Shireesh Apte

Melanin Aggregation and Polymerization: Possible Implications in Age-Related Macular Degeneration

The state of aggregation of the polymer melanin may determine its propensity to act either as an antioxidant or as a pro-oxidant. Age-related alterations in its state of aggregation are suggested to alter the degree of polymerization so as to confer increased pro-oxidant propensity to the melanin polymer. Degradative processes in/of melanosomes and lysosomes in the retinal pigment epithelium (RPE) appear to be intimately connected so that they may involve exchange of contents between these two organelles. An increased pro-oxidant environment inside lysosomes has been associated with preventing the digestion of cellular components including photoreceptor outer rod segments partly by altering function of lysosomal hydrolases. It is speculated that age-related accumulation of low-molecular-weight phototoxic pro-oxidant melanin oligomers within lysosomes in the RPE may be partly responsible for decreasing the digestive rate of incorporated cellular components (including photoreceptor outer rod segments) which may lead to lipofuscin formation. More work is required to definitively refute or support such a hypothesis.

Cellular Respiration and Carcinogenesis

More than eight decades ago, the German physiologist Otto Warburg observed that cancer cells in the presence of oxygen produced large amounts of lactate and proposed that impaired oxidative metabolism may cause cancer. This formulation, later known as the Warburg hypothesis, was investigated and debated for several decades. The development of molecular biology and the discovery of oncogenes and tumor suppressor genes in subsequent years shifted the general interest in the cancer field into directions other than metabolism and promoted the abandoning of the Warburg hypothesis or its consideration as an epiphenomenon of cell transformation. In recent years, a renaissance in the field of mitochondria has occurred in biological studies. This has happened mostly by the recognition of the key functional role that this organelle plays in the execution of cell death and, thus, for its participation in the development of a vast array of human pathologies. The cancer field was not indifferent to these changes, and the Warburg hypothesis was brought back to the scene with renewed strength. Specifically, recent findings suggest that cancer is associated with a decrease in the activity and expression of -F1-ATPase, a key subunit of the mitochondrial ATP synthase. This alteration has been shown to limit oxidative phosphorylation and to trigger the induction of glycolysis to provide energy to the cell thus configuring the earlier Warburg observation in an additional hallmark of the cancer cell. Moreover, increased and decreased cellular mitochondrial activities are respectively associated with suppression and development of cancer. We suggest that reactivating mitochondrial metabolism by pharmacologic or dietary measures and/or tackling the deviant glycolysis in cancer cells may efficiently suppress malignant growth. M. Ristow (B) Chair, Department of Human Nutrition, Institute of Nutrition, University of Jena, D-07743 Jena, Germany e-mail: michael.ristow@mristow.org J.M. Cuezva (B) Departamento de Biologia Molecular, Centro de Biologia Molecular “Severo Ochoa”, CIBER de Entermedades Rasas, Universidad Autonoma de Madrid, 28049 Madrid, Spain. e-mail: jmcuezva@cbm.uam.es S.P. Apte, R. Sarangarajan (eds.), Cellular Respiration and Carcinogenesis, DOI 10.1007/978-1-59745-435-3 1, C

Ocular Melanogenesis: The Role of Antioxidants

Given the propensity of a large number of melanogenic pathways that can be modulated by cellular redox status, a causal role of the deficiency of ocular pigments such as melanin in the pathogenesis of age-related macular degeneration and evidence that melanin production does occur in the adult eye, it seems not improbable that antioxidants (or agents that modify cellular redox status) may have melanin stimulatory (or inhibitory) effects that are superimposible on their effects as mere free radical scavengers. More empirical studies are needed to investigate this phenomenon so that antioxidant therapy may prove more beneficial to patients with ocular degenerative diseases.

Metabolic Modulation of Carcinogenesis

Emerging evidence inextricably links cellular pathways that involve glucose metabolism (via oxidative phosphorylation and glycolysis), oxygen sensing, apoptosis, cell cycle regulation, and immune recognition and response. This accounts for the epidemiologic and epigenetic effects of calorie intake and quality, obesity, diabetes, immunosuppression, chronic infection or inflammation, aging, and viral diseases on carcinogenic rates and trends. The mitochondrion is a critical organelle that coordinates and integrates the above-mentioned signaling pathways so as to ultimately affect cell proliferation or cell death. The differential regulation of these pathways not only depends on the varying levels of stress induced by the above-mentioned epigenetic factors but also on acquired genetic mutations, thereby attempting the prediction of cell survival or death, an exceedingly difficult proposition. Concepts that have not received much attention in the literature—such as the role of the exogenous cytochrome C/NADH pathway in apoptosis and oxidative phosphorylation; the switch to glycolysis at lower pyruvate thresholds in cancer cells and the paradox that this glycolytic switch may be necessary to provide ATP and matrix alkalinization necessary for apoptosis to occur; reconciling the observations that caloric restriction causes a generalized decrease in apoptosis yet incidences of cancer are significantly decreased in calorie-restricted animals; the unsaturation patterns of the fatty acids comprising the mitochondria-specific phospholipids; and the variation of the intermediary metabolism of tumors—with time will be addressed from the viewpoint of altered cellular respiration. The implications of attenuation of cellular respiration on the mitochondrial adhesion and localization of key immunoregulatory and glycolytic-apoptotic enzymatic or protein complexes will be discussed.

Use of sodium chloride to facilitate reduction of particle size of dexamethasone during ball milling

Ballmilling is frequently used to reduce theparticle size of hydrophobic drugs. The milling slurry typically is between 5–100 times more concentrated with respect to the active drug. Sodium chloride is frequently used as a tonicity adjusting agent. A typical formulation may contain hydrophobic drug, surfactant, sodium chloride, and other ingredients. It was of interest to determine the effect of the milling slurry composition on the particle size of the suspended drug. A reduction in particle size could potentially translate into a more robust manufacturing process, as well as improved bioavailability of the suspended active.