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71.
Endalkachew Nibret Frank Sporer Kaleab Asres Professor Dr Michael Wink 《The Journal of pharmacy and pharmacology》2009,61(6):801-808
Objectives The objective was to determine the in‐vitro effect of extracts from 19 Ethiopian plant species and four pure pyrrolizidine alkaloids on bloodstream forms of Trypanosoma brucei brucei and human leukaemia HL‐60 cells. Methods Crude plant extracts were prepared using methanol and dichloromethane. The alkaloidal extracts from Solanecio angulatus flowers were prepared with and without zinc reduction using the acid‐base extraction method. Cell proliferation inhibitory activity of the extracts and compounds was assessed using Alamarblue. Key findings The most active extract was the dichloromethane extract of Solanecio angulatus flowers, with an IC50 value of 12.17 μg/ml. The best selectivity index (SI > 41.08) was obtained for the same extract determined with HL‐60 cells. The reduced alkaloidal extract prepared from S. angulatus flowers and after acid‐base extraction showed more antitrypanosomal activity than unreduced alkaloidal extract with an IC50 value of 14.35 μg/ml and with a selectivity index of 12.23. The second most active extract was the dichloromethane extract of Crotalaria phillipsiae twigs with an IC50 value of 12.67 μg/ml and a selectivity index of 34.35. Most of the other extracts tested showed moderate antitrypanosomal activities to variable extents. Among the four pure pyrrolizidine alkaloids tested, senecionine showed moderate antitrypanosomal activity with an IC50 value of 41.78 μg/ml. Conclusions Solanecio angulatus (flowers) and Crotalaria phillipsiae (twigs) could serve as sources of novel trypanocidal compounds for the treatment of trypanosomiasis. 相似文献
72.
73.
Hahn S Backhaus M Broecker-Preuss M Tan S Dietz T Kimmig R Schmidt M Mann K Janssen OE 《European journal of endocrinology / European Federation of Endocrine Societies》2007,157(2):201-207
OBJECTIVE: Insulin resistance and obesity are common features of the polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4), a new fat-derived adipokine, has been described to be elevated in obesity and type 2 diabetes. The aim of the present study was to investigate whether serum RBP4 levels are correlated with metabolic parameters, indices of insulin resistance, and endocrine variables in German PCOS women. DESIGN: We assessed the correlation between metabolic and endocrine parameters with RBP4 levels in 200 PCOS patients and 64 healthy controls. METHODS: Serum RBP4 was measured by enzyme-linked immunosorbent assay (Immundiagnostik AG, Bensheim, Germany). In addition, anthropometric variables, clinical signs of hyperandrogenism, and body fat were evaluated, and a glucose tolerance test was performed to assess parameters of insulin resistance and glucose metabolism. RESULTS: Taking the entire PCOS cohort, RBP4 levels were positively correlated with body mass index (BMI), body fat, waist circumference, fasting glucose, and area under the curve for glucose (all P<0.05), but not with indices of insulin resistance. On the other hand, PCOS women with impaired glucose metabolism had higher RBP4 levels than PCOS women with normal glucose metabolism (median 30.6, range 23.3-73.9 versus median 26.3, range 6.4-61.4, P<0.05). Furthermore, no differences were found in RBP4 levels between lean PCOS women and BMI-matched healthy controls. CONCLUSION: In German PCOS women, serum RBP4 levels are associated with obesity and parameters of glucose metabolism but not with PCOS per se. 相似文献
74.
de Kloet ER Derijk RH Meijer OC 《Nature clinical practice. Endocrinology & metabolism》2007,3(2):168-179
In severely depressed patients, emotional arousal, cognitive abnormality and vulnerability to psychotic episodes are linked to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis and high levels of circulating cortisol. The susceptibility pathways underlying these disturbed brain functions are influenced by genetic factors, early-life priming experiences and later-life events. Cortisol is an important determinant in this so-called three hit model. The action of cortisol is protective, but can become harmful if exposure of susceptibility pathways to the stress hormone is excessive and sustained or inadequate. In this article we argue that this change in role of cortisol from protective into harmful depends on the functioning of the mineralocorticoid and glucocorticoid receptors and the context in which the organism experiences the stressor. Actions mediated by the mineralocorticoid and glucocorticoid receptors are complementary and operate in different time domains of the stress response: the mineralocorticoid receptor normally prevents stress-induced disturbances, but if such disturbances occur the glucocorticoid receptor helps the recovery process. An imbalance in these receptor-mediated actions is thought to increase vulnerability to stress-related psychiatric disorders in predisposed individuals. Correction of the imbalance between the mineralocorticoid receptor and the glucocorticoid receptor can, therefore, facilitate recovery processes still present in the diseased brain, provided that the right psychological context is offered to the individual. 相似文献
75.
State-of-the-art radioactive drug development has become a helpful tool in new functional imaging technologies in neurosciences. Drug development programs are evaluated in terms of effective biodistribution, costs and time. This article details the existing drug development parameters for neuroimaging and highlights some examples, as in Parkinson's disease, alcoholic neuritis and psychotic diseases, showing the benefit and the potential of using new functional neuroimaging technologies for specific studies of the central nervous system. 相似文献
76.
Raats DA de Bruijn MT Steller EJ Emmink BL Borel-Rinkes IH Kranenburg O 《Cellular oncology (Dordrecht)》2011,34(4):307-313
Background
Oxaliplatin is frequently used in the treatment of metastatic colorectal cancer (CRC). Our previous work shows that oxaliplatin induces the pro-apoptotic protein Noxa in CRC cells. The Bcl2-inhibitor ABT-737 is particularly effective in cells with high Noxa levels. Therefore, we tested whether oxaliplatin and ABT-737 display synergy in killing CRC cells.Methods
A panel of CRC cell lines was treated with oxaliplatin and ABT-737, either alone or in combination. Apoptosis was measured by FACS analysis of sub-G1 DNA content and by Western blot analysis of caspase-3 processing. Noxa expression was suppressed by lentiviral RNA interference.Results
Oxaliplatin and ABT-737 displayed a strong synergistic apoptotic response, which was dependent on wildtype TP53 and oncogenic KRAS. TP53 and KRAS were required for drug-induced Noxa expression and this was essential for tumor cell apoptosis. Oxaliplatin, but not ABT-737, induced p53 accumulation, but both drugs stimulated Noxa expression. Combination treatment of mice with subcutaneous tumor xenografts drastically reduced tumor volume, while single drug treatment had no effect.Conclusion
ABT-737 synergizes with oxaliplatin to kill colorectal cancer cells. This requires induction of Noxa by wildtype TP53 and oncogenic KRAS. Future studies should explore the anti-tumor efficacy of this drug combination in mouse models for spontaneous CRC development and in patient-derived tumor cell cultures and xenografts. 相似文献77.
78.
Blockade of thrombospondin-1-CD47 interactions prevents necrosis of full thickness skin grafts 总被引:1,自引:0,他引:1
Isenberg JS Pappan LK Romeo MJ Abu-Asab M Tsokos M Wink DA Frazier WA Roberts DD 《Annals of surgery》2008,247(1):180-190
BACKGROUND: Skin graft survival and healing requires rapid restoration of blood flow to the avascular graft. Failure or delay in the process of graft vascularization is a significant source of morbidity and mortality. One of the primary regulators of blood flow and vessel growth is nitric oxide (NO). The secreted protein thrombospondin-1 (TSP1) limits NO-stimulated blood flow and growth and composite tissue survival to ischemia. We herein demonstrate a role for TSP1 in regulating full thickness skin graft (FTSG) survival. METHODS AND RESULTS: FTSG consistently fail in wild type C57BL/6 mice but survive in mice lacking TSP1 or its receptor CD47. Ablation of the TSP1 receptor CD36, however, did not improve FTSG survival. Remarkably, wild type FTSG survived on TSP1 null or CD47 null mice, indicating that TSP1 expression in the wound bed is the primary determinant of graft survival. FTSG survival in wild type mice could be moderately improved by increasing NO flux, but graft survival was increased significantly through antibody blocking of TSP1 binding to CD47 or antisense morpholino oligonucleotide suppression of CD47. CONCLUSIONS: TSP1 through CD47 limits skin graft survival. Blocking TSP1 binding or suppressing CD47 expression drastically increases graft survival. The therapeutic applications of this approach could include burn patients and the broader group of people requiring grafts or tissue flaps for closure and reconstruction of complex wounds of diverse etiologies. 相似文献
79.
Cytotoxic and apoptosis-inducing effects of the alkaloid emetine from Psychotria ipecacuanha (Rubiaceae) were studied in human cell lines. In Jurkat T-cells emetine leads to phosphatidylserine exposure, mitochondrial depolarisation, and DNA fragmentation. Furthermore, activation of several caspases (caspase-3, -9/6, and -8) was demonstrated in a fluorescent caspase assay. Bcl-2 over-expressing cells are less sensitive to emetine while caspase-8-deficient Jurkat T-cells react similarly to wild-type cells. This indicates that apoptosis induction is mediated via the mitochondrial pathway. By using hepatoma cell lines with differing p53 expression, it was concluded that p53 does not seem to play a role in apoptosis induction by emetine. Alterations of protein profiles during emetine-induced apoptosis were analysed by 2D-PAGE and MALDI-TOF-MS. A new protein spot was apparent after treatment with emetine: It could be identified as the N-terminal fragment lamin B1, which is released after cleavage by caspase-6. 相似文献
80.