Examinando por Autor "Arismendi Morillo, Gabriel J."

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    Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma
    (BioMed Central Ltd, 2024-12) Duraj, Tomás; Kalamian, Miriam; Zuccoli, Giulio; Maroon, Joseph C.; D’Agostino, Dominic P.; Scheck, Adrienne C.; Poff, Angela; Winter, Sebastian F.; Hu, Jethro; Klement, Rainer J.; Hickson, Alicia; Lee, Derek C.; Cooper, Isabella; Kofler, Barbara; Schwartz, Kenneth A.; Phillips, Matthew C.L.; Champ, Colin E.; Zupec-Kania, Beth; Tan-Shalaby, Jocelyn; Serfaty, Fabiano M.; Omene, Egiroh; Arismendi Morillo, Gabriel J.; Kiebish, Michael; Cheng, Richard; El-Sakka, Ahmed M.; Pflueger, Axel; Mathews, Edward H.; Worden, Donese; Shi, Hanping; Cincione, Raffaele Ivan; Spinosa, Jean Pierre; Slocum, Abdul Kadir; Iyikesici, Mehmet Salih; Yanagisawa, Atsuo; Pilkington, Geoffrey J.; Chaffee, Anthony; Abdel-Hadi, Wafaa; Elsamman, Amr K.; Klein, Pavel; Hagihara, Keisuke; Clemens, Zsófia; Yu, George W.; Evangeliou, Athanasios E.; Nathan, Janak K.; Smith, Kris; Fortin, David; Dietrich, Jorg; Mukherjee, Purna; Seyfried, Thomas N.
    Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.
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    From mitochondrial cristae pathobiology to metabolic reprogramming in cancer: the α and ω of Malignancies?
    (Walter de Gruyter GmbH, 2025-11-14) Arismendi Morillo, Gabriel J.; Duraj, Tomás; Lee, Derek C.; Mukherjee, Purna; Seyfried, Thomas N.
    Mitochondrial cristae pathobiology, involving partial or total cristolysis, is a hallmark of human and mammalian cancer. This feature represents the basis of metabolic dysfunction in neoplastic cells. Consequently, most cancer cells with mitochondrial cristae defects would be incapable of producing adequate amounts of energy through oxidative phosphorylation. ATP production through increased glucose-driven cytosolic and glutamine-driven mitochondrial substrate-level phosphorylation thus becomes necessary to compensate for OxPhos insufficiency. The aim of this article is to offer a brief perspective on the link between the mitochondrial cristae pathobiology and the metabolic reprogramming in cancer cells, whose origin is linked to chronic mitochondrial cristae lesion (named α) and its eventual resolution by means of a progressive and continuous process of tumor cell death (named ω), induced by metabolic targeting. Dietary and pharmacological metabolic therapies that restrict the utilization of glucose and glutamine in tumor cells while elevating circulating ketone bodies represent a non-toxic therapeutic strategy for cancer management. Metabolic therapy can induce a persistent state of energy stress with a consequent increase in tumor cell death and reduction of tumor mass while improving the energy efficiency of non-neoplastic cells. Recent clinical studies suggest that ketogenic metabolic therapies may be therapeutically useful and well-tolerated in the long term.
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    The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer
    (Springer, 2025-04-08) Seyfried, Thomas N.; Lee, Derek C.; Duraj, Tomás; Ta, Nathan L.; Mukherjee, Purna; Kiebish, Michael; Arismendi Morillo, Gabriel J.; Chinopoulos, Christos
    Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg’s hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg’s original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.