critical situation of a small tumour completely embedded in air. A significant dose overestimation (from few to 5–7%) was confirmed for PB in complex inhomogeneous arrangements.     

Hydrolytic resolution of (R,S)-2-hydroxycarboxylic acid esters in biphasic media: implication for rate-limiting formation or breakdown of tetrahedral intermediates in acylation step

A thermally stable esterase (SNSM‐87) from Klebsiella oxytoca is explored as an enantioselective biocatalyst for the hydrolytic resolution of (R,S)‐2‐hydroxycarboxylic acid esters in biphasic media, where the best methyl esters possessing the highest enantioselectivity and reactivity are selected and elucidated in terms of the structure–enantioselectivity correlations and substrate partitioning in the aqueous phase. With (R,S)‐2‐chloromandelates as the model substrates, an expanded Michaelis–Menten mechanism for the rate‐limiting acylation step is adopted for the kinetic analysis. The Brønsted slope of 25.7 for the fast‐reacting (S)‐2‐chloromandelates containing a difficult leaving alcohol moiety, as well as that of 4.13 for the slow‐reacting (R)‐2‐chloromandelates in the whole range of leaving alcohol moieties, indicates that the breakdown of tetrahedral intermediates to acyl‐enzyme intermediates is rate‐limiting. However, the rate‐limiting step shifts to the formation of tetrahedral intermediates for the (S)‐2‐chloromandelates containing an easy leaving alcohol moiety, and leads to an optimal enantioselectivity for the methyl ester substrate. Biotechnol. Bioeng. 2007; 98: 30–38. © 2007 Wiley Periodicals, Inc.