The laying hen and flaxseed: A model for dietary intervention of human ovarian cancer.

The laying hen and flaxseed: A model for dietary intervention of human ovarian cancer

The peroxidase activity of mitochondrial superoxide dismutase

Maria Montesori svoju koncepciju odgoja zasniva na spoznajama o razvojnim fazama dječje osjetljivosti. Zadovoljavanje tih razvojnih faza polazi od dviju pretpostavki, da djeca imaju prirođene snage za samorazvoj i da se prirođene snage aktiviraju ako su djeca okružena povoljnom sredinom (Matijević, 2001). Zadaća Montessori odgojitelja je da osigura odgovarajuću sredinu i materijale koji će poticati samoaktivnost djece. On nije poučavatelj ni predavač već osoba koja daje inicijalne upute te usmjerava i potiče aktivnosti pojedinog djeteta. Svako dijete se razvija svojim tempom i ima određene prirođene unutarnje potrebe koje se pojavljuju u različito vrijeme, zbog toga Maria Montessori zagovara individualizirani odgoj. Materijali i prostor su važan dio samoodgoja djeteta. Oni trebaju dati potporu djetetovu samorazvoju. Svi su materijali u Montessori prostoru uredno složeni, a od svake vrste materijala postoji samo jedan komplet. Dok se jedno dijete koristi nekim materijalom, drugo dijete koje poželi isti materijal treba pričekati. To je važno sredstvo u socijalizaciji jer privikava na uljudnu međuljudsku komunikaciju. Montessori pedagogija polazi od ideje slobode, odnosno slobodnog odgoja. Dijete samo inicira i upravlja aktivnostima kojima se hoće baviti prema svojim potrebama i interesima. Preko slobodnog izbora dijete uči donositi odluke, ono uči što je to kreativnost. Odgojitelj pokazuje djetetu kako da likovne aktivnosti izvede sam. Ono samo bira vrstu likovnog materijala i temu svog rada, dok mu odgojitelj, bez govorenja, pokazuje kako se koristi tim materijalom. Trajanje likovne aktivnosti ovisi o djetetu i zadovoljavanju njegovih potreba.Maria Montessori based her basic idea of education on insights of development stages of children's sensitivities. Fulfilment of this development stages is based on two hypothesis, children have inborn forces for self-development and this inborn forces are activated if children are surrounded with suitable environment (Matijević, 2001). Montessori educators have a task to prepare suitable environment and materials that will encourage children's self-activity. They are not a teacher or lecturer, but a person that gives initiative instructions and a person that directs and encourages activites of every single child. Every child develops differently, in its own pace, and every child has its own internal needs which appear in different time. Therefore, Maria Montessori advocates individual education. Materials and environment are very important part of child's self-education. They need to give support for child's self-development. All materials in Montessori environment are neatly arranged and there's only one set of every sort of material. While one child is using some material and some other child is interested in using the same material, it has to wait until the first child is done with the activity. This is very important for child's social development because it teaches children how to be polite while communicating with others. Montessori pedagogy is based on freedom. Therefore, child initiates and manages activities which are result of its needs and interests. While having freedom to choose its own activities, child is learning to make its own decisions, it is learning what creativity is. Educator is showing the children how to do art activities all by themselves. Child chooses what type of art material it wants to use and it chooses a topic of its piece, while educator, without speaking, shows the child how to use this material. Duration of this activity depends on the child and on satisfaction of its needs

MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer

Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H2O2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell metabolism

Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis.

Aerobic glycolysis is an indispensable component of aggressive cancer cell metabolism. It also distinguishes cancer cells from most healthy cell types in the body. Particularly for this reason, targeting the metabolism to improve treatment outcomes has long been perceived as a potentially valuable strategy. In practice, however, our limited knowledge of why and how metabolic reprogramming occurs has prevented progress towards therapeutic interventions that exploit the metabolic peculiarities of tumors. We recently described that in breast cancer, MnSOD upregulation is both necessary and sufficient to activate glycolysis. Here, we focused on determining the molecular mechanisms of MnSOD upregulation. We found that Caveolin-1 (Cav-1) is a central component of this mechanism due to its suppressive effects of NF-E2-related factor 2 (Nrf2), a transcription factor upstream of MnSOD. In transformed MCF10A(Er/Src) cells, Cav-1 loss preceded the activation of Nrf2 and its induction of MnSOD expression. Consistently, with previous observations, MnSOD expression secondary to Nrf2 activation led to an increase in the glycolytic rate dependent on mtH2O2 production and the activation of AMPK. Moreover, rescue of Cav-1 expression in a breast cancer cell line (MCF7) suppressed Nrf2 and reduced MnSOD expression. Experimental data were reinforced by epidemiologic nested case-control studies showing that Cav-1 and MnSOD are inversely expressed in cases of invasive ductal carcinoma, with low Cav-1 and high MnSOD expression being associated with lower 5-year survival rates and molecular subtypes with poorest prognosis

Natural Allelic Variations in Glutathione Peroxidase-1 Affect Its Subcellular Localization and Function

Glutathione peroxidase 1 (GPx-1) has been implicated in the etiology of several common diseases due to the association between specific allelic variations and cancer risk. The most common among these variations are the codon 198 polymorphism that results in either a leucine or proline and the number of alanine repeat codons in the coding sequence. The molecular and biological consequences of these variations remain to be characterized. Towards achieving this goal, we have examined the cellular location of GPx-1 encoded by allelic variants by ectopically expressing these genes in MCF-7 human breast carcinoma cells that produce undetectable levels of GPx-1, thus achieving exclusive expression in the same cellular environment. A differential distribution between the cytoplasm and mitochondria was observed, with the allele expressing the leucine-198 polymorphism and 7 alanine repeats being more cytoplasmically located than the other alleles examined. To assess whether the distribution of GPx-1 between the cytoplasm and mitochondria had a biological consequence, we engineered derivative GPx-1 proteins that were targeted to the mitochondria by the addition of a mitochondria targeting sequence and expressed these proteins in MCF-7 cells. These cells were examined for their response to oxidative stress, energy metabolism and impact on cancer-associated signaling molecules. The results obtained indicated that both primary GPx-1 sequence and cellular location have a profound impact on cellular biology and offer feasible hypotheses as to how expression of distinct GPx-1 alleles can impact cancer risk

Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus).

Cyclooxygenase (COX) (PTGS) is the rate-limiting enzyme in the biosynthesis of prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2, which show distinct cell-specific expression and regulation. Ovarian cancer is the most lethal gynecological malignancy and the disease is poorly understood due to the lack of suitable animal models. The laying hen spontaneously develops epithelial ovarian cancer with few or no symptoms until the cancer has progresses to a late stage, similar to the human disease. The purpose of this study was to examine the relative expression and distribution of COX-1 and COX-2 in the ovaries of normal hens and in hens with ovarian cancer. The results demonstrate that COX-1 was localized to the granulosa cell layer and cortical interstitium, ovarian surface epithelium (OSE) and postovulatory follicle (POF) of the normal ovary. In ovarian cancer, COX-1 mRNA was significantly increased and COX-1 protein was broadly distributed throughout the tumor stroma. COX-2 protein was localized to the granulosa cell layer in the follicle and the ovarian stroma. COX-2 mRNA expression did not change as a function of age or in ovarian cancer. There was significantly higher expression of COX-1 mRNA in the first POF (POF-1) compared to POF-2 and POF-3. COX-2 mRNA expression was not significantly different among POFs. There was no difference in COX-1 or COX-2 mRNA in the OSE isolated from individual follicles in the follicular hierarchy. The results confirm previous findings of the high expression of COX-1 in ovarian tumors further supporting the laying hen as a model for ovarian cancer, and demonstrate for the first time the high expression of COX-1 in POF-1 which is the source of prostaglandins needed for oviposition

MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer.

Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H2O2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell