Oncosis (from Greek ónkos, meaning “swelling”) is a non-apoptotic cell death process related to energy depletion. In contrast to apoptosis, which is the main form of cell death induced by anticancer drugs, oncosis has been relatively less explored but holds potential to overcome drug resistance phenomena. In this study, we report a novel rationally designed mitochondria-targeted iridium(III) complex (OncoIr3) with advantageous properties as a bioimaging agent. OncoIr3 exhibited potent anticancer activity in vitro against cancer cells and displayed low toxicity to normal dividing cells. Flow cytometry and fluorescence-based assays confirmed an apoptosis-independent mechanism involving energy depletion, mitochondrial dysfunction and cellular swelling that matched with the oncotic process. Furthermore, a Caenorhabditis elegans tumoral model was developed to test this compound in vivo, which allowed us to prove a strong oncosis-derived antitumor activity in animals (with a 41% reduction of tumor area). Indeed, OncoIr3 was non-toxic to the nematodes and extended their mean lifespan by 18%. Altogether, these findings might shed new light on the development of anticancer metallodrugs with non-conventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers. Graphical abstract

Betalains are plants pigments identified as potent antioxidant molecules, naturally present in foods like beetroot and prickly pears. Although activities described for betalain-containing formulations include cancer prevention and treatment, the use of extracts instead of purified pigments has avoided the investigation of the real chemopreventive and chemotherapeutic potential of these phytochemicals. Three betalain-rich extracts and six individual pure betalains were used in this work to characterize the activity and to explore possible molecular mechanisms. The animal model Caenorhabditis elegans (tumoral strain JK1466) was used to evaluate the effect of betalains as chemotherapeutics drugs. An objective evaluation method of tumor growth in C. elegans has been developed to assess the possible antitumoral activity of the different treatments. This protocol allowed a fast and reliable screening of possible antitumoral drugs. Among the betalains tested, tryptophan-betaxanthin reduced tumor size by 56.4% and prolonged the animal’s lifespan by 9.3%, indicating high effectiveness and low toxicity. Structure–activity relationships are considered. Assays with mutant strains of C. elegans showed that the mechanism underlying these effects was the modulation of the DAF-16 transcription factor and the insulin signaling pathway. Our results indicate that tryptophan-betaxanthin and related betalains are strong candidates as antitumoral molecules in cancer treatment.

Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and potentially leading to therapeutic failure or toxicity. This narrative review compiles current evidence on dietary modulation of CYP3A4, with a particular focus on pharmacological and clinical implications for lipid-lowering and glucose-lowering drugs. Literature was identified through a comprehensive search in PubMed, Scopus, and Web of Science, including preclinical and clinical studies addressing food–drug interactions involving CYP3A4 substrates. Numerous dietary compounds, such as citrus furanocoumarins, polyphenols, herbal extracts, and vitamins, act as CYP3A4 inhibitors or inducers through competitive, mechanism-based, or nuclear receptor-mediated pathways. Specific examples include simvastatin, atorvastatin, repaglinide, and saxagliptin, whose systemic exposure can be significantly altered by dietary factors. Moreover, interindividual variability in CYP3A4 activity may be shaped by genetic polymorphisms, microbiota-derived metabolites, and epigenetic regulation, further influencing drug response. Understanding these interactions is crucial, especially in polymedicated patients or those receiving drugs with a narrow therapeutic index. Clinicians should remain aware of potential CYP3A4-related food–drug interactions and consider dietary habits and supplement use in therapeutic decision-making. Future research should aim to integrate pharmacogenomics, gut microbiome profiling, and personalized nutrition in order to improve the prediction and prevention of clinically significant interactions.

Betalains are plant pigments characterized by showing a wide range of beneficial properties for health. Its bioactive potential has been studied for the first time after its encapsulation in liposomes and subsequent administration to the animal model Caenorhabditis elegans. Phenylalanine-betaxanthin and indoline carboxylic acid-betacyanin encapsulated at concentrations of 25 and 500 μM managed to reduce lipid accumulation and oxidative stress in the nematodes. Highly antioxidant betalains dopaxanthin and betanidin were also included in the survival analyses. The results showed that phenylalanine-betaxanthin was the most effective betalain by increasing the lifespan of C. elegans by 21.8%. In addition, the administration of encapsulated natural betanidin increased the nematodes' survival rate by up to 13.8%. The preservation of the bioactive properties of betalains manifested in this study means that the stabilization of the plant pigments through encapsulation in liposomes can be postulated as a new way for administration in pharmacological and food applications.

Betalains are the nitrogenous pigments that replace anthocyanins in the plant order Caryophyllales. Here, we describe unconventional decarboxylated betalains in quinoa (Chenopodium quinoa) grains. Decarboxylated betalains are derived from a previously unconsidered activity of the 4,5-DOPA-extradiol-dioxygenase enzyme (DODA), which has been identified as the key enzymatic step in the established biosynthetic pathway of betalains. Here, dopamine is fully characterized as an alternative substrate of the DODA enzyme able to yield an intermediate and structural unit of plant pigments: 6-decarboxy-betalamic acid, which is proposed and described. To characterize this activity, quinoa grains of different colors were analyzed in depth by chromatography, time-of-flight mass spectrometry, and reactions were performed in enzymatic assays and bioreactors. The enzymatic-chemical scheme proposed leads to an uncharacterized family of 6-decarboxylated betalains produced by a hitherto unknown enzymatic activity. All intermediate compounds as well as the final products of the dopamine-based biosynthetic pathway of pigments have been unambiguously determined and the reactions have been characterized from the enzymatic and functional perspectives. Results evidence a palette of molecules in quinoa grains of physiological relevance and which explain minor betalains described in plants of the Caryophyllales order. An entire family of betalains is anticipated.

With two compounds first discovered in quinoa, an entire novel family of betalain pigments derived from dopamine is obtained and characterized. Betalains are nitrogenous water-soluble pigments and bioactive molecules with health-promoting effects and nutraceutical potential. It was assumed that all betalains contained betalamic acid as a structural unit derived from l-dihydroxyphenylalanine (l-DOPA). However, hitherto ignored compounds derived from dopamine have recently been discovered in nature. Here an entire family of betalains is described as decarboxylated pigments where 6-decarboxy-betalamic acid is the chromophoric and structural unit. This paper shows for the first time the production, purification and characterization of color and fluorescent properties of this novel family of pigments. Antioxidant and anti-aging effects of the just discovered betalains were tested in vivo using the animal model Caenorhabditis elegans. Some of them presented extraordinary properties, being glutamic acid-6-decarboxy-betaxanthin the most fluorescent molecule among both families of betalains. Methionine sulfoxide-6-decarboxy-betaxanthin is described as the most potent betalain in the reduction of oxidative stress in vivo in C. elegans (99.5 % at 25 µM) and dopa-6-decarboxy-betaxanthin increased the lifespan of the animal model up to 7.0 % at 25 µM. These results open new research lines in the search for molecules from plants with health-promoting properties and bioactivities.