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- Alternative SplicingPublication . Jordan, PeterAlternative splicing (AS) is a critical post-transcriptional regulatory mechanism used by more than 95% of transcribed human genes and responsible for structural transcript variation and proteome diversity.
- Biomedical Application of FullerenesPublication . Milic Torres, Vukosava; Srdjenovic, Branislava; Verner, Robert F.; Benvegnu, CarlosFullerene, 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.
- Cellular and Molecular Mechanisms of Toxicity of Ingested Titanium Dioxide NanomaterialsPublication . Vieira, Adriana; Gramacho, Ana; Rolo, Dora; Vital, Nádia; Silva, Maria João; Louro, HenriquetaAn exponential increase in products containing titanium dioxide nanomaterials (TiO2), in agriculture, food and feed industry, lead to increased oral exposure to these nanomaterials (NMs). Thus, the gastrointestinal tract (GIT) emerges as a possible route of exposure that may drive systemic exposure, if the intestinal barrier is surpassed. NMs have been suggested to produce adverse outcomes, such as genotoxic effects, that are associated with increased risk of cancer, leading to a concern for public health. However, to date, the differences in the physicochemical characteristics of the NMs studied and other variables in the test systems have generated contradictory results in the literature. Processes like human digestion may change the NMs characteristics, inducing unexpected toxic effects in the intestine. Using TiO2 as case-study, this chapter provides a review of the works addressing the interactions of NMs with biological systems in the context of intestinal tract and digestion processes, at cellular and molecular level. The knowledge gaps identified suggest that the incorporation of a simulated digestion process for in vitro studies has the potential to improve the model for elucidating key events elicited by these NMs, advancing the nanosafety studies towards the development of an adverse outcome pathway for intestinal effects.
- Colorectal Cancer Subtypes – The Current PortraitPublication . Jordan, PeterColorectal cancer (CRC) is one prominent example for how chemotherapy has been changing by moving from the use of general cytotoxic agents to more tumour-specific drugs. For example, antibody-based drugs neutralize a growth factor receptor protein on the surface of tumour cells. The development of such new therapeutic opportunities requires a more thorough and systematic subclassification of CRC because tumour cells can exploit several alternative genetic pathways for their survival. This chapter gives an overview on CRC subtypes as an introduction to the following book chapters that will describe aspects of specific subtypes, and how these may lead to the development of novel pathway-specific drugs for a more precise therapeutic intervention.
- Cost/Benefit of Mutation Induction under PARP1 Deficiency: From Genomic Instability to TherapyPublication . Louro, Henriqueta; Silva, Maria João; Urbano, Kevin V.Mutation is a possible consequence of DNA damage and it is the most prominent event of the carcinogenic process. Spontaneous mutations originate from endogenous metabolic processes, such as inaccurate DNA replication or repair, whereas induced mutations arise from exposure to exogenous agents. Once DNA damage occurs, a complex network of repair functions is triggered to protect cells against the deleterious consequences of mutations and in order to maintain genomic stability. Among the several DNA repair pathways available in eukaryotic cells, base excision repair (BER) is required to repair non-bulky DNA adducts such as oxidized bases. Poly (ADP-ribose) polymerase-1 (PARP1) is a ubiquitous protein in mammalian cells, with a relevant role in BER and participating also in other complex biochemical processes including double strand break repair, chromatin remodelling and cell death. Hence, defective PARP1 activity would be expected to influence the number or type of gene and/or chromosome mutations resultant from exposure to genotoxic agents and, eventually, to be implicated in cancer. Recently, we generated a Parp1-/- lacZ transgenic mouse model to investigate the effect of PARP1 deficiency in vivo on the mutagenic and clastogenic responses to carcinogens. In this chapter, we present data showing the occurrence of a higher spontaneous genomic instability and a modified mutagenic response to genotoxic insults in Parp1-deficient mice. Particularly, the higher level of deletion mutations in the germ line of those mice might constitute an added risk for hereditary diseases. Inversely, it might provide genetic diversity, representing an advantage for survival. Interestingly, although we found that PARP1 inactivation causes some genomic instability in vivo, cancer propensity was not observed either in this mouse line or in two other different Parp1-deficient mouse models. Even though, defects in DNA damage responses that are not directly responsible for a disease can be important and exploited to be used for the benefit of health. This has been the case of molecules acting as PARP inhibitors, which have been developed to enhance the effectiveness of anticancer drugs or even to function as chemotherapeutic agents per se. The rational for their therapeutic application is based, precisely, on the increase of mutations in tumor cells upon PARP1 abrogation, triggering cell death. However, considering the present knowledge about the impact of PARP1 deficiency in mutation accumulation and the uncertainties about its association with somatic or hereditary diseases, the cost/benefit of the clinical use of PARP inhibitors in humans should be carefully evaluated.
- Dermal Delivery of Lipid Nanoparticles: Effects on Skin and Assessment of Absorption and SafetyPublication . Pinto, Fátima; Fonseca, Luis P.; de Barros, Dragana P.C.During the recent decades, dermal delivery has achieved visible popularity mainly due to the increase of chronic skin diseases and the demand for targeted delivery and patient compliance. Dermal delivery provides an attractive alternative to oral drug delivery, promoting the drug application directly at the site of action, resulting in higher localized drug concentration with reduced systemic drug exposure. Among several types of drug delivery systems used in dermal delivery are the lipid nanoparticles, which include solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers have attracted great interest and have been intensively studied for their use in dermal applications. Lipid nanoparticles increase the transport of active compounds through the skin by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Moreover, these nanocarriers are composed of biologically active and biodegradable lipids that show less toxicity and offer many favorable attributes such as adhesiveness, occlusion, skin hydration, lubrication, smoothness, skin penetration enhancement, modified release, improvement of formulation appearance providing a whitening effect, and offering protection of actives against degradation. This chapter focuses on the effects of lipid nanoparticles in dermal delivery, on the types of active compounds that are used in their formulation and application, some aspects related to their possible toxicity, and a description of the most commonly used techniques for the evaluation of drug absorption on the skin.
- Doxorubicin-induced oxidative injury of cardiomyocytes - do we have right strategies for prevention?Publication . Milic Torres, Vukosava; Dragojevic Simic, ViktorijaAnthracyclines 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.
- Erythropoietin in Familial Amyloidosis ATTR V30MPublication . Beirão, I.; Costa, P.P.Familial amyloidosis ATTR V30M is an hereditary disorder, the most frequent type of transthyretin related amyloidosis. The main manifestation of the disease is a sensory-motor and autonomic polyneuropathy. Other manifestations occur such as cardiovascular, gastrointestinal, ocular, renal and hematological disorders. Anemia is a common feature, and occurs late in the disease course. It is associated with low erythropoietin production. Decreased production can start early in the course of the disease and precede clinical symptoms. The possible underlying pathogenic mechanisms are discussed.
- Genoma: bem público ou privado?Publication . Lavinha, JoãoPara responder à questão "genoma: bem público ou privado?" apresenta-se a complexidade dos sistemas vivos e a relevância da interação de fatores ambientais e genéticos e até das leis do acaso na dinâmica vital das espécies e da biosfera no seu conjunto. Questiona-se, em particular, a ideia de que o genoma seria uma espécie de "livro (de instruções) da vida" ou de que o ADN possuiria o estatuto de molécula-mestra determinante da própria natureza dos organismos vivos. Sustenta-se que a informação genética não é fundamentalmente diferente de outros tipos de informação de saúde, desmontando-se a visão simplista e reducionista segundo a qual os traços fenotípicos dos seres humanos são uma consequência direta da sua constituição genética.
- Hazard Assessment of Benchmark Metal-Based Nanomaterials Through a Set of In Vitro Genotoxicity AssaysPublication . Vital, Nádia; Pinhão, Mariana; Yamani, Naouale El; Rundén-Pran, Elise; Louro, Henriqueta; Dušinská, Maria; Silva, Maria JoãoFor safety assessment of nanomaterials (NMs), in vitro genotoxicity data based on welldesigned experiments is required. Metal-based NMs are amongst the most used in consumer products. In this chapter, we report results for three metal-based NMs, titanium dioxide (NM- 100), cerium dioxide (NM-212) and silver (NM-302) in V79 cells, using a set of in vitro genotoxicity assays covering different endpoints: the medium-throughput comet assay and its modified version (with the enzyme formamidopyrimidine DNA glycosylase, Fpg), measuring DNA strand beaks (SBs) and oxidized purines, respectively; the micronucleus (MN) assay, assessing chromosomal damage; and the Hprt gene mutation test. The results generated by this test battery showed that all NMs displayed genotoxic potential. NM-100 induced DNA breaks, DNA oxidation damage and point mutations but not chromosome instability. NM-212 increased the level of DNA oxidation damage, point mutations and increased the MN frequency at the highest concentration tested. NM-302 was moderately cytotoxic and induced gene mutations, but not DNA or chromosome damage. In conclusion, the presented in vitro genotoxicity testing strategy allowed the identification of genotoxic effects caused by three different metal-based NMs, raising concern as to their impact on human health. The results support the use of this in vitro test battery for the genotoxicity assessment of NMs, reducing the use of more expensive, time-consuming and ethically demanding in vivo assays, in compliance with the 3 R’s.