1,721,037 research outputs found
Endoplasmic reticulum pentose phosphate pathway in the cancer cell redox state and fate.
No full textIn recent years interest in cancer metabolism has risen. A relevant role of the pentose phosphate pathway (PPP) is recognized in cancer metabolic reprogramming, involving both the cytosolic glucose-6-phosphate dehydrogenase (G6PD) and especially the less characterized endoplasmic reticulum (ER) hexose-6-phosphate dehydrogenase (H6PD). In breast and lung cancer cells, H6PD gene silencing decreased PPP intermediates content, similarly to G6PD silencing. G6PD or H6PD gene silencing impaired at a similar extent NADPH content, proliferating activity, and oxidative status of the cancer cell1. Cancer cells may direct glucose flux to the PPP to produce ribose-5-phosphate for nucleic acid biosynthesis and of NADPH for regulation of the cell redox state. Cancer cells metabolic disturbances can trigger an ER stress, that if not relieved by activating the unfolded protein response (UPR), can activate PERK/ATF6/IRE1α-mediated apoptosis pathways. The substrates for H6PD are many hexoses also non-phosphorylated. It was supposed that galactose could become the substrate of H6PD, generating xylulose2. Notably, a xylulokinase (EC 2.7.1.17) exists and its product, xylulose-5-phosphate, determines the respective flux rates of the oxidative and non-oxidative PPP. The latter involves transketolase and transaldolase enzymes for the interconversion of sugar phosphate intermediates. It was shown that transketolase (TKT) is required for cancer growth. A transketolase-like 1 (TKTL1) enzyme was found3 in aggressive cancers, suggestive of rapid glucose utilization. TKTL1 would act on xylulose-5-phosphate to generate cytosolic lipogenesis precursors. The study of the reticular PPP and of the role of H6PD in ER redox balance might help our comprehension of the cancer cell biology. Moreover, targeting H6PD to disturb the ER redox homeostasis of cancer cells by either genetic knockdown or pharmacologic intervention provides a promising approach for cancer therapy
Metabolic reprogramming and substrate preference in cancers: a hypothesis
No full textCancer is a complex pathology, whose burden is growing worldwide. It appears that our vision considering cancer cells as a uniform population is partial: cancer cells evolve in time, building up mutations to adapt to their environment. They become able to evade cellular controls, and then immune response. A hallmark of cancer adaptation ability is metabolic reprogramming. Consistently, inhibitors of glycolysis, and of fatty acid uptake into the mitochondria are promising anticancer agents. The classical Warburg effect has been revised in the last years, and it appears that the increased glucose requirement of cancer cells is related to the shifting of glucose flux to the pentose phosphate pathway, to obtain trioses, NADPH and ribose 5-P, in face of increased lactate production and oxygen consumption (Vander Heiden, et al. 2009, Cossu, et al. 2020). Typically, metastasizing cancer cells heavily rely on the oxidative phosphorylation. In particular, apparently encephalic tumours preferentially utilize glucose and glutamine as nutrients, as opposed to tumours in the rest of the body, which preferentially catabolize fatty acids. This implies an obligatory role for functional mitochondria, where the beta-oxidation occurs. A shift toward the oxidative metabolism is also a main driver of chemotherapy resistance. The expression of the electron transfer chain complexes I to IV and the F1Fo-ATP synthase was reported out of the mitochondria, in plasma membrane derived structures (Ravera, et al. 2021), and also on the surface of cancer cells. It is tempting to presume that the difference in substrate preference is due to the diverse respiring structures in the brain, above or below the vascular Willis circle. A future therapeutic vision may hopefully involve targeting the tumour cell metabolism at multiple levels. It will then be crucial to target tumour cells at the level of their metabolism, which would be tumour- and location-specific
JHC762389_Supplemental_Material – Supplemental material for Evidence of Oxidative Phosphorylation in Zebrafish Photoreceptor Outer Segments at Different Larval Stages
No full textSupplemental material, JHC762389_Supplemental_Material for Evidence of Oxidative Phosphorylation in Zebrafish Photoreceptor Outer Segments at Different Larval Stages by Daniela Calzia, Greta Garbarino, Federico Caicci, Mario Pestarino, Lucia Manni, Carlo Enrico Traverso, Isabella Panfoli and Simona Candiani in Journal of Histochemistry & Cytochemistry</p
The potential role of the Pentose Phosphate Pathway in Chronic Lymphocytic Leukemia disease and chemotherapy resistance.
No full textChronic lymphocytic leukemia (CLL) is a hematological malignancy displaying a highly heterogeneous clinical course.
Several studies highlight the capability of CLL B cells to control the persistent redox stress1,2 by triggering antioxidant pathways that are particularly efficient in aggressive CLL cells3. Antioxidant pathways and anabolic reactions strictly depend on NADPH, whose intracellular pool is provided by the pentose phosphate pathway (PPP). Recent evidence showed that the level of PPP rate-limiting enzyme, glucose-6-phosphate-dehydrogenase (G6PD), is significantly increased in CLL B cells in comparison to normal B cells4,5 and is directly correlated with poor prognosis6, underlying a possible key role of PPP in CLL disease aggressiveness.
To this purpose, we thus evaluated i) the catalytic function of G6PD, ii) the mitochondrial respiratory function and iii) the glycolytic flux, in CLL cells derived from patient with ‘indolent’ and ‘aggressive’ disease, classified based on the molecular prognostic marker.
The results showed that in vitro stimulation selectively increased G6PD activity only in samples with features of higher aggressiveness (Fig.A). Interestingly, in activated CLL cells, the mitochondrial dependence on fatty acid was significantly higher in patients with more aggressive disease, whereas mitochondrial dependence on pyruvate appears to be reduced (Fig.B). Given that levels of glucose consumed from the culture medium and the lactate produced are similar in ‘indolent’ and ‘aggressive’ activated samples (Fig.C), these data suggested that part of the cell-entering glucose might be processed through PPP, thus configuring the limitation of this enzyme as a possible therapeutic target. In line with these data, we observed a possible involvement of G6PD in the resistance to the Bcl-2 inhibitor Venetoclax. Indeed, recent studies showed that the anti-apoptotic protein Mcl-1 increment might be involved in resistance to Venetoclax7,8. In line with these observations, we observed a possible direct correlation between G6PD and Mcl-1 expression (Fig.D).
These data highlight a novel role of G6PD function in the aggressiveness of CLL patients and anti-Bcl-2 therapy resistance, suggesting the PPP-limiting enzyme may represent a new therapeutic target in CLL
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Polyphenols in Anti-cancer Therapy and Prevention: Should we Add the FoF1-ATP Synthase Inhibition?
No full textSi tratta di una "Perspective", pertanto non è previsto un Abstract, sulla rilevanza della azione di modulazione della F1Fo-ATP sintasi da parte dei polifenoli, nella loro nota attività anti-cancro
Pathophysiology of the extra-mitochondrial oxidative phosphorylation
No full textA major challenge in biomedical science is ATP supply in the nervous system (NS). The mitochondrial Electron Transfer Chain (ETC), Fo F1 -ATP synthase and Tricarboxylic Acid (TCA) Cycle enzymes are functionally expressed outside the mitochondrion, in myelin and rod outer segments (OS). These extra-mitochondrial sites of oxidative phosphorylation (OXPHOS), devoid of mitochondria, consume oxygen (O2 ) and synthesize ATP in the presence of any TCA Cycle intermediate, in a manner sensitive to mitochondrial probes and inhibitors. During rat myelinogenesis expression of myelin basic protein, ETC, Fo F1 - ATP synthase and mitochondrial fusion proteins increased from day 0 to 33, while that of inner mitochondrial membrane proteins decreased. Exosomes from various sources conduct an extra-mitochondrial OXPHOS, suggesting a protein transfer from mitochondria to the endoplasmic reticulum. The OXPHOS is a major source of reactive O2 species in the rod OS, that polyphenols can scavenge, by inhibiting the ectopic Fo F1 -ATP synthase. Oxidative stress originated by the extramitochondrial OXPHOS may represent a pivotal pathogenic mechanism for many neurodegenerative diseases
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