Milk-derived bioactive peptides exhibit antioxidant activity through the Keap1-Nrf2 signaling pathway

Bioactive peptides are relevant nutritional factors that exhibit many functions including antioxidant, anti-hypertensive, anticancer and antimicrobial properties. In this paper, four synthetic peptides ARHPHPHLSFM (A-11-M), AVPYPQR (A-7-R), NPYVPR (N-6-R) and KVLPVPEK (K-8-K) with sequences present in milk proteinswere examined for their antioxidant properties. The compounds show moderate free radical scavenging activityin the ABTS and crocin assays (A-7-R and N-6-R) and lipid peroxidation inhibition in Caco-2 cells (N-6-R and K-8-K). All peptides, in particular K-8-K, activate the Keap1-Nrf2 system by allowing the translocation of the tran-scription factor Nrf2 from the cytosol to nucleus. This activation triggers the overexpression of the antioxidantenzymes Trx1, TrxR1, GR, NQO1 and SOD1. Furthermore, molecular modeling shows that K-8-K is able to hinderthe interaction of Nrf2 with Keap1. The reported results show that the antioxidant action in cells of thesebioactive peptides is mostly due to the activation of Keap1-Nrf2 signaling pathwa

Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria

Two new 'hybrid' metallodrugs of Au(III)(AuTAML)and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophoreto ideally synergize the anticancer activity of both the metal centerand the organic ligand. The compounds have antiproliferative effectsagainst human MCF-7 and MDA-MB 231 breast cancer cells. Moleculardynamics studies suggest that the compounds retain the binding activityto estrogen receptor (ER & alpha;). In vitro and in silico studies showed that the Au(III) derivative isan inhibitor of the seleno-enzyme thioredoxin reductase, while theCu(II) complex may act as an oxidant of different intracellular thiols.In breast cancer cells treated with the compounds, a redox imbalancecharacterized by a decrease in total thiols and increased reactiveoxygen species production was detected. Despite their different reactivitiesand cytotoxic potencies, a great capacity of the metal complexes toinduce mitochondrial damage was observed as shown by their effectson mitochondrial respiration, membrane potential, and morphology

New Platinum(II) Complexes Affecting Different Biomolecular Targets in Resistant Ovarian Carcinoma Cells

Resistance to platinum-based anticancer drugs represents an important limit for their clinical effectiveness and one of the most important field of investigation in the context of platinum compounds. From our previous studies, PtII complexes containing the triphenylphosphino moiety have been emerging as promising agents, showing significant cytotoxicity to resistant ovarian carcinoma cells. Two brominated triphenylphosphino trans-platinum derivatives were prepared and evaluated on human tumor cell lines, sensitive and resistant to cisplatin. The new complexes exert a notable antiproliferative effect on resistant ovarian carcinoma cells, showing a remarkable intracellular accumulation and the ability to interact with different intracellular targets. The interaction with DNA, the collapse of mitochondrial transmembrane potential, and the impairment of intracellular redox state were demonstrated. Moreover, a selectivity towards the selenocysteine of thioredoxin reductase was observed. The mechanism of action is discussed with regard to the resistance phenomenon in ovarian carcinoma cells

Exploring the theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes

A family of cyclometalated Au(III) complexes featuring a tridentate C^N^C scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(C^N^C)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules

Insights into the strong in-vitro anticancer effects for bis(triphenylphosphane)iminium compounds having perchlorate, tetrafluoridoborate and bis(chlorido)argentate anions

Three new compounds containing the bis(triphenylphosphane)iminium cation (PPN+) with ClO4−, BF4− and [AgCl2]− as counter anions have been synthesized and structurally characterized. The two derivatives with ClO4− and BF4− were found to be isostructural by single crystal X-ray diffraction. Interestingly, the three compounds show extremely potent antiproliferative effects against the human cancer cell line SKOV3. To gain insights into the possible mechanisms of biological action, several intracellular targets have been considered. Thus, DNA binding has been evaluated, as well as the effects of the compounds on the mitochondrial function. Furthermore, the compounds have been tested as possible inhibitors of the seleno-enzyme thioredoxin reductase

Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria

Two new 'hybrid' metallodrugs of Au(III)(AuTAML)and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophoreto ideally synergize the anticancer activity of both the metal centerand the organic ligand. The compounds have antiproliferative effectsagainst human MCF-7 and MDA-MB 231 breast cancer cells. Moleculardynamics studies suggest that the compounds retain the binding activityto estrogen receptor (ER & alpha;). In vitro and in silico studies showed that the Au(III) derivative isan inhibitor of the seleno-enzyme thioredoxin reductase, while theCu(II) complex may act as an oxidant of different intracellular thiols.In breast cancer cells treated with the compounds, a redox imbalancecharacterized by a decrease in total thiols and increased reactiveoxygen species production was detected. Despite their different reactivitiesand cytotoxic potencies, a great capacity of the metal complexes toinduce mitochondrial damage was observed as shown by their effectson mitochondrial respiration, membrane potential, and morphology

Fermented soy-derived bioactive peptides selected by a molecular docking approach show antioxidant properties involving the keap1/nrf2 pathway

Bioactive peptides are a group of molecules with health beneficial properties, deriving from food matrices. They are protein fragments consisting of 2–20 amino acids that can be released by microbial fermentation, food processing and gastrointestinal digestion. Once hydrolyzed from their native proteins, they can have different functions including antioxidant activity, which is important for cell protection by oxidant agents. In this work, fermented soy products were digested in vitro in order to improve the release of bioactive peptides. These were extracted, purified and analyzed in vitro and in a cellular model to assess their antioxidant activity. Peptide sequences were identified by LC-MS/MS analysis and a molecular docking approach was used to predict their ability to interact with Keap1, one of the key proteins of the Keap1/Nrf2 pathway, the major system involved in redox regulation. Peptides showing a high score of interaction were selected and tested for their antioxidant properties in a cellular environment using the Caco-2 cell line and examined for their capability to defend cells against oxidative stress. Our results indicate that several of the selected peptides were indeed able to activate the Keap1/Nrf2 pathway with the consequent overexpression of antioxidant and phase II enzymes