Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression. Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with l-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism. CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose- and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

Breast cancer is the most prevalent type of tumor and the second leading cause of death due to cancer among women. Although screening methods, diagnosis and therapeutic options have improved in the last decade, chemoresistance remains an important challenge. There is evidence relating breast cancer resistance with signaling pathways involving hormone and growth receptors, survival, apoptosis and the activation of efflux pumps. However, the resistance mechanisms linked to drug uptake are poorly understood, despite it often being observed that the drug content is lower in resistant cancer cells and that the entry of the drug into these cells is a limiting process for the subsequent therapeutic effect.In this review, we provide an overview of drug uptake-based resistance mechanisms developed by cancer cells in the four main types of chemotherapy used in breast cancer: anthracyclines, taxanes, oxazaphosphorines and platinum-based drugs. The contribution of tumor microenvironment to reduced drug-uptake and multidrug resistance is also analyzed. As a developing field, nanomedicine-based approaches provide promising opportunities to improve drug specific targeting, cell interaction and uptake into cancer cells. The endocytic-mediated pathways attributed to the different types of nanoformulations as well as the contribution of nanotherapeutics to overcoming chemoresistance affecting drug uptake in breast cancer will be described. New approaches focusing on drug uptake mechanisms could improve breast cancer chemotherapy, obtaining better dose-response outcomes and reducing toxic side effects.

‘Orujo’ olive oil is obtained by chemical processes from the waste resulting from the mechanical extraction of virgin olive oil. The aim of the present study was to evaluate a new pharmacological property of two natural triterpenoids contained in olive oil, as vasodilatory agents, and to determine their mechanism of action. The two compounds studied were oleanolic acid and erythrodiol. The vasorelaxant effect induced by these pentacyclic triterpenoids was studied in isolated thoracic rat aorta. Oleanolic acid and erythrodiol, accumulatively added, showed vasorelaxant activities in aortic rings with endothelium pre-contracted by 10⁻⁶M-phenylephrine (maximum percentage of relaxation 86·38 (SEM 2·89) and 73·53 (SEM 6·01), respectively). They had almost no relaxant effect on depolarised or endothelium-denuded aortic segments. The relaxation was significantly attenuated by pre-treatment with the NO synthase inhibitor N^ω-nitro-L-arginine-methylester (L-NAME; 3×10⁻⁴m). To characterise the involvement of endothelial factors, in addition to NO, arteries with endothelium were exposed to 10⁻⁵M-indomethacin (INDO), a cyclo-oxygenase inhibitor, or INDO plus L-NAME. INDO did not have any significant effect on the relaxant response of both compounds. The combination of L-NAME plus INDO only abolished the oleanolic acid-induced relaxation. The present results suggest that the mechanism of relaxation seems to be mainly mediated by the endothelial production of NO; however, other mechanisms cannot be excluded. It can be concluded that oleanolic acid and erythrodiol may have interesting therapeutic potential as new vasodilator drugs, thus protecting the cardiovascular system. Therefore, the intake of ‘orujo’ olive oil, as a source of these compounds, might be beneficial in this regard.

Oleanolic acid and related triterpenoids from olives modulate different signaling pathways, showing a wide range of pharmacological activities against inflammation, cancer or cardiovascular diseases. In particular, emerging evidences reveal the potential of oleanolic acid to restore vascular disorders associated to cardiovascular risk factors, i.e. hypertension, obesity and diabetes, and atherosclerosis. During the previous years, in vitro and in vivo studies with these triterpenoids have positioned them as being mainly responsible for cardiovascular risk protection traditionally associated to olive oil. This review updates recent investigations in olive oil triterpenoids function related to cardiovascular diseases, as well as the underlying mechanisms and structural implications. Important aspects of olive oil triterpenoids such as bioavailability and clinical perspectives on cardiovascular disorder are also extensively analyzed. All these investigations evidence the potential of triterpenoids from olive oil as a promising therapeutic strategy against vascular function, thus efficiently preventing the progression of cardiovascular diseases.