Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient’s quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca²⁺ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30–100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.     

Immobilization of Lathyrus cicera Amine Oxidase on Magnetic Microparticles for Biocatalytic Applications

Amine oxidases are enzymes belonging to the class of oxidoreductases that are widespread, from bacteria to humans. The amine oxidase from Lathyrus cicera has recently appeared in the landscape of biocatalysis, showing good potential in the green synthesis of aldehydes. This enzyme catalyzes the oxidative deamination of a wide range of primary amines into the corresponding aldehydes but its use as a biocatalyst is challenging due to the possible inactivation that might occur at high product concentrations. Here, we show that the enzyme’s performance can be greatly improved by immobilization on solid supports. The best results are achieved using amino-functionalized magnetic microparticles: the immobilized enzyme retains its activity, greatly improves its thermostability (4 h at 75 °C), and can be recycled up to 8 times with a set of aromatic ethylamines. After the last reaction cycle, the overall conversion is about 90% for all tested substrates, with an aldehyde production ranging between 100 and 270 mg depending on the substrate used. As a proof concept, one of the aldehydes thus produced was successfully used for the biomimetic synthesis of a non-natural benzylisoquinoline alkaloid.     

Localization-limited exciton oscillator strength in colloidal CdSe nanoplatelets revealed by the optically induced stark effect

2D materials are considered for applications that require strong light-matter interaction because of the apparently giant oscillator strength of the exciton tra...     

原油标准体积管结蜡造成的后果及解决方法

探讨了原油动态计量中标准体积管结蜡所引起的误差、原因分析和经济损失,提出了解决问题的办法。     

冷却工艺对新型高速列车焊接构架用钢组织演变的影响

针对高速列车焊接构架用钢的性能要求,设计了一种低成本的Mn-Cu微合金低碳钢,并对该实验钢的连续冷却转变规律以及冷却工艺对组织演变的影响进行了研究.结果表明,实验钢在较宽的冷速范围(1～30℃/s)内均可以获得先共析铁素体和中温相变组织.冷却速度和卷取温度对最终组织形态和细化有着重要影响,轧制结束后立即加速冷却至500～600℃,再缓冷,可以获得以细小准多边形铁素体、针状铁素体和粒状贝氏体为主的混合组织.经实验室控轧控冷验证了具有该组织形态的12 mm中厚钢板屈服强度可达540 MPa,同时拥有良好的塑性和低温韧性.     

Effect of Controlled Cooling After Hot Rolling on Mechanical Properties of Hot Rolled TRIP Steel

A three-step cooling pattern on the runout table（ROT）was conducted for the hot rolled TRIP steel.Microstructural evolution during thermomechanical controlled processing（TMCP）was investigated.Processing condition of controlled cooling on a ROT in the laboratory rolling mill was discussed.The results indicated that the microstructure containing polygonal ferrite,granular bainite and a significant amount of the stable retained austenite can be obtained through three-step cooling on the ROT after hot rolling.TMCP led to ferrite grain refinement.Controlled cooling after hot rolling resulted in the stability of the remaining austenite and a satisfactory TRIP effect.Excellent mechanical properties were obtained through TMCP for the hot rolled TRIP steel.     

Molecular Effects of Chronic Exposure to Palmitate in Intestinal Organoids: A New Model to Study Obesity and Diabetes

Intestinal cell dysfunctions involved in obesity and associated diabetes could be correlated with impaired intestinal cell development. To date, the molecular mechanisms underlying these dysfunctions have been poorly investigated because of the lack of a good model for studying obesity. The main aim of this study was to investigate the effects of lipotoxicity on intestinal cell differentiation in small intestinal organoid platforms, which are used to analyze the regulation of cell differentiation. Mouse intestinal organoids were grown in the presence/absence of high palmitate concentrations (0.5 mM) for 48 h to simulate lipotoxicity. Palmitate treatment altered the expression of markers involved in the differentiation of enterocytes and goblet cells in the early (Hes1) and late (Muc2) phases of their development, respectively, and it modified enterocytes and goblet cell numbers. Furthermore, the expression of enteroendocrine cell progenitors (Ngn3) and I cells (CCK) markers was also impaired, as well as CCK-positive cell numbers and CCK secretion. Our data indicate, for the first time, that lipotoxicity simultaneously influences the differentiation of specific intestinal cell types in the gut: enterocytes, goblet cells and CCK cells. Through this study, we identified novel targets associated with molecular mechanisms affected by lipotoxicity that could be important for obesity and diabetes therapy.     

江苏油田三种典型钻具组合复合井导向力计算分析

结合江苏油田导向钻井技术现场试验中采用的三种典型的滑动导向钻具组合,在计算复合钻井导向力的基础上,探讨了两个主要因素对复合钻井导向力的影响规律,理论计算结果与现场试验结果基本吻合,通过设计钻具组合的结构和施工参数,可以提高井眼轨迹控制精度。     

3次加密挂环井井口计量准确度研究

3次加密井在投产过程中,对地面集输工艺流程进行了大力简化。简化流程后,井口计量存在的一个主要问题是软件量油的准确度。为此结合现场应用情况,对挂环井的计量问题进行分析、探讨,提出了挂环井的计量解决方案。     

The Potentiality of Plant-Derived Nanovesicles in Human Health—A Comparison with Human Exosomes and Artificial Nanoparticles

Research in science and medicine is witnessing a massive increases in literature concerning extracellular vesicles (EVs). From a morphological point of view, EVs include extracellular vesicles of a micro and nano sizes. However, this simplistic classification does not consider both the source of EVs, including the cells and the species from which Evs are obtained, and the microenvironmental condition during EV production. These two factors are of crucial importance for the potential use of Evs as therapeutic agents. In fact, the choice of the most suitable Evs for drug delivery remains an open debate, inasmuch as the use of Evs of human origin may have at least two major problems: (i) autologous Evs from a patient may deliver dangerous molecules; and (ii) the production of EVs is also limited to cell factory conditions for large-scale industrial use. Recent literature, while limited to only a few papers, when compared to the papers on the use of human EVs, suggests that plant-derived nanovesicles (PDNV) may represent a valuable tool for extensive use in health care.