Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.
This consensus describes 25 statements regarding the acquisition and interpretation of microcirculatory images needed to guide the assessment of the microcirculation in critically ill patients.
The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature. metabolism | altitude | skeletal muscle | hypoxia | mitochondria
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