37 research outputs found
Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells
No full textActivating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.Fil: Ozcan, Selahattin C.. Koc University Research Center For Translational Medici; TurquíaFil: Mutlu, Aydan. Bursa Uludag University; TurquíaFil: Altunok, Tugba H.. Bursa Uludag University; TurquíaFil: Gurpinar, Yunus. Bursa Uludag University; TurquíaFil: Sarioglu, Aybike. Bursa Uludag University; TurquíaFil: Guler, Sabire. Bursa Uludag University; TurquíaFil: Muchut, Robertino José. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Iglesias, Alberto Alvaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral; ArgentinaFil: Celikler, Serap. Bursa Uludag University; TurquíaFil: Campbell, Paul M.. The Marvin and Concetta Greenberg Pancreatic Cancer Institute; Estados UnidosFil: Yalcin, Abdullah. Bursa Uludag University; Turquí
PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells
No full textTumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2’s requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.Fil: Ozcan, Selahattin C.. Koc University Research Center For Translational Medici; TurquíaFil: Sarioglu, Aybike. Bursa Uludag University; TurquíaFil: Altunok, Tugba H.. Bursa Uludag University; TurquíaFil: Akkoc, Ahmet. Bursa Uludag University; TurquíaFil: Guzel, Saime. Bursa Uludag University; TurquíaFil: Guler, Sabire. Bursa Uludag University; TurquíaFil: Imbert-Fernandez, Yoannis. University of Louisville; Estados UnidosFil: Muchut, Robertino José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Iglesias, Alberto Alvaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Gurpinar, Yunus. Bursa Uludag University; TurquíaFil: Clem, Amy L.. University of Louisville; Estados UnidosFil: Chesney, Jason A.. University of Louisville; Estados UnidosFil: Yalcin, Abdullah. Bursa Uludag University; Turquí
Effects of royal jelly on ovary cancer cells proliferation and apoptosis
No full textThe aim of the present study is to investigate the proliferative or apoptotic effects of different doses and durations of Royal jelly (RJ) on serous type epithelial ovarian cancer, which is the most common epithelial ovarian cancer. For this purpose, cells of the Skov-3 human ovarian adenocarcinoma cell line were grown in McCoy medium and seeded in 6-well plates. RJ was prepared as a stock solution (1000 mg RJ/10 ml dH2O) and 1, 5, 10, 20, and 50 mg/ml RJ doses from the prepared stock solution were added to the medium for 24, 48, and 72 h incubated. After the treatment of RJ, the cell viability test (Tripan Blue), Ki-67 to determine the proliferative effect, cleaved-Caspase-3 and cleaved PARP expressions to determine its apoptotic effect were examined by immunocytochemical and immunofluorescence methods. In addition, findings were supported by the TUNEL method. As a result of the experiments, it was determined that 1 mg/ml and 24 h treatment of RJ did not affect cell proliferation and apoptosis, but generally, 50 mg/ml of RJ for 72 h inhibited proliferation in cancer cells and induced apoptosis. The use of royal jelly both monotherapeutically and in combination as an alternative treatment for ovarian cancer may provide the basis for new experimental protocols
Effect of high-fat diet on the various morphological parameters of the ovary
No full textIncreased food consumption rich in fat and carbohydrate and sedentary lifestyle have seriously increased the rates of obesity and obesity-associated diseases in developed countries. Female mice with diet-induced obesity exhibit infertility and thus can serve as a model for human polycystic ovary syndrome. The aim of the present study was to examine how ovary is affected by diet-induced obesity. The effects of high-fat diet (HFD) on ovary morphology in mice fed with HFD were investigated using unbiased stereological methods. The ovary of mice fed with HFD (n=8, C1090-60, Altromine) for 9 weeks, were compared with that of mice fed with standard chow diet (n=8, C1090-10, Altromine). Stereological parameters were obtained in diestrus cycle. The samples were processed through routine and standard paraffin embedding and were serially sectioned in 5-mu m thickness then, every 10th section was saved, stained with Crossman's triple stain for counting and measuring. In all sampled sections mean follicle numbers, diameters, total ovarian volume cortex to medulla ratio (Vv), ovum to cell ratio in secondary follicle were examined in all sampled sections. The present results showed that weight of ovarian and amount of intraperitoneal adipose tissue and the body weight markedly increased in obese mice when compared with control groups. Moreover, follicle numbers (except primordial follicles) and diameters were significantly increased in obese mice. Cortex to medulla ratio (Vv) and ovum to cell ratio in secondary follicle were also considerably different between experimental and the control groups. The present findings indicate that obesity adversely affects overall ovarian morphology.Eskisehir Osmangazi University Research Projects Center [2014-586]The present study was also financially supported by Eskisehir Osmangazi University Research Projects Center with the project code 2014-586
Normality and quotient of crossed modules within group with operations
No full textInternational Conference of Mathematical Sciences 2018, ICMS 2018 -- 31 July 2018 through 6 August 2018 -- -- 146701In this note we define the notions of normal subcrossed module and quotient crossed module within groups with opera-tions; and give same results on these crossed modules. © 2019 Author(s)
Quotients of monodromy groupoids
No full textInternational Conference of Mathematical Sciences 2018, ICMS 2018 -- 31 July 2018 through 6 August 2018 -- -- 146701In this note we explain how to develop the quotient groupoid of the monodromy groupoid for given a topological group-groupoid using crossed modules. © 2019 Author(s)
Group-groupoids and crossed module aspects of monodromy groupoids
No full textInternational Conference of Mathematical Sciences 2018, ICMS 2018 -- 31 July 2018 through 6 August 2018 -- -- 146701In this extended abstract considering the topological version of categorical equivalence of crossed modules and group-groupoids we develop crossed module aspects of monodromy group-groupoids for topological group-groupoids and give some examples for monodromy groupoids. © 2019 Author(s)
In Halit Ziya's stories, the writer's compassion, the conscience of the reader
No full textHalit Ziya Uşaklıgil, hikâyelerinde çok çeşitli konuları ele almıştır. Bazı hikâyelerinde kahramanlarının özellikleri arasında hastalık, fakirlik, zayıflık ve güçsüzlük özellikle vurgulanmaktadır. Düşüncemize göre bunun nedeni yazarın okuyucuda acıma duyguları uyandırmak istemesidir. Yazarın Onu Beklerken adlı kitabından seçilen Onu Beklerken, Türk Eri, Hikâye Değil, Deliler Evinde, Büyük Adam, Hüzünlü Bir Cuma ve Bir Gün İçinde adlı öykülerinde bu durum görülebilir. Ayrıca yazar Hikâye adlı inceleme kitabında realist yazarları övmekte, onların ele aldığı konuların okuyucuyu ağlattığını vurgulamaktadır. Yazarın Hikâye adlı kitabından yola çıkarak şu sonucu çıkarabiliriz: Halit Ziya'ya göre iyi bir eserin konusu okuyucuyu ağlatabilir.Halit Ziya Uşaklıgil discusses a variety of topics in his stories. In some of his stories, the characteristics of heroes are emphasized with particular emphasis on disease, poverty, weakness and weakness. In our opinion, the reason for this is that the author wants to awaken feelings of pity in the reader. This situation can be seen in his short stories The Great, The Sad Man, The Mad At Home, The Great Man, A Sad Friday And A Day As We Wait For Him, who is chosen from the book His Waiting For Him. In addition, the author Hikâye praises realist writers in his book, emphasizing that the issues that they address make the readers cry. We can deduce from the author's book Hikâye that: According to Halit Ziya, the subject of a good work can make the reader cry
Glimepiride Administered in Chow Reversibly Impairs Glucose Tolerance in Mice
No full textSulfonylureas are a class of antidiabetes medications prescribed to millions of individuals worldwide. Rodents have been used extensively to study sulfonylureas in the laboratory. Here, we report the results of studies treating mice with a sulfonylurea (glimepiride) in order to understand how the drug affects glucose homeostasis and tolerance. We tested the effect of glimepiride on fasting blood glucose, glucose tolerance, and insulin secretion, using glimepiride sourced from a local pharmacy. We also examined the effect on glucagon, gluconeogenesis, and insulin sensitivity. Unexpectedly, glimepiride exposure in mice was associated with fasting hyperglycemia, glucose intolerance, and decreased insulin. There was no change in circulating glucagon levels or gluconeogenesis. The effect was dose-dependent, took effect by two weeks, and was reversed within three weeks after removal. Glimepiride elicited the same effects in all strains evaluated: four wild-type strains, as well as the transgenic Grn−/− and diabetic db/db mice. Our findings suggest that the use of glimepiride as a hypoglycemic agent in mice should proceed with caution and may have broader implications about mouse models as a proxy to study the human pharmacopeia
