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Managing of Chronic Myeloid Leukemia via Au- nanoconjugates In TKIs Sensitive/Resistance CML Cells
Publication . Abdulmawjood, Bilal Rabah Qasim; Fernandes, Maria Alexandra; Baptista, Pedro
Chronic myeloid leukemia (CML) is a rare disease caused by the presence of Philadelphia
chromosome as a result of the fusion between the Breakpoint Cluster Region (BCR) gene in
chromosome 22 and the Abelson tyrosine-protein kinase1 (ABL1) gene in chromosome 9.
This fusion encodes a tyrosine kinase (TK) constitutively expressed in CML cells. Imatinib
(IM) is the first line TK inhibitor used in CML treatment. Molecular detection of BCR-ABL1
transcription is crucial for diagnosis and treatment strategies. Point mutations in the ABL1
gene contribute to resistance against TKIs, suggesting a need for modification in treatment
protocols. In a high percentage of CML patients, poor response with relapses and disease
progression is associated with resistance through various mechanisms, including dysregulation of the c-MYC proto-oncogene.
Gold nanoconjugates (Au-nanoconjugates) have shown improved efficacy in gene silencing approaches towards cancer therapy. Herein, we evaluated the silencing potential of
AuNPs functionalized with antisense oligonucleotides targeting e14a2BCR-ABL1 or the c-MYC alone and combination, demonstrating efficient silencing of gene expression and
downregulation of protein levels in IM-senstive and IM-resistant cell lines. Combining TK
inhibitor (IM) with other kinase inhibitors showed synergistic activity in IM-sensitive cell
line. Moreover, the effect of the Au-nanoconjugates with danusertib (Danu), volasertib (Vola)
and adavosertib (Adavo) on IM-resistant cells was also analyzed and showed a synergistic
effect.
These Au-nanoconjugates may be useful to tackle IM-resistance mechanisms and provide an additional tool for future combinatory schemes to fight CML with imatinib resistance.
Evaluation of Novel Platinum-Based Combination Therapies in 2D and 3D Colorectal Cancer Models
Publication . Salas, Beatriz Filipa Bengala; Fernandes, Maria Alexandra
With rapidly increasing numbers, cancer continues to be a major cause of death globally, with colorectal cancer ranking as the second deadliest. Although chemotherapy continues to play a central role, its lack of selectivity and frequent resistance development highlight the urgent need for new therapeutic approaches. Thus, four platinum compounds and one manganese compound, along with their respective free ligands, were evaluated for their antiproliferative potential in doxorubicin-sensitive (HCT116) and resistant (HCT116-DoxR) colorectal carcinoma cell lines, as well as in non-tumorigenic human fibroblasts. Preliminary stability and solubility studies identified Pt-Methoxy and Mn-Methoxy as the most stable compounds, while the ligands showed poor solubility. Cytotoxicity assays in 2D cultures revealed that all tested metal compounds exhibited activity in the low micromolar range, with all but one platinum derivative showing enhanced potency against resistant cells. Selectivity analysis highlighted Pt-diF-terpy-OTf and the Methoxy ligand as particularly promising candidates, combining strong anti-cancer activity with low fibroblast toxicity. In 3D spheroid cultures, the three platinum complexes maintained their cytotoxicity for the HCT116-DoxR cell line and were selected for further evaluation. Mechanistic studies demonstrated that the compounds primarily induced cell death via apoptosis and autophagy, associated with high ROS production, residual mitochondrial depolarization, and cell cycle disruption. Furthermore, combination treatments with FOLFOX, shown to induce extrinsic apoptosis, significantly potentiated cytotoxic and pro-apoptotic effects. In vivo analysis revealed strong antiangiogenic activity for FOLFOX and contrasting vascular responses for Pt-Methoxy. Collectively, these findings support these platinum-based compounds, especially Pt-diF-terpy-OTf, as promising candidates for further preclinical development and highlight the therapeutic potential of combinatorial approaches.
PARP1
Publication . Conceição, Carlota J.F.; Moe, Elin; Ribeiro, Paulo A.; Raposo, Maria; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); LIBPhys-UNL; Faculdade de Ciências e Tecnologia (FCT); Elsevier
The Poly (ADP-ribose) polymerase-1 (PARP1) enzyme is involved in several signalling pathways related to homologous repair (HR), base excision repair (BER), and non-homologous end joining (NHEJ). Studies demonstrated that the deregulation of PARP1 function and control mechanisms can lead to cancer emergence. On the other side, PARP1 can be a therapeutic target to maximize cancer treatment. This is done by molecules that can modulate radiation effects, such as DNA repair inhibitors (PARPi). With this approach, tumour cell viability can be undermined by targeting DNA repair mechanisms. Thus, treatment using PARPi represents a new era for cancer therapy, and even new horizons can be attained by coupling these molecules with a nano-delivery system. For this, drug delivery systems such as liposomes encompass all the required features due to its excellent biocompatibility, biodegradability, and low toxicity. This review presents a comprehensive overview of PARP1 biological features and mechanisms, its role in cancer development, therapeutic implications, and emerging cancer treatments by PARPi-mediated therapies. Although there are a vast number of studies regarding PARP1 biological function, some PARP1 mechanisms are not clear yet, and full-length PARP1 structure is missing. Nevertheless, literature reports demonstrate already the high usefulness and vast possibilities offered by combined PARPi cancer therapy.
Laminaria digitata Supplementation as a Climate-Smart Strategy to Counteract the Interactive Effects of Marine Heatwaves and Disease Outbreaks in Farmed Gilthead Seabream (Sparus aurata)
Publication . Marmelo, Isa; Chainho, Tomás; Bolotas, Daniel; Pereira, Alícia; Özkan, Busenur; Marques, Cátia; Silva, Iris A.L.; Soares, Florbela; Pousão-Ferreira, Pedro; Vieira, Elsa F.; Delerue-Matos, Cristina; Silva, Zélia; Videira, Paula A.; Repolho, Tiago; Diniz, Mário Sousa; Marques, António; Maulvault, Ana Luísa; UCIBIO - Applied Molecular Biosciences Unit; Faculdade de Ciências e Tecnologia (FCT); DCV - Departamento de Ciências da Vida; DQ - Departamento de Química; MDPI AG
Extreme weather events, such as marine heatwaves (MHWs), pose serious threats to the aquaculture sector, facilitating the occurrence of disease outbreaks and compromising farmed animals’ welfare and survival. Hence, finding eco-innovative strategies to improve animal immunocompetence is essential to assure aquaculture’s sustainability and resilience in a rapidly changing ocean. This study evaluated the immunostimulatory potential of Laminaria digitata powder (0.3% and 1.5%) and extract (0.3%) in juvenile gilthead seabream (Sparus aurata) exposed to a Vibrio harveyi outbreak during a Category III MHW event (T = 25.7 °C). Overall, L. digitata supplementation did not significantly affect fish immunocompetence under optimal rearing conditions (T = 21.4 °C; no infection), nor did it induce any adverse effects. However, both the powder (1.5%) and extract (0.3%) forms of L. digitata supplementation effectively mitigated the negative impacts prompted by the MHW and Vibrio harveyi infection—evidenced by improvements in fish health indicators, hematological parameters, leukocyte viability, granulocyte proportions, and reductions in peroxidase activity and immunoglobulin M levels. From an economic standpoint, supplementation with 1.5% L. digitata powder emerged as the most promising strategy, offering a practical balance between effectiveness and affordability for large-scale applications. These findings highlight the potential of L. digitata as an immunostimulatory aquafeed supplement, with promising benefits for fish health and resilience under adverse rearing conditions.
New insights in uranium bioremediation by cytochromes of the bacterium Geotalea uraniireducens
Publication . Almeida, Alexandre; Turner, David L.; Silva, Marta A.; Salgueiro, Carlos A.; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); UCIBIO - Applied Molecular Biosciences Unit; DQ - Departamento de Química; Faculdade de Ciências e Tecnologia (FCT); ASBMB - American Society for Biochemistry and Molecular Biology
The bacterium Geotalea uraniireducens, commonly found in uranium-contaminated environments, plays a key role in bioremediation strategies by converting the soluble hexavalent form of uranium (U(VI)) into less soluble forms (e.g., U(IV)). While most of the reduction and concomitant precipitation of uranium occur outside the cells, there have been reports of important reduction processes taking place in the periplasm. In any case, the triheme periplasmic cytochromes are key players, either by ensuring an effective interface between the cell's interior and exterior or by directly participating in the reduction of the metal. Therefore, understanding the functional mechanism of the highly abundant triheme cytochromes in G. uraniireducens’ is crucial for elucidating the respiratory pathways in this bacterium. In this work, a detailed functional characterization of the triheme cytochromes PpcA and PpcB from G. uraniireducens was conducted using NMR and visible spectroscopy techniques. Despite sharing high amino acid sequence identity and structural homology with their counterparts from Geobacter sulfurreducens, the results showed that the heme reduction potential values are less negative, the order of oxidation of the hemes is distinct, and the redox and redox-Bohr network of interactions revealed unprecedented functional mechanisms in the cytochromes of G. uraniireducens. In these cytochromes, the reduction potential values of the three heme groups are much more similar, resulting in a narrower range of values, that facilitates directional electron flow from the inner membrane, thereby optimizing the uranium reduction.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso de avaliação no âmbito do Programa Plurianual de Financiamento de Unidades de I&D (2017/2018) - Financiamento Base
Número da atribuição
UIDB/04378/2020