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- Untargeted urinary 1H NMR-based metabolomic pattern as a potential platform in breast cancer detectionPublication . Silva, Catarina L.; Olival, Ana; Perestrelo, Rosa; Silva, Pedro; Tomás, Helena; Câmara, José S.: Breast cancer (BC) remains the second leading cause of death among women worldwide. An emerging approach based on the identification of endogenous metabolites (EMs) and the establishment of the metabolomic fingerprint of biological fluids constitutes a new frontier in medical diagnostics and a promising strategy to differentiate cancer patients from healthy individuals. In this work we aimed to establish the urinary metabolomic patterns from 40 BC patients and 38 healthy controls (CTL) using proton nuclear magnetic resonance spectroscopy (1H-NMR) as a powerful approach to identify a set of BC-specific metabolites which might be employed in the diagnosis of BC. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to a 1H-NMR processed data matrix. Metabolomic patterns distinguished BC from CTL urine samples, suggesting a unique metabolite profile for each investigated group. A total of 10 metabolites exhibited the highest contribution towards discriminating BC patients from healthy controls (variable importance in projection (VIP) >1, p < 0.05). The discrimination efficiency and accuracy of the urinary EMs were ascertained by receiver operating characteristic curve (ROC) analysis that allowed the identification of some metabolites with the highest sensitivities and specificities to discriminate BC patients from healthy controls (e.g. creatine, glycine, trimethylamine N-oxide, and serine). The metabolomic pathway analysis indicated several metabolism pathway disruptions, including amino acid and carbohydrate metabolisms, in BC patients, namely, glycine and butanoate metabolisms. The obtained results support the high throughput potential of NMR-based urinary metabolomics patterns in discriminating BC patients from CTL. Further investigations could unravel novel mechanistic insights into disease pathophysiology, monitor disease recurrence, and predict patient response towards therapy.
- Cinnamic acid terminated dendrimers – Synthesis, characterization, biological evaluation and NMR metabolomics analysisPublication . Olival, Ana Cristina Dias; Rodrigues, João Manuel Cunha; Tomás, Helena Maria Pires GasparGiven the widespread use and enormous therapeutic potential of nanoparticles, the study of their biological effects is a relevant and current issue. In this project, were synthesized new cinnamic acid-terminated PAMAM G4NH2 dendrimers (CATDEN) to target the monocarboxylate transporter (MCTs) overexpressed in cancer cells. The cinnamic acid chosen was alpha-cyano-4-hydroxycinnamic acid, given its effectiveness in vitro and in vivo in inhibiting MCTS. The metabolic profile of cell extracts and cell culture supernatants were studied by NMR metabolomics methods to evaluate the dendrimer’s mechanism of action. After statistical analysis, the results showed that all cell lines were affected by the treatment with the PAMAM G4NH2, with the assays in human osteosarcoma cells (CAL 72) showing higher discrimination between treated and non-treated cells. The results suggested that native dendrimer and CATDEN influence metabolic alterations in energy production (glucose metabolism) and protein synthesis (amino acid catabolism). This finding indicates that the cytotoxicity associated with PAMAM may result from the depletion of the components of the medium. Furthermore, CATDEN dendrimers were also used to encapsulate the anticancer drug DOX. Our results indicated that in CATDEN, even with a lower encapsulation capacity (probably due to steric hindrance), the release of DOX is similar to that of the commercial dendrimer not functionalized with cinnamic acid. The cytotoxicity of both dendrimer/DOX complexes is shown to be superior when compared to free DOX.
- Design, synthesis and biological evaluation of Arylpiperazine-based novel Phthalimides: active inducers of testicular germ cell apoptosisPublication . Singh, Anil K.; Bhardwaj, Jitender K.; Olival, Ana; Kumar, Yogesh; Podder, Avijit; Maheshwari, Ankur; Agrawal, Renuka; Latha, N.; Singh, Brajendra K.; Tomás, Helena; Rodrigues, João; Kishan, Ram; Rupini, B.; Rathi, BrijeshUnderstanding of apoptosis or programmed cell death has provided the basis for novel therapeutics that has resulted in rationally designed anticancer strategies. Recently, inducers of apoptosis have been used in cancer therapy. In this work, we describe the role of chiral phthalimides functionalized with piperazines as potential apoptotic inducers. The listed twenty phthalimides were assessed for their in vitro apoptotic activity against testicular germ cells. All phthalimides showed a significant apoptotic response (∼39 to ∼68%). TUNEL assay and acridine orange fluorescence staining were carried out to investigate the molecular mechanisms responsible for the cell death. Phthalimides exhibited substantial apoptotic induction following the intrinsic pathway mechanism. Studies advocated that the apoptotic induction was mediated through caspase-9, caspase-3, JNK MAP kinase and tumor suppressor p53, which was accompanied by DNA fragmentation and nuclear condensation. Besides, the best five phthalimides regarding apoptotic action were evaluated for in vitro cytotoxic effects against CAL-72 and MCF-7 cancer cell lines. Compounds showed efficient killing of cancer cells. This discovery of functionalized phthalimides as apoptotic inducers would be highly valuable in understanding the mechanism of apoptosis at the molecular level and opens up new possibilities for therapeutic strategies.