The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP and anabolic substrates at distinct phases of the cell cycle. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of 6-phosphofructo-1-kinase (Pfk-1). PFKFB3 is overexpressed in human cancers, regulated by HIF-1α, Akt and PTEN, and required for the survival and growth of multiple cancer types. Although most functional studies of the role of PFKFB3 in cancer progression have invoked its well-recognized function in the regulation of glycolysis, recent observations have established that PFKFB3 also traffics to the nucleus and that its product, F2,6BP, activates cyclin-dependent kinases (Cdks). In particular, F2,6BP stimulates the Cdk-mediated phosphorylation of the Cip/Kip protein p27 (threonine 187), which in turn results in p27's ubiquitination and proteasomal degradation. As p27 is a potent suppressor of the G1/S transition and activator of apoptosis, we hypothesized that the known requirement of PFKFB3 for cell cycle progression and prevention of apoptosis may be partly due to the ability of F2,6BP to activate Cdks. In this study, we demonstrate that siRNA silencing of endogenous PFKFB3 inhibits Cdk1 activity, which in turn stabilizes p27 protein levels causing cell cycle arrest at G1/S and increased apoptosis in HeLa cells. Importantly, we demonstrate that the increase in apoptosis and suppression of the G1/S transition caused by siRNA silencing of PFKFB3 expression is reversed by co-siRNA silencing of p27. Taken together with prior publications, these observations support a model whereby PFKFB3 and F2,6BP function not only as regulators of Pfk-1 but also of Cdk1 activity, and therefore serve to couple glucose metabolism with cell proliferation and survival in transformed cells.
Probiotics and their components have been used to improve growth performance and immunity, as well as intestinal health. This study evaluated the effect of different doses of Saccharomyces cerevisiae on the morphological properties of duodenums of rabbits. Twenty 6-7 weeks old male New Zealand White Rabbits were randomly allocated into three groups for 90 days. The first group (control group) received the basal diet, the second group received basal diet supplemented with S.cerevisiae at a level of 2g/kg of feed, and the third group was fed with S.cerevisiae live yeast culture added at 4.0 g/kg. At the end of the experiment duodenum segments were taken, fixed in 10% neutral buffered formalin and processed for histological examination. In this study, the total thickness of the mucosa, the height of the villi and depth of the crypts and depth of the glands of the duodenum were found to be longer with the increased yeast doses. However, there was no significant difference among the villus crypt ratio of the groups. In conclusion, the total thickness of the mucosa, villus heights, crypt depths and gland depths were increased significantly in both of the yeast groups of rabbits. Therefore, it may be proposed that administration of S.cerevisiae in either low or high doses may be used for intestinal health.
We investigated eight adult dogs that were brought to veterinary clinics with a history of transmissible venereal tumors (TVT). Our goal was to demonstrate the occurrence of apoptosis and the cessation of cell proliferation at every phase of scheduled chemotherapy for naturally occurring TVT. Tissue samples were collected immediately after weekly treatments with vincristine sulfate and processed for histological purposes. Sections 5 μm thick were stained by the TUNEL reaction for apoptosis and immunostained for Ki67 as a proliferation marker. We observed that after vincristine applications, tumor cell proliferation ceased and apoptosis increased. Ki67 HSCORE values were significantly lowered after the first and second treatments with the chemotherapeutic agent compared to controls, whereas TUNEL HSCORE values were significantly higher after two applications of vincristine compared to controls. Our results suggest that scheduled vincristine sulfate applications stabilize the induction of tumor regression by inducing apoptosis and preventing cell proliferation.
The incidence of premenopausal breast cancer is 15.1 per 100,000 woman-years for white women under 40 years of age (1). As such, it is the most common malignancy among women of reproductive age (1). While surgery is the mainstay of treatment, adjuvant chemotherapy significantly improves the survival of women with breast cancer. The 15-year survival rate of breast cancer patients under age 40 is increased by 6.1% if they receive chemotherapy (2). However, chemotherapy can be gonadotoxic and impair the reproductive potential of women who survive the disease. The extent of gonadal damage inflicted by chemotherapy depends on several factors, including the age and pre-treatment ovarian reserve status of the patient, as well as the type, dose, and duration of the chemotherapy regimen. Tamoxifen (TMX) is one of the commonly used agents for adjuvant chemotherapy following breast cancer. Compared to placebo, TMX results in a 13% and 15% reduction in the risk of recurrence and breast cancer mortality, respectively (3). While the gonadotoxicity of some chemotherapeutics, such as alkylating agents, is well established, there is limited information regarding whether TMX is harmful to the ovaries. In the present study, we evaluated ovarian reserve, as assessed by serum anti-Müllerian hormone (AMH) levels and follicle counts, before and after TMX administration in a mouse model. Material and MethodsThe study protocol was in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and was approved by the Animal Care Committee of Uludağ University (no: 2012-04/08) (4). Animals and experimental protocolThirty 8-week-old female inbred BALB/C mice weighing 25-30 g were housed in ambient temperature of 20-24°C and humidity of 60%-70%. The lab had a 12-h light and dark cycle. Mice had access to chow and water ad libitum. Objective: To determine whether tamoxifen (TMX) exposure causes a permanent decrease in ovarian reserve. Material and Methods: A randomized controlled assessor-blind trial including 30 adult female inbred BALB/C mice. Fifteen mice in the TMX group were given a single 0.1-mg dose of TMX intraperitoneally. Fifteen mice in the control group were given a single dose of the vehicle at the same volume intraperitoneally. Two cycles later, blood samples were collected for determination of anti-Müllerian hormone (AMH) levels, and the mice were sacrificed. After gonadectomy, ovarian size was measured, and follicles were counted under light microscopy. Results:Median serum AMH levels were 6.53 and 6.14 ng/ml in the control and TMX groups, respectively (p=0.03). Ovarian size was significantly decreased in the TMX group. While the number of primordial (9 vs 8), primary (6 vs 3), and secondary (4.5 vs 5) follicles were similar, there were significantly fewer preantral (11.5 vs 6, p<0.01) and antral (2 vs 1, p: 0.03) follicles, as well as corpora lutea (6 vs 3, p: 0.04), in the TMX group than in the control group. The number of atretic (2.5 vs 5, p: 0.048) follicles was increased in the TMX ...
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