Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new ...blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of ...cysteine in cancer, by contributing for hydrogen sulphide (H
S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: ...first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H
S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H
S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BACKGROUNDOvarian cancer is the second most common gynaecologic malignancy and the most common cause of death from gynaecologic cancer, especially due to diagnosis at an advanced stage, when a cure ...is rare. As ovarian tumour grows, cancer cells are exposed to regions of hypoxia. Hypoxia is known to be partially responsible for tumour progression, metastasis and resistance to therapies. These suggest that hypoxia entails a selective pressure in which the adapted cells not only have a fitness increase under the selective environment, but also in non-selective adverse environments. In here, we used two different ovarian cancer cell lines - serous carcinoma (OVCAR3) and clear cell carcinoma (ES2) - in order to address the effect of cancer cells selection under normoxia and hypoxia mimicked by cobalt chloride on the evolutionary outcome of cancer cells.RESULTSOur results showed that the adaptation to normoxia and CoCl2 mimicked hypoxia leads cells to display opposite strategies. Whereas cells adapted to CoCl2 mimicked hypoxia conditions tend to proliferate less but present increased survival in adverse environments, cells adapted to normoxia proliferate rapidly but at the cost of increased mortality in adverse environments. Moreover, results suggest that cysteine allows a quicker response and adaptation to hypoxic conditions that, in turn, are capable of driving chemoresistance.CONCLUSIONSWe showed that cysteine impacts the adaptation of cancer cells to a CoCl2 mimicked hypoxic environment thus contributing for hypoxia-drived platinum-based chemotherapeutic agents' resistance, allowing the selection of more aggressive phenotypes. These observations support a role of cysteine in cancer progression, recurrence and chemoresistance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several studies have demonstrated the feasibility of pulsed electric fields (PEF) for different applications in food industry. PEF technology is therefore a valuable tool that can improve ...functionality, extractability, and recovery of nutritionally valuable compounds as well as the bioavailability of micronutrients and components in a diverse variety of foods. Additionally, other studies have shown the potential of PEF treatments to reduce food processing contaminants and pesticides. This opens the doors to new PEF applications in the food industry. This review focused on some of the most renowned traditional and emerging PEF applications for improvement of osmotic dehydration, extraction by solvent diffusion, or by pressing, as well as drying and freezing processes. The impact of PEF on different products of biological origin including plant tissues, suspension of cells, by-products and wastes will be analyzed in detail. In addition, recent examples of PEF-assisted biorefinery application will be presented, and finally, the main aspects of PEF-assisted cold pasteurization of liquid foods will also be described.
•PEF potential to develop energy efficient and environmentally friendly processes•PEF is a useful tool to improve extractability, and bioavailability of bioactives.•PEF ability to decrease drying temperature•PEF potential to reduce freezing time•PEF ability to reduce formation of processing contaminants and pesticides
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•Zea mays plants were inoculated with phosphate solubilizing bacteria (PSB).•P-deficiency in soils negatively influenced Z. mays growth.•Inoculation of PSB promoted Z. mays biomass production in ...P-deficient soils.•PSB were able to colonize rhizosphere soils of the Z. mays plants.•These PSB can be used as biofertlizers in P-deficient soils.
This work aimed to evaluate the ability of phosphate-solubilizing bacteria (PSB) to enhance Zea mays growth in an agricultural P-deficient soil. Five strains were screened for their ability to solubilize P and to produce plant growth promoting (PGP) substances. The best P-solubilizing strains Rhodococcus sp. EC35 (B1), Pseudomonas sp. EAV (B2) and Arthrobacter nicotinovorans EAPAA (B3) were inoculated in maize plants growing in P-deficient soils without P fertilization and amended with soluble (KH2PO4) and with tricalcium phosphate (TCP). The inoculated PSB were monitored in soil by DGGE. PSB enhanced maize biomass production in all P-treatments. In soils without P fertilization, bacterial inoculation increased P concentration in roots and shoots and plant dry biomass (ca. 20%). In soils amended with soluble P, strain B2 was the bacteria that better performed improving root and shoot biomass by 102% and 63%, respectively. In soils amended with TCP, plant biomass was also enhanced by bacterial inoculation as well as P accumulation in plant tissues (B3 and BM – mixed inoculation). Plant growth enhancement seems to be related not only to P solubilization but also to other PGP traits, like indol-3-acetic acid and ACC-deaminase activity. DGGE profiles allowed to confirm the presence of PSB in maize rhizosphere after 45 days. This work clearly indicates that inoculated PSB have great potential to be used as biofertilizers in P-deficient soils, especially strains Pseudomonas sp. EAV and A. nicotinovorans EAPAA since both highly increased P availability in soils and promoted maize growth, constituting an attractive alternative to the phosphatic fertilizers amendments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The last few years have seen great leaps in the use of mechano-chemically modified carbon nanotubes in catalysis. While high improvements in catalytic performance have been achieved, the nature of ...the technique is not compatible with typical strategies for CNT coating of macro-structured catalysts by chemical vapour deposition. Developing macro-structured catalysts is a key step towards the sustainability of multi-phase catalysis and requires a methodology for coating with mechano-chemical modified CNT metallic catalysts. Preparing water-based slurries is not straightforward due to the CNT's hydrophobicity, and the use of organic solvents is unsustainable. A novel methodology for the washcoating of macro-structures with pre-modified monometallic CNT catalysts was assessed. A compromise between surfactant use, post-coating treatment, and the catalyst activity/integrity, was achieved by solubilization of the surfactant in a isopropanol:acetone mixture. The activity of the prepared catalysts was affected by the metallic dispersion, surfactant coverage, and distribution of the palladium throughout the catalytic layer. Palladium centres in the bottommost layers were found to be unavailable for liquid phase reaction. The activity of the catalysts prepared with pre-formed carbon monometallic powders was improved by adopting a coating strategy to maximize the availability of the metallic particles near the surface of the catalytic layer.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Ruthenium-based complexes have been suggested as promising anticancer drugs exhibiting reduced general toxicity compared to platinum-based drugs. In particular, Ru(η
6
-arene)(PTA)Cl
2
(PTA = ...1,3,5-triaza-7-phosphaadamantane), or RAPTA, complexes have demonstrated efficacy against breast cancer by suppressing metastasis, tumorigenicity, and inhibiting the replication of the human tumor suppressor gene BRCA1. However, RAPTA compounds have limited cytotoxicity, and therefore comparatively high doses are required. This study explores the activity of a series of RAPTA-like ruthenium(
ii
) arene compounds against MCF-7 and MDA-MB-231 breast cancer cell lines and Ru(η
6
-toluene)(PPh
3
)
2
Cl
+
was identified as a promising candidate. Notably, Ru(η
6
-toluene)(PPh
3
)
2
ClCl was found to be remarkably stable and highly cytotoxic, and selective to breast cancer cells. The minor groove of DNA was identified as a relevant target.
A ruthenium(ii) arene compound was identified as the most promising candidate for breast cancer treatment amongst a library of rationally designed and fully synthesized compounds where the impact of different counterions' cytotoxicity was evaluated.
Sulfotransferase enzymes (SULT) catalyse sulfoconjugation of drugs, as well as endogenous mediators, gut microbiota metabolites and environmental xenobiotics. To address the limited evidence on ...sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. A total of 36 healthy adult volunteers (12 men, 12 women and 12 women on oral contraceptives) received paracetamol in a 1 g-tablet formulation on three separate occasions. Paracetamol and its metabolites were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. A metabolic ratio (Paracetamol Sulfonation Index-PSI) was used to estimate phenol SULT activity. PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual's sulfonator status. To the best of our knowledge, our method provides the first standardised in vivo empirical measure of an individual's phenol sulfonation capability and of its intraindividual variability. EUDRA-CT 2016-001395-29, NCT03182595 June 9, 2017.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chronic intermittent hypoxia (CIH) is the dominant pathological feature of human obstructive sleep apnoea (OSA), which is highly prevalent and associated with cardiovascular and renal diseases. CIH ...causes hypertension, centred on sympathetic nervous overactivity, which persists following removal of the CIH stimulus. Molecular mechanisms contributing to CIH‐induced hypertension have been carefully delineated. However, there is a dearth of knowledge on the efficacy of interventions to ameliorate high blood pressure in established disease. CIH causes endothelial dysfunction, aberrant structural remodelling of vessels and accelerates atherosclerotic processes. Pro‐inflammatory and pro‐oxidant pathways converge on disrupted nitric oxide signalling driving vascular dysfunction. In addition, CIH has adverse effects on the myocardium, manifesting atrial fibrillation, and cardiac remodelling progressing to contractile dysfunction. Sympatho‐vagal imbalance, oxidative stress, inflammation, dysregulated HIF‐1α transcriptional responses and resultant pro‐apoptotic ER stress, calcium dysregulation, and mitochondrial dysfunction conspire to drive myocardial injury and failure. CIH elaborates direct and indirect effects in the kidney that initially contribute to the development of hypertension and later to chronic kidney disease. CIH‐induced morphological damage of the kidney is dependent on TLR4/NF‐κB/NLRP3/caspase‐1 inflammasome activation and associated pyroptosis. Emerging potential therapies related to the gut–kidney axis and blockade of aryl hydrocarbon receptors (AhR) are promising. Cardiorenal outcomes in response to intermittent hypoxia present along a continuum from adaptation to maladaptation and are dependent on the intensity and duration of exposure to intermittent hypoxia. This heterogeneity of OSA is relevant to therapeutic treatment options and we argue the need for better stratification of OSA phenotypes.
figure legend Chronic intermittent hypoxia (CIH) refers to a pathological pattern of oxygen dysregulation, characterised by brief (seconds‐to‐minutes), recurrent cycling between normal physiological and low levels of O2 (multiple events per hour), that is prolonged (days‐to‐years). CIH induces molecular and functional responses in the heart, vessels and kidneys that initially might be protective and adaptive but become deleterious according to the severity and chronicity of the exposure. In rodents, there is some consensus that exposure to 10% O2, 15 cycles/h, 12 h/day, less than 14 days is a mild/short‐term CIH paradigm while exposure to 2–5% O2, 48 cycles/h, 6 h/day, for 30 days is severe/long‐term and causes detrimental effects. The molecular pattern caused by CIH has many similarities among the heart, vessels and kidney and is compatible with sympathetic and renin–angiotensin–aldosterone system activation, HIF activation, oxidative stress and inflammation. The translation of the molecular signatures found in rodent models to humans is a challenge to be addressed in the future to allow a better patient stratification and to predict responses to drug and mainstay treatments such as continuous positive airway pressure (CPAP). CHOP, C/EBP homologous protein (endoplasmic reticulum stress‐induced apoptosis pathway); EPO, erythropoietin; ET‐1, endothelin‐1; HIF, hypoxia inducible factor; iNOS, inducible nitric oxide synthase; VEGF, vascular endothelial growth factor.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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