Melanins form a diverse group of pigments synthesized in living organisms in the course of hydroxylation and polymerization of organic compounds. Melanin production is observed in all large taxa from both Pro- and Eukaryota. The basic functions of melanins are still a matter of controversy and speculation, even though their adaptative importance has been proved. Melanogenesis has probably evolved parallel in various groups of free living organisms to provide protection from environmental stress conditions, but in pathogenic microorganisms it correlates with an increased virulence. The genes responsible for melanization are collected in some cases within operons which find a versatile application in genetic engineering. This review summarizes current views on melanogenesis in Pro- and Eukaryotic microorganisms in terms of their biotechnological and biomedical importance.

Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions.

Purpose: Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well.We previously reported the antimetastatic activity of the PPARa ligand, fenofibrate, against melanoma tumors in vivo.Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action. Experimental Design: Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARa expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system. Results: Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar.These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal^regu-lated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model. Conclusions: Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.

e Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR␣). FF and several other agonists of PPAR␣ have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPAR␣-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPAR␣-dependent metabolic switch from glycolysis to fatty acid ␤-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. F enofibrate (FF) is a common lipid-lowering drug and a potent agonist of peroxisome proliferator-activated receptor alpha (PPAR␣). Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1-7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8). In cell culture and animal studies, various members of the fibrate family, which are all agonists of PPAR␣, demonstrate interesting anticancer effects, which are not fully understood. FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9, 10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients wit...