http://hdl.handle.net/10400.18/41 2013-05-14T22:23:32Z http://hdl.handle.net/10400.18/1282 Title: Signaling Pathways of Proteostasis Network Unraveled by Proteomic Approaches on the Understanding of Misfolded Protein Rescue Authors: Gomes-Alves, Patricia; Neves, Sofia; Penque, Deborah Abstract: Attempts to promote normal processing and function of F508del-CFTR, the most common mutant in cystic fibrosis (CF), have been described as potential therapeutic strategies in the management of this disease. Here we described the proteomic approaches, namely two-dimensional electrophoresis (2DE), mass spectrometry (MS), and bioinformatics tools used in our recent studies to gain insight into the proteins potentially involved in lowtemperature or mutagenic treatment-induced rescue process of F508del-CFTR. The proteins identified are part of the proteostasis network, such as the unfolded protein response (UPR) signaling pathways that may regulate the processing of CF transmembrane conductance regulator (CFTR) through the folding and trafficking progression. The complete characterization of these signaling pathways and their regulators in CF will certainly contribute to the development of novel therapeutic strategies against CF. 2011-01-01T00:00:00Z http://hdl.handle.net/10400.18/1055 Title: Nuclear-Mitochondrial Intergenomic Communication Disorders Authors: Almeida, L.S.; Nogueira, C.; Vilarinho, L. Abstract: The focus of this chapter is to review the clinical and molecular etiologies of nuclear defects involved in mtDNA stability and in mitochondrial protein synthesis. The overview done here will hopefully provide insights towards best diagnostic strategies of mitochondrial cross–talk disorders, being useful for clinicians when facing similar cases. Additionally we will present a diagnostic algorithm for these diseases based on our knowledge. 2012-01-01T00:00:00Z http://hdl.handle.net/10400.18/665 Title: Doxorubicin-induced oxidative injury of cardiomyocytes - do we have right strategies for prevention? Authors: Milic Torres, Vukosava; Dragojevic Simic, Viktorija Abstract: Anthracyclines are among the most utilised antitumour drugs ever developed. The discovery of one of the leading compounds, doxorubicin (DOX) in early 1960s was a major advance in the fight against cancer. According to the WHO, it belongs to the group of 17 essential drugs that are used to treat curable cancers or cancers for which the cost-benefit ratio clearly favours drug treatment (Sikora et al., 1999). It is used, often with other antineoplastic, in the treatment of Hodgkin's disease, non-Hodgkin's lymphomas, acute leukaemias, bone and soft-tissue sarcoma, neuroblastoma, Wilm's tumour, and malignant neoplasms of the bladder, breast, lung, ovary, and stomach. The mechanisms of cytotoxicity of DOX in cancer cells is complex including: inhibition of both DNA replication and RNA transcription; free radicals generation, leading to DNA damage or lipid peroxidation; DNA cross-linking; DNA alkylation; direct membrane damage due to lipid oxidation and inhibition of topoisomerase II (Gewirtz, 1999; Minotti et al., 2004). Today, topoisomarase II is generally recognized to be the cellular target of DOX, which act by stabilizing a reaction intermediate in which DNA strands are cut and covalently linked to this enzyme (Simunek et al., 2009). It blocks subsequent DNA resealing. Failure to relax the supercoiled DNA blocks DNA replication and transcription. Furthermore, DNA strand breaks may trigger apoptosis of cancer cells. However, as with all traditional antineoplastic drugs, DOX administration is accompanied by adverse drug reactions arising from the limited selectivity of their anticancer action (Aronson et al., 2006; McEvoy et al., 2010). Particularly common are bone marrow depression, which may be dose-limiting. White cell count reaches a nadir 10 to 15 days after a dose and usually recovers by about 21 days. Gastrointestinal disturbances include moderate or sometimes severe nausea and vomiting; stomatitis and oesophagitis may progress to ulceration. Alopecia occurs in the majority of patients. Occasional hypersensitivity reactions may also occur. However, a cumulative-dose dependent cardiac toxicity has been a major limitation of DOX use. 2011-12-21T00:00:00Z http://hdl.handle.net/10400.18/310 Title: Biomedical Application of Fullerenes Authors: Milic Torres, Vukosava; Srdjenovic, Branislava Editors: Verner, Robert F.; Benvegnu, Carlos Abstract: Fullerene, the third carbon allotrope, is a classical engineered material with the potential application in biomedicine. Since their discovery in 1985, fullerenes have been extensively investigated. The biological activities of fullerenes are considerably influenced by their chemical modifications and light treatment. The most relevant feature of fullerene C60 is the ability to act as a free radical scavenges. Properties attributed to the delocalized π double bond system of fullerene cage allow C60 to quench various free radicals more efficiently than conventional antioxidants. However, extremely high hydrophobicity of fullerene hampers its direct biomedical evaluation and application. To overcome this problem, several approaches for the transfer fullerenes into physiological friendly media have been developed: chemical modification of the fullerene carbon cage, incorporation of fullerenes into water soluble micellar supramolecular structures, solvent exchange and long term stirring of pure C60 in water. These steps created army of different classes of functionalized fullerenes which exhibit vast range of biological activities, especially in the field of photodynamic therapy, neuroprotection, apoptosis, drug and gene delivery. It was found that certain classes of functionalized fullerenes can be used for diagnostic purposes. So far, the most promising applications include the use of gadolinium endohedral complexes in magnetic resonance imaging and therpautic (as a primary or adjuvant) exploration of tris-adducts and polyhidroxlated C60 fullerenes. In this chapter we are summarizing and discussing main biological and medicinal aspects of fullerenes and its functionalized derivates with special regards to the recent achievements. 2011-01-01T00:00:00Z