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- Effect of 1-carbaldehyde-3,4-dimethoxyxanthone on prostate and HPV-18 positive cervical cancer cell lines and on human THP-1 macrophagesPublication . Medeiros, Rui; Horta, Bruno; Freitas-Silva, Joana; Silva, Jani; Dias, Francisca; Sousa, Emília; Pinto, Madalena; Cerqueira, FátimaXanthone derivatives have shown promising antitumor properties, and 1-carbaldehyde-3,4-dimethoxyxanthone (1) has recently emerged as a potent tumor cell growth inhibitor. In this study, its effect was evaluated (MTT viability assay) against a new panel of cancer cells, namely cervical cancer (HeLa), androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer, and nonsolid tumor derived cancer (Jurkat) cell lines. The effect of xanthone 1 on macrophage functions was also evaluated. The effect of xanthone 1-conditioned THP-1 human macrophage supernatants on the metabolic viability of cervical and prostate cancer cell lines was determined along with its interference with cytokine expression characteristic of M1 profile (IL-1 ≤ β; TNF-α) or M2 profile (IL-10; TGF-β) (PCR and ELISA). Nitric oxide (NO) production by murine RAW264.7 macrophages was quantified by Griess reaction. Xanthone 1 (20 µM) strongly inhibited the metabolic activity of the cell lines and was significantly more active against prostate cell lines compared to HeLa (p < 0.05). Jurkat was the cell most sensitive to the effect of xanthone 1. Compound 1-conditioned IL-4-stimulated THP-1 macrophage supernatants significantly (p < 0.05) inhibited the metabolic activity of HeLa, LNCaP, and PC-3. Xanthone 1 did not significantly affect the expression of cytokines by THP-1 macrophages. The inhibiting effect of compound 1 observed on the production of NO by RAW 264.7 macrophages was moderate. In conclusion, 1-carbaldehyde-3,4-dimethoxyxanthone (1) decreases the metabolic activity of cancer cells and seems to be able to modulate macrophage functions.
- Omega-3- and resveratrol-loaded lipid nanosystems for potential use as topical formulations in autoimmune, inflammatory, and cancerous skin diseasesPublication . Caldas, Ana R.; Catita, José; Machado, Raul; Ribeiro, Artur; Cerqueira, Fátima; Horta, Bruno; Medeiros, Rui; Lúcio, Marlene; Lopes, Carla M.Resveratrol (RSV) and omega 3 (!3), because of their biological favorable properties, have become subjects of interest for researchers in dermocosmetic and pharmaceutical industries; however, these bioactives present technological limitations that hinder their effective delivery to the target skin layer. To overcome the stability and skin permeation limitations of free bioactives, this work proposes a combined strategy involving two different lipid nanosystems (liposomes and lipid nanoparticles) that include ω3 in their lipid matrix. Additionaly, RSV is only encapsulated in liposomes that provid an adequate amphiphilic environment. Each formulation is thoroughly characterized regarding their physical–chemical properties. Subsequently, the therapeutic performance of the lipid nanosystems is evaluated based on their protective roles against lipid peroxidation, as well as inhibition of cicloxygenase (COX) and nitric oxid (NO) production in the RWA264.7 cell line. Finally, the lipid nanosystems are incorporated in hydrogel to allow their topical administration, then rheology, occlusion, and RSV release–diffusion assays are performed. Lipid nanoparticles provide occlusive effects at the skin surface. Liposomes provide sustained RSV release and their flexibility conferred by edge activator components enhances RSV diffusion, which is required to reach NO production cells and COX cell membrane enzymes. Overall, the inclusion of both lipid nanosystems in the same semisolid base constitutes a promising strategy for autoimmune, inflammatory, and cancerous skin diseases.
- Fractionation of sugarcane fermentation spent broths aqueous phase for production of value-added components towards an integrated biorefinery concept in synthetic biotechnologyPublication . Horta, Bruno Miguel Guedes; Oliveira, Catarina Silva Simão de; Burgal, João Porfírio da Silva; Cálix, Carla Maria Dias Marques de OliveiraFarnese aqueous waste (FAW) consists of the fermentation spent broth generated from the production of trans-β-farnesene, by Amyris, Inc.. It is generated in high scale and is usually disposed of by land disposal and fertirrigation, causing environmental problems. The main objective of this PhD project was to study and fractionate FAW, developing value-added products in line with the circular economy concept. Consequently, an integrated downstream process was developed, and the compositional and bioactive characteristics of the resulting products were assessed to determine their potential applications. FAW has an average dry matter content of 63.56±18.67 g/L, 10.08±3.75 g/L of ash content, 18.71±5.97 g/L of proteins, 1.15±0.47 g/L of ammonia, 2.08±1.35 g/L of total lipids, 12.83±7.35 g/L of organic acids, 10.63±4.95 g/L of sugars, 1.00±0.56 g/L of volatile compounds and 23.31±15.8 mg/L phenolic compounds. FAW proteinaceous compounds were comprised of small peptides with molecular weight below 1 kDa, and a great variety of amino acids (AA). The most interesting compounds to target in subsequent fractionation were the proteinaceous fractions, which could be used as ingredients for animal feed; minerals, with potential benefits for plant fertilisation; and phenolic compounds, known for their bioactive properties and their potential applications in cosmetic formulations. Chemical methods, such as precipitation, salting-out, aqueous two-phase systems, were initially used to recover protein and mineral-rich fractions. However, the use and disposal of chemicals could give rise to environmental concerns and compromise the sustainability of the valorisation strategy. Therefore, a chemical-free and environmentally friendly process was developed to remove nutrients from FAW creating a potential product for agriculture. In this regard, natural zeolites were used to treat FAW and removing and recovering nutrients, mainly potassium (K), peptides and AA (nitrogenous compounds – N). The optimal conditions for the simultaneous recovery of K and total N were obtained with a 0.2 Z/F (zeolite/FAW) ratio, 50 rpm mixing, 10 hours of contact and the use of 2 contact units, in a counter-current scheme. This process resulted in the production of zeolites loaded with 3597.23±368.33 mg/kg of ammoniacal N, 255.84±28.99 mg/kg of P, 36626.45±4215.54 mg/kg of K, 113.06±4.75 mg/kg of free AA and 4700.31±346.90 mg/kg of total AA. Peptides were also detected in the loaded zeolites. The composition displayed promising attributes for agricultural practices and exhibited encouraging results in preliminary phytotoxicity assessments, indicating its safety application on plants. The secondary output obtained from this process, consisted of treated FAW, which was an aqueous fraction that still contained a considerable nutrient load. Therefore, a cascade membrane filtration, using membranes with different molecular-weight cut-off (MWCO), was developed to recover compounds for application in cosmetic and animal feed formulations. It consisted of a sequential filtration employing micro-, ultra- and nano- filtration membranes. Two stages of ultrafiltration generated two retentates with compositional similarities in terms of the protein content (15.79±0.06 g/L and 6.96±0.03 g/L, respectively), minerals (7.83±0.14 g/L and 5.30±0.05 g/L, respectively), total analysed phenolic compounds (22.65±0.44 mg/L and 27.15±0.06 mg/L, respectively), and exhibited an interesting antioxidant activity. These fractions were hypothesised as aquafeed ingredients. As for the nanofiltration stage, a retentate with a protein content of 8.34±0.01 g/L, minerals content of 10.67±0.14 g/L and the total analysed phenolic compounds of 56.35 ± 0.29 mg/L, was obtained. The peptide profile of this sample consisted of 2.59% of peptides with MW between 1000 and 5000 Da, 50.58% in the 500- 1000 Da range and 46.83% with MW below 500 Da. This fraction also demonstrated interesting antioxidant activity. Due to its significant content in small peptides and the need for more extensive sample processing and capital investment, this retentate was targeted towards more lucrative markets, such as cosmetics. The permeate had a low nutrient load and could be considered as treated effluent. Thus, an integrated process for the valorisation of FAW was developed, which allows obtaining five products with potential commercial interest – an agricultural additive, ingredients for aquafeed and ingredients for cosmetics – additionally to a treated effluent.