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Laura Micheli Lara Testai Andrea Angeli Donatello Carrino Alessandra Pacini Francesco Margiotta Lorenzo Flori Claudiu T. Supuran Vincenzo Calderone Carla Ghelardini Lorenzo Di Cesare Mannelli 《International journal of molecular sciences》2022,23(11)
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. 相似文献
44.
Xavier Vanhoye Alexandre Janin Amandine Caillaud Antoine Rimbert Fabienne Venet Morgane Gossez Wieneke Dijk Oriane Marmontel Sverine Nony Charlotte Chatelain Christine Durand Pierre Lindenbaum Jennifer Rieusset Bertrand Cariou Philippe Moulin Mathilde Di Filippo 《International journal of molecular sciences》2022,23(8)
Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry APOB missense variants of uncertain significance (VUS). We here aimed to develop a proof-of-principle experiment to assess the pathogenicity of VUS using the genome editing of human liver cells. We identified a novel heterozygous APOB-VUS (p.Leu351Arg), in a FHBL family. We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in Huh7 cells using CRISPR-Cas9 technology and studied the APOB expression, synthesis and secretion by digital droplet PCR and ELISA quantification. The APOB expression was decreased by 70% in the heterozygous APOB-KO cells and almost abolished in the homozygous-KO cells, with a consistent decrease in apoB production and secretion. The APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Thus, the p.Leu351Arg affected the apoB secretion, which led us to classify this new variant as likely pathogenic and to set up a hepatic follow-up in this family. Therefore, the functional assessment of APOB-missense variants, using gene-editing technologies, will lead to improvements in the molecular diagnosis of FHBL and the personalized follow-up of these patients. 相似文献
45.
New stainless steel inserts are developed for fastening sheet molding compound (SMC). Using these molded-in inserts, SMC components can be assembled without protrusions. The inserts consist of two mating surfaces which interlock through the existence of a shoulder male boss and a shoulder female counterbore. Repeated assembly and disassembly can take place without damaging the material being fastened. The strength of the joint, when using these interlocking inserts, is comparable to that when using bolts. Also being investigated is the strength of the joint after being immersed in water for half a month. The difference between the dry and wet strengths for the inserted samples is less than that for the bolted samples. Load versus extension plots show that these particular inserts provide a more rigid joint than a bolted connection. 相似文献
46.
Elisa Di Fabio Antonia Iazzetti Alessio Incocciati Valentina Caseli Giancarlo Fabrizi Alberto Boffi Alessandra Bonamore Alberto Macone 《International journal of molecular sciences》2022,23(12)
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. 相似文献
47.
原油标准体积管结蜡造成的后果及解决方法 总被引:1,自引:0,他引:1
徐涤 《天津城市建设学院学报》2000,6(1):53-55
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。 相似文献
48.
Shaoming Liang Shanbin Xu Di Qu Luomiao Yang Jingguo Wang Hualong Liu Wei Xin Detang Zou Hongliang Zheng 《International journal of molecular sciences》2022,23(15)
Caffeic acid O-methyltransferase (COMT) is one of the core enzymes involved in lignin synthesis. However, there is no systematic study on the rice COMT gene family. We identified 33 COMT genes containing the methyltransferase-2 domain in the rice genome using bioinformatic methods and divided them into Group I (a and b) and Group II. Motifs, conserved domains, gene structure and SNPs density are related to the classification of OsCOMTs. The tandem phenomenon plays a key role in the expansion of OsCOMTs. The expression levels of fourteen and thirteen OsCOMTs increased or decreased under salt stress and drought stress, respectively. OsCOMTs showed higher expression levels in the stem. The lignin content of rice was measured in five stages; combined with the expression analysis of OsCOMTs and multiple sequence alignment, we found that OsCOMT8, OsCOMT9 and OsCOMT15 play a key role in the synthesis of lignin. Targeted miRNAs and gene ontology annotation revealed that OsCOMTs were involved in abiotic stress responses. Our study contributes to the analysis of the biological function of OsCOMTs, which may provide information for future rice breeding and editing of the rice genome. 相似文献
49.
生物医用钛合金具有高强度、良好的耐蚀性能、较低的弹性模量、优异的生物相容性,已成为具有广阔应用前景的医用金属材料之一.与传统医用钛合金相比,超细晶医用钛合金具有更高的强度与更好的疲劳性能以及耐腐蚀性能.此外,超细晶钛合金可诱导骨组织向内生长,增加界面结合强度,加快骨修复进程,在硬组织修复材料领域具有广阔的应用前景.阐述了各种大塑性变形(Severe Plastic Deformation)法制备超细晶生物医用钛合金的研究状况与最新进展,指出了SPD法制备医用钛合金中存在的技术问题和发展方向,并展望了利用SPD法对生物医用钛合金改性将成为生物医用材料的研究热点. 相似文献
50.
Self-organizing Cloud is a scalable model to provide powerful computability with distributed computers. The resource allocation on it is very challenging since it not only involves various types of divisible resources but needs to cope with social competitions. We propose a novel resource allocation scheme with three features on ex-post efficiency. (1) Ex-post win–win effect: each participant (consumers and suppliers) should always feel satisfied with their ex-post payoffs. (2) Incentive compatibility: we can prove each rational participant gets its optimal payoff iff their resource demands and expected prices are truthfully declared. (3) Ex-post maximized efficiency: more powerful resources should be consumed with higher likelihood, such that the whole system runs quite efficiently with maximized resource utilization. Our simulation shows the approach significantly improves resource suppliers’ incomes by 20% compared to their expectations. Meanwhile, we can guarantee consumers’ payments below their budgets, with no any degradation of task execution performance. 相似文献