Decreased Glucocorticoid Signaling Potentiates Lipid-Induced Inflammation and Contributes to Insulin Resistance in the Skeletal Muscle of Fructose-Fed Male Rats Exposed to Stress

The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and β-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Akt, as well as the level of 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor. At the same time, increased levels of protein tyrosine phosphatase-1B, nuclear factor-κB, tumor necrosis factor-α, were observed in the muscle of fructose-fed stressed rats. Based on these results, we propose that decreased glucocorticoid signaling in the skeletal muscle can make a setting for lipid-induced inflammation and the development of insulin resistance in fructose-fed stressed rats.     

Association of toxic and essential metals with atopy markers and ventilatory lung function in women and men

The association of age, smoking, alcohol, superoxide dismutase (SOD), glutathione peroxidase (GPx), blood lead (BPb) and cadmium (BCd) levels, and serum levels of copper (SCu), zinc (SZn) and selenium (SSe) with atopic status and ventilatory function was examined in the groups of 166 women and 50 men with no occupational exposure to metals or other xenobiotics. Markers of atopy included serum total IgE, skin prick test (SPT) to common inhalatory allergens, non-specific nasal reactivity (NNR) and non-specific bronchial reactivity (NBR). Parameters of ventilatory function included forced vital capacity (FVC) and forced expiratory volume in the first second (FEV(1)). Significantly higher BPb, SZn, IgE and prevalence of positive SPT, and lower SCu and NNR was found in men than in women. Fifteen women taking female sex hormones (HT) had significantly higher SCu than women without HT. Regression models showed significant inverse associations between IgE and SCu (P=0.021) and NNR and SCu (P=0.044) in women. When excluding women with HT, the association of SCu and total IgE became of borderline significance (P=0.051), association between SCu and NNR disappeared, and significant positive association between total IgE and BPb emerged (P=0.046). In men, significant inverse association was found between positive SPT and SSe, and between NBR and SSe. A decrease in FVC% and FEV(1)% was associated with an increase in smoking intensity (P<0.001) and a decrease in SZn (P=0.043 and P=0.053, respectively). These results were observed at the levels of the metals comparable to those in general populations worldwide. The observed differences between men and women may partly be explained by different levels of relevant toxic and essential metals, and their combination. The role of female HT in associations of atopy markers and SCu should be further investigated.     

Bacterial population in counter flow and parallel flow water chilling of poultry meat

In this study, a survey was carried out to determine the hygiene aspects of counter flow and parallel flow water chilling of poultry meat. Samples were taken in five sectors: in the sector subsequent to evisceration of the poultry, in the sector after water chilling, and in the sector after final washing. At the same time, the samples of water were taken from the pre-chilling sector and in the chilling sector. Bacterial detection of the inherence of various bacteria, their isolation, identification and determination was carried out. The results showed higher numbers of positive samples obtained from the section of water chilling in comparison to other sections, as well as a higher number of positive samples in the process of parallel flow water chilling in comparison to the results from counter flow chilling.     

后悬对正碰车身加速度的影响研究

针对同一车型的高配车与低配车正碰法规试验结果差异明显的情况,应用有限元仿真技术,进行了时间分解、空间分解、碰撞力分解,绘制了正碰耐撞性能图谱,对造成试验结果差异的后悬总成进行子系统动态分析,研究结果表明,发动机前置后驱式车辆的底盘传力对正碰有重要影响,五杆螺旋弹簧式后悬比钢板弹簧式后悬纵向刚度更大,导致第二时间段内高配车车身加速度明显高于低配车,在此基础上提出了相应的解决方案。     

Stilbene levels and antioxidant activity of Vranec and Merlot wines from Macedonia: Effect of variety and enological practices

The content of the stilbenes trans-resveratrol and piceid as well as the antioxidant activity of Macedonian red wines from the two main grape varieties Vranec and Merlot have been evaluated. Тhe effects of time of maceration, type of yeast and the level of sulphur dioxide applied on stilbene content and antioxidant activity have been studied. The most important factor in winemaking technology is the maceration time since the highest concentrations of trans-resveratrol, piceid and highest antioxidant activity were found following 6 and 10 days of maceration. Concerning the yeast type, higher concentrations of trans-resveratrol and piceid have been obtained with French yeast “Levuline CHP” in comparison to Macedonian yeast “Vinalco”. In contrast, the higher antioxidant activity of wines from both varieties of grapes was observed by application of Macedonian yeast “Vinalco”.     

N-甲基甘氨酸及类乙二胺二乙酸型配体钴(Ⅲ)配合物的合成与表征

合成了N-甲基甘氨酸及相应四齿配体[乙二胺二乙酸(edda)、乙二胺二丙酸(eddp)、1,3-丙二胺二乙酸(pdda)]钴(Ⅲ)配合物的几种经式几何异构体,其中edda和eddp钴(Ⅲ)配合物的合成是通过相应的N-甲基甘氨酸与edda碳酸合钴(Ⅲ)酸钠及反对称-顺式-pdda碳酸合钴(Ⅲ)酸钠二水合物来制备的.而pdda-Co(Ⅲ)配合物采用一种新方法直接合成(CoCl2*H2O在有PbO2存在下直接与pdda反应).诸配合物通过层析色谱柱分离,并用元素分析、电子光谱、红外和1H核磁共振所表征.     

Decoding the Role of DVL1 in Intracranial Meningioma

In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active β-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway.     

Biocompatibility Analyses of HF-Passivated Magnesium Screws for Guided Bone Regeneration (GBR)

Background: Magnesium (Mg) is one of the most promising materials for human use in surgery due to material characteristics such as its elastic modulus as well as its resorbable and regenerative properties. In this study, HF-coated and uncoated novel bioresorbable magnesium fixation screws for maxillofacial and dental surgical applications were investigated in vitro and in vivo to evaluate the biocompatibility of the HF coating. Methods: Mg alloy screws that had either undergone a surface treatment with hydrofluoric-acid (HF) or left untreated were investigated. In vitro investigation included XTT, BrdU and LDH in accordance with the DIN ISO 10993-5/-12. In vivo, the screws were implanted into the tibia of rabbits. After 3 and 6 weeks, degradation, local tissue reactions and bony integration were analyzed histopathologically and histomorphometrically. Additionally, SEM/EDX analysis and synchrotron phase-contrast microtomography (µCT) measurements were conducted. The in vitro analyses revealed that the Mg screws are cytocompatible, with improved results when the surface had been passivated with HF. In vivo, the HF-treated Mg screws implanted showed a reduction in gas formation, slower biodegradation and a better bony integration in comparison to the untreated Mg screws. Histopathologically, the HF-passivated screws induced a layer of macrophages as part of its biodegradation process, whereas the untreated screws caused a slight fibrous tissue reaction. SEM/EDX analysis showed that both screws formed a similar layer of calcium phosphates on their surfaces and were surrounded by bone. Furthermore, the µCT revealed the presence of a metallic core of the screws, a faster absorbing corrosion front and a slow absorbing region of corroded magnesium. Conclusions: Overall, the HF-passivated Mg fixation screws showed significantly better biocompatibility in vitro and in vivo compared to the untreated screws.     

The Enhanced Cytotoxic Effects in B-Cell Leukemia and Lymphoma Following Activation of Prostaglandin EP4 Receptor and Targeting of CD20 Antigen by Monoclonal Antibodies

Anti-CD20 monoclonal antibodies (MAbs) have revolutionized the treatment of B-cell leukemia and lymphoma. However, many patients do not respond to such treatment due to either deficiency of the complementary immune response or resistance to apoptosis. Other currently available treatments are often inadequate or induce major side effects. Therefore, there is a constant need for improved therapies. The prostaglandin E2 receptor 4 (EP4) receptor has been identified as a promising therapeutic target for hematologic B-cell malignancies. Herein, we report that EP4 receptor agonists PgE1-OH and L-902688 have exhibited enhanced cytotoxicity when applied together with anti-CD20 MAbs rituximab, ofatumumab and obinutuzumab in vitro in Burkitt lymphoma cells Ramos, as well as in p53-deficient chronic lymphocytic leukemia (CLL) cells MEC-1. Moreover, the enhanced cytotoxic effects of EP4 receptor agonists and MAbs targeting CD20 have been identified ex vivo on primary lymphocytes B obtained from patients diagnosed with CLL. Incubation of cells with PgE1-OH and L-902688 preserved the expression of CD20 molecules, further confirming the anti-leukemic potential of EP4 receptor agonists in combination with anti-CD20 MAbs. Additionally, we demonstrated that the EP4 receptor agonist PgE-1-OH induced apoptosis and inhibited proliferation via the EP4 receptor triggering in CLL. This work has revealed very important findings leading towards the elucidation of the anticancer potential of PgE1-OH and L-902688, either alone or in combination with MAbs. This may contribute to the development of potential therapeutic alternatives for patients with B-cell malignancies.     

The Discovery and Structure-Activity Evaluation of (+)-Floyocidin B and Synthetic Analogs

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug-resistant M. tuberculosis makes the discovery of novel anti-tuberculosis active structures an urgent priority. Here, we show that (+)-floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus-derived natural products, displays promising antitubercular hit properties. (+)-Floyocidin B was identified by activity-guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X-ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)-floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure-activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.