Lung cancer is one of the most common malignancies in the world and one of the leading causes of death from cancer. In the search for molecules that may be involved in lung tumor induction and progression, the receptor of advanced glycation end products (RAGE) comes across as a critical regulator of lung physiology. RAGE is a multiligand receptor that presents a differential expression pattern in lung epithelial cells compared to other cell types being gradually increased from fetal to birth and adult life. Under stress conditions, RAGE expression and activation are rapidly elevated resulting in chronic inflammation, which, in turn, in many instances, promotes epithelial cell malignant transformation. RAGE overexpression in normal lung alveolar type I epithelial cells is followed by rapid downregulation upon malignant transformation, being associated with increased aggressiveness. This is a striking paradox, since in every other cell type the pattern of RAGE expression follows the opposite direction, suggesting the involvement of RAGE in the well-functioning of lung cells. Additionally, RAGE has been attributed with the role of adhesion molecule, since it can stabilize mature alveolar epithelial cells to their substrate (basal lamina) by interacting electrostatically with other molecules. However, the reduction of RAGE observed in lung tumorigenesis interrupts cell-to-cell and cell-to-substrate communication, which is a critical step for cancer cell induction, progression and migration. This review addresses the differential properties of RAGE in lung physiology and carcinogenesis, providing evidence of therapeutic possibilities.
Mitochondrial dysfunction has been implicated in the development of a wide spectrum of major human diseases, including diabetes mellitus, heart disorders, neurodegeneration and cancer. Several therapeutic approaches targeting mitochondrial function have been applied in most cases without however the desired outcome. The limited effectiveness of these therapeutic schemes is due to the fact that several important aspects of mitochondrial function have not been elucidated as yet, including the detailed mechanism of ATP production. Although it is known that electron transport chain (ETC) is the central machinery responsible for mitochondrial oxidative ATP production, major important functions attributed to ETC are still unresolved while other activities which are in fact carried out by the ETC have been overlooked. This review revisits ATP synthesis providing a detailed account of the experimentally-verified ETC functions focused on the ability of ETC to act as an electro-electric converter, able to accept different electrons from any given energy source (light, food or metals) in order to produce the correct voltage and store it in the form of electrostatic potentials (mitochondrial membrane potential). This stored electric energy, in the order of 3x10(7) V/m, can then be used by F1F0 ATP synthase for ATP production. The present review provides supportive evidence that this ETC function suffices to fully explain the missing parts of ATP production, thus redirecting the current therapeutic schemes for the management of mitochondrial diseases to a more complete and effective avenue.
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