Depsipeptides Targeting Tumor Cells: Milestones from In Vitro to Clinical Trials.

Cancer is currently considered one of the most threatening diseases worldwide. Diet could be one of the factors that can be enhanced to comprehensively address a cancer patient's condition. Unfortunately, most molecules capable of targeting cancer cells are found in uncommon food sources. Among them, depsipeptides have emerged as one of the most reliable choices for cancer treatment. These cyclic amino acid oligomers, with one or more subunits replaced by a hydroxylated carboxylic acid resulting in one lactone bond in a core ring, have broadly proven their cancer-targeting efficacy, some even reaching clinical trials and being commercialized as "anticancer" drugs. This review aimed to describe these depsipeptides, their reported amino acid sequences, determined structure, and the specific mechanism by which they target tumor cells including apoptosis, oncosis, and elastase inhibition, among others. Furthermore, we have delved into state-of-the-art in vivo and clinical trials, current methods for purification and synthesis, and the recognized disadvantages of these molecules. The information collated in this review can help researchers decide whether these molecules should be incorporated into functional foods in the near future.

nurP28, a New-to-Nature Zein-Derived Peptide, Enhances the Therapeutic Effect of Docetaxel in Breast Cancer Monolayers and Spheroids.

The development of novel cancer therapeutic strategies has garnered increasing interest in cancer research. Among the therapeutic choices, chemosensitizers have shown exciting prospects. Peptides are an attractive alternative among the molecules that may be used as chemosensitizers. We rationally designed a new-to-nature peptide, nurP28, derived from the 22-kDa α-zein protein sequence (entry Q00919_MAIZE). The resultant sequence of the nurP28 peptide after the addition of arginine residues was LALLALLRLRRRATTAFIIP, and we added acetyl and amide groups at the N- and C-terminus, respectively, for capping. We evaluated the cytotoxicity of the nurP28 peptide alone and in combination with docetaxel in fibroblast monolayers and breast cancer monolayers and spheroids. Our results indicated that nurP28 is not cytotoxic to human fibroblasts or cancer cells. Nevertheless, when combined with 1 µM docetaxel, 3 ng/mL nurP28 induced equivalent (in MCF7 monolayers) and higher (in MCF7 spheroids) cytotoxic effects than 10-fold higher doses of docetaxel alone. These findings suggest that nurP28 may act as a chemosensitizer in breast cancer treatment. This study describes the enhancing "anti-cancer" effects of nurP28 in breast cancer 2D and 3D cultures treated with docetaxel. Further studies should explore the mechanisms underlying these effects and assess the clinical potential of our findings using animal models.

Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics.

Nowadays, cancer has become the second highest leading cause of death, and it is expected to continue to affect the population in forthcoming years. Additionally, treatment options will become less accessible to the public as cases continue to grow and disease mechanisms expand. Hence, specific candidates with confirmed anticancer effects are required to develop new drugs. Among the novel therapeutic options, proteins are considered a relevant source, given that they have bioactive peptides encrypted within their sequences. These bioactive peptides, which are molecules consisting of 2-50 amino acids, have specific activities when administered, producing anticancer effects. Current databases report the effects of peptides. However, uncertainty is found when their molecular mechanisms are investigated. Furthermore, analyses addressing their interaction networks or their directly implicated mechanisms are needed to elucidate their effects on cancer cells entirely. Therefore, relevant peptides considered as candidates for cancer therapeutics with specific sequences and known anticancer mechanisms were accurately reviewed. Likewise, those features which turn certain peptides into candidates and the mechanisms by which peptides mediate tumor cell death were highlighted. This information will make robust the knowledge of these candidate peptides with recognized mechanisms and enhance their non-toxic capacity in relation to healthy cells and further avoid cell resistance.

In Silico Analysis and In Vitro Characterization of the Bioactive Profile of Three Novel Peptides Identified from 19 kDa α-Zein Sequences of Maize.

In this study, we characterized three novel peptides derived from the 19 kDa α-zein, and determined their bioactive profile in vitro and developed a structural model in silico. The peptides, 19ZP1, 19ZP2 and 19ZP3, formed α-helical structures and had positive and negative electrostatic potential surfaces (range of -1 to +1). According to the in silico algorithms, the peptides displayed low probabilities for cytotoxicity (≤0.05%), cell penetration (10-33%) and antioxidant activities (9-12.5%). Instead, they displayed a 40% probability for angiotensin-converting enzyme (ACE) inhibitory activity. For in vitro characterization, peptides were synthesized by solid phase synthesis and tested accordingly. We assumed α-helical structures for 19ZP1 and 19ZP2 under hydrophobic conditions. The peptides displayed antioxidant activity and ACE-inhibitory activity, with 19ZP1 being the most active. Our results highlight that the 19 kDa α-zein sequences could be explored as a source of bioactive peptides, and indicate that in silico approaches are useful to predict peptide bioactivities, but more structural analysis is necessary to obtain more accurate data.

Assessment of potential impacts associated with gene flow from transgenic hybrids to Mexican maize landraces.

Genetically modified (GM) maize has been grown and safely consumed on a global scale since its commercialization in 1996. However, questions have been raised about the potential impact that GM maize could have on native maize landraces in Mexico, which is the center of origin and diversity of maize. This research was conducted to evaluate potential changes to maize landraces in an unlikely event of transgene introgression. For this study, two GM traits that confer insect protection and herbicide tolerance in maize (MON 89034 and MON 88017), designated as VT3Pro, were introgressed into two Mexican landraces, Tuxpeño and Tabloncillo. Field trials were conducted across four environments to assess phenotypic characteristics, plant response to stressors, and kernel composition of landraces with and without VT3Pro traits. Furthermore, materials from four backcrossing generations were analyzed for segregation of these GM traits. Generally, no significant differences were observed between landraces with and without VT3Pro traits for the evaluated characteristics and the segregation analysis showed that GM traits, when introgressed into landraces, followed Mendelian principles. These results support the conclusion that, if inadvertently introgressed into landraces, VT3Pro traits are not expected to alter phenotypic or kernel characteristics, plant response to stressors (except for targeted insect protection and herbicide tolerance traits) and would segregate like any endogenous gene. These results should be taken into consideration when discussing benefits and risks associated with commercial production of GM maize hybrids in the centers of origin and diversity of maize.

Current Methods for the Discovery of New Active Ingredients from Natural Products for Cosmeceutical Applications.

Cosmeceuticals are designed to serve a dual purpose: to provide desired esthetical effects and to treat dermatological conditions. Natural products derived from plants and marine organisms are a novel source of potential cosmeceutical active ingredients for incorporation into new formulations due to consumer demands. Contrary to common perceptions, most regulatory agencies do not view cosmeceuticals as being a separate category from cosmetics; thus, these products are not regulated accordingly, thereby forcing the consumer to rely on the self-regulatory policies of the cosmetics industry. Cosmeceuticals are advertised as having capabilities that include anti-aging, anti-acne, solar-protective, wound healing, and skin whitening. Such traits normally comprise several biological activities. In order to ensure the safety and efficacy of these products, active ingredients employed in the formulations must undergo a series of tests. In this review, in vitro (enzymatic and cellular) and in vivo tests employed to evaluate the potential of new cosmeceutical active ingredients are discussed, and new trends that are being explored by the cosmeceutical industry are described.

In vitro plant tissue culture: means for production of biological active compounds.

MAIN CONCLUSION: Plant tissue culture as an important tool for the continuous production of active compounds including secondary metabolites and engineered molecules. Novel methods (gene editing, abiotic stress) can improve the technique. Humans have a long history of reliance on plants for a supply of food, shelter and, most importantly, medicine. Current-day pharmaceuticals are typically based on plant-derived metabolites, with new products being discovered constantly. Nevertheless, the consistent and uniform supply of plant pharmaceuticals has often been compromised. One alternative for the production of important plant active compounds is in vitro plant tissue culture, as it assures independence from geographical conditions by eliminating the need to rely on wild plants. Plant transformation also allows the further use of plants for the production of engineered compounds, such as vaccines and multiple pharmaceuticals. This review summarizes the important bioactive compounds currently produced by plant tissue culture and the fundamental methods and plants employed for their production.

Antioxidant Activity of Zein Hydrolysates from Zea Species and Their Cytotoxic Effects in a Hepatic Cell Culture.

In recent years, food proteins with bioactivity have been studied for cancer treatment. Zein peptides have shown an important set of bioactivities. This work compares the cytotoxic activity of zein hydrolyzed, extracted from four Zea species: teosinte, native, hybrid, and transgenic (Teo, Nat, Hyb, and HT) in a hepatic cell culture. Zein fraction was extracted, quantified, and hydrolyzed. Antioxidant capacity and cytotoxicity assays were performed on HepG2 cells. The levels of expression of caspase 3, 8, and 9 were evaluated in zein-treated cell cultures. Zea parviglumis showed the highest zein content (46.0 mg/g) and antioxidant activity (673.40 TE/g) out of all native zeins. Peptides from Hyb and HT showed high antioxidant activity compared to their native counterparts (1055.45 and 724.32 TE/g, respectively). Cytotoxic activity was observed in the cell culture using peptides of the four Zea species; Teo and Nat (IC50: 1781.63 and 1546.23 ng/mL) had no significant difference between them but showed more cytotoxic activity than Hyb and HT (IC50: 1252.25 and 1155.56 ng/mL). Increased expression of caspase 3 was observed in the peptide-treated HepG2 cells (at least two-fold more with respect to the control sample). These data indicate the potential for zein peptides to prevent or treat cancer, possibly by apoptosis induction.

Steroidal Saponin and Flavonol Content and Antioxidant Activity during Sporophyte Development of Maguey (Agave salmiana).

Agave salmiana Otto ex Salm-Dyck has traditionally been used for the production of fermented beverage known as "pulque" that has recently gained acceptance as a functional food. However, the plant requires up to 10 years to be used as raw material. The objective of this work was to evaluate the antioxidant and bioactive principles of Agave salmiana during different stages of development. Wild grown plants from Coahuila, Mexico, were identified based on leaf and spine traits to obtain a representative sample from six different stages of development (I-VI) from 1 to 7 years old. Total phenolic content (TPC), antioxidant activity (AOX), as well as composition and content of flavonols and saponins by HPLC-MS-TOF and HPLC-ELSD-PDA were evaluated. Concentrations of TPC were found to be between 5 to 13 mg gallic acid equivalents/g, reaching a maximum at stage II. The AOX presented a negative tendency from stage I to stage VI (from 148 to 50 µmol Trolox equivalents/g respectively). Kaempferol, quercetin and five saponins were identified. Similar to AOX, flavonols presented a negative concentration tendency with a reduction of 65% between the stage I and VI. Plants of stage III and IV presented the highest content of saponins, particularly chlorogenin glycoside, containing 3.19 and 2.90 mg protodioscin equivalents/g, respectively. These data suggest that plants from stages I to IV may be used as a source of antioxidant and bioactive principles, and that the content of these metabolites could be used as a marker to determine the developmental stage of the plant.

Genetic mapping of QTL for maize weevil resistance in a RIL population of tropical maize.

KEY MESSAGE: A tropical RIL maize population was subjected to phenotypic and genotypic analysis for maize weevil resistance during four seasons, and three main genomic areas were detected as main QTLs. The maize weevil (Sitophilus zeamais) (MW) is a common and important pest of stored maize (Zea mays) worldwide, especially in tropical areas. Quantitative trait loci (QTLs) associated with the MW have been analyzed previously in an F2 maize population. In this work, new germplasm-based F6 recombinant inbred line (RIL) families, derived from the cross of Population 84 and Kilima, were analyzed using insect bioassays during four seasons. The parameters analyzed for MW resistance were grain weight losses (GWL), adult progeny (AP), and flour production (FP). Composite interval mapping identified a total of 15 QTLs for MW parameters located on six chromosomes, explaining between 14 and 51 % of phenotypic variation (σ p (2) ) and 27 and 81 % of genotypic variation (σ g (2) ). The QTL obtained for GWL was located in bin 2.05, which explained 15 % of σ p (2) . For AP and FP, the QTLs were located on regions 1.09 and 2.05, explaining 7 and 15 % of σ p (2) , respectively. Comparative analysis between F2 and F6 families showed similarities in QTL localization; three main regions were co-localized in chromosomes 4.08, 10.04, and 10.07, where no resistance-associated genes have been reported previously. These regions could be used for a marker-assisted selection in breeding programs for MW resistance in tropical maize.

Maize hydroxycinnamic acids: unveiling their role in stress resilience and human health.

Maize production is pivotal in ensuring food security, particularly in developing countries. However, the crop encounters multiple challenges stemming from climatic changes that adversely affect its yield, including biotic and abiotic stresses during production and storage. A promising strategy for enhancing maize resilience to these challenges involves modulating its hydroxycinnamic acid amides (HCAAs) content. HCAAs are secondary metabolites present in plants that are essential in developmental processes, substantially contributing to defense mechanisms against environmental stressors, pests, and pathogens, and exhibiting beneficial effects on human health. This mini-review aims to provide a comprehensive overview of HCAAs in maize, including their biosynthesis, functions, distribution, and health potential applications.

Biomedical applications of synthetic peptides derived from venom of animal origin: A systematic review.

Development of therapeutic agents that have fewer adverse effects and have higher efficacy for diseases, such as cancer, metabolic disorders, neurological diseases, infections, cardiovascular diseases, and respiratory diseases, are required. Recent studies have focused on identifying novel sources for pharmaceutical molecules to develop therapies against these diseases. Among the sources for potentially new therapies, animal venom-derived molecules have generated much interest. Various animal venom-derived proteins and peptides have been isolated, identified, synthesized, and tested to develop drugs. Venom-derived peptides have several biomedical properties, such as proapoptotic, cell migration, and autophagy regulation activities in cancer cell models; induction of vasodilation by nitric oxide and regulation of angiotensin II; modification of insulin response by controlling calcium and potassium channels; regulation of pain receptor activity; modulation of immune cell activity; alteration of motor neuron activity; degradation or inhibition of ß-amyloid plaque formation; antibacterial, antifungal, antiviral, and antiprotozoal activities; increase in sperm motility and potentiation of erectile function; reduction of intraocular pressure; anticoagulation, fibrinolytic, and antithrombotic activities; etc. This systematic review compiles these biomedical properties and potential biomedical applications of synthesized animal venom-derived peptides reported in the latest research. In addition, the limitations and areas of opportunity in this research field are discussed so that new studies can be developed based on the data presented.

Micropropagation effect on the anti-carcinogenic activitiy of polyphenolics from Mexican oregano (Poliomintha glabrescens Gray) in human colon cancer cells HT-29.

Phenolic extracts obtained from spices are known to have anti-carcinogenic activities but little is known about the effect of micropropagation on these beneficial effects. The main objective of this study was to evaluate the cytotoxic activity of flavonoid-enriched extracts (FEE) from the leaves of wild (WT), in vitro (IN), and ex vitro (EX) grown oregano plants in colon cancer cells HT-29 and the non-cancer cells CCD-18Co. Cell proliferation of HT-29 cells was reduced to 50 % by WT, IN, and EX at concentrations of 4.01, 1.32, and 4.84 mg of gallic acid equivalents (GAE)/L, respectively. In contrast, in CCD-18Co cells, higher concentrations were required for the same cytotoxic effect. At 6 mg GAE/L, WT and IN reduced the production of reactive oxygen species (ROS) of lipopolysaccharides (LPS)-stimulated control cells to 59.89 and 59.43 %, respectively, and EX to 73.89 %. The mRNA of Caspase-3 was increased 1.53-fold when cells were treated with 4 mg GAE/L of IN extract, and tumor necrosis factor receptor superfamily, member 6 (FAS), and BCL2-associated X protein (BAX) mRNA increased 2.55 and 1.53 fold, respectively. Results on protein expression corroborated the apoptotic effects with a significant decrease of B-cell lymphoma 2 (BCL2) expression for all treatments but more remarkable for EX that also showed the most intense signal of BAX. Overall, FEE extracts derived from micropropagation had increased pro-apoptotic effects, however extracts from the in vitro plants produced more efficacy at the transcriptional level while extracts from the ex vitro plant were superior at the traductional level.

Multivariate Analysis on the Properties of Intact Cereal Kernels and Their Association with Viscoelasticity at Different Moisture Contents.

The viscoelastic properties of cereal kernels are strongly related to their quality, which can be applied to the development of a more selective and objective classification process. In this study, the association between the biophysical and viscoelastic properties of wheat, rye, and triticale kernels was investigated at different moisture contents (12% and 16%). A uniaxial compression test was performed under a small strain (5%), and the increase in viscoelasticity at 16% moisture content corresponded to proportional increases in biophysical properties such as the appearance and geometry. The biophysical and viscoelastic behaviors of triticale were between those of wheat and rye. A multivariate analysis showed that the appearance and geometric properties significantly influenced kernel features. The maximum force showed strong correlations with all viscoelastic properties, and it can be used to distinguish between cereal types and moisture contents. A principal component analysis was performed to discriminate the effect of the moisture content on different types of cereals and to evaluate the biophysical and viscoelastic properties. The uniaxial compression test under a small strain and the multivariate analysis can be considered a simple and non-destructive tool for assessing the quality of intact cereal kernels.

Chemopreventive effects of free and bound phenolics associated to steep waters (nejayote) obtained after nixtamalization of different maize types.

Free and bound phenolics extracts from nejayote solids were obtained after optimally lime-cooking blue, normal white, red, normal yellow, high-carotenoid and quality protein maize types. The extraction yield ranged from 4.47 to 10.05%. Bound phenolics extracts had higher content of total phenolics, antioxidant activity and ferulic acid compared to the free phenolics extracts. In general, free phenolics extracts were less cytotoxic than the bound phenolics counterparts. Bound phenolics extracts had higher induction of quinone reductase (QR) and particularly the normal yellow nejayote exerted the highest chemopreventive index tested in Hepa1c1c7 cells. When tested for monofunctional phase 2 induction capacity in BPrc1 cells, the bound phenolics extracts of blue, normal white and quality protein nejayotes were better inducers than the normal yellow counterpart. Particularly, the free phenolics extract of the white maize nejayote induced BPrc1 cells QR and exerted a higher chemopreventive index compared to the bound phenolics extract. Therefore, the nejayote of the normal white maize was the best source of monofunctional phase 2 enzyme inducers.

Application of metabolic engineering to enhance the content of alkaloids in medicinal plants.

Plants are a rich source of bioactive compounds, many of which have been exploited for cosmetic, nutritional, and medicinal purposes. Through the characterization of metabolic pathways, as well as the mechanisms responsible for the accumulation of secondary metabolites, researchers have been able to increase the production of bioactive compounds in different plant species for research and commercial applications. The intent of the current review is to describe the metabolic engineering methods that have been used to transform in vitro or field-grown medicinal plants over the last decade and to identify the most effective approaches to increase the production of alkaloids. The articles summarized were categorized into six groups: endogenous enzyme overexpression, foreign enzyme overexpression, transcription factor overexpression, gene silencing, genome editing, and co-overexpression. We conclude that, because of the complex and multi-step nature of biosynthetic pathways, the approach that has been most commonly used to increase the biosynthesis of alkaloids, and the most effective in terms of fold increase, is the co-overexpression of two or more rate-limiting enzymes followed by the manipulation of regulatory genes.

Novel Combination of the Biophysical, Nutritional, and Nutraceutical Properties in Subtropical Pigmented Maize Hybrids.

Maize (Zea mays L.) represents the main caloric source for much of the world's population. Pigmented maize varieties are an excellent source of nutraceutical compounds: blue and yellow maize are rich in anthocyanins as well as carotenoids and phenolic acids, respectively. However, blue maize is usually grown in small quantities as a specialty crop because it lacks the qualities and adaptations of commercial white and yellow varieties. Here, a new high-yield variety of blue maize called Vitamaiz was developed from inbred lines of subtropical blue, white, and yellow maize. The aim of this study was to characterize the nutraceutical and physical properties of 30 Vitamaiz hybrids in two subtropical locations. Kernel physical traits, nutrient composition, and nutraceutical components (free phenolic acids, FPA; cell wall-bound phenolic acids, BPA; total monomeric anthocyanin content, TAC; antioxidant capacity, AOX by oxygen radical absorbance capacity assay, and total carotenoid content, TCC) were evaluated. The biophysical traits of the hybrids were suitable for nixtamalized and flour maize industries. High levels of FPA (228 mg GAE/100 g), BPA (635 mg GAE/100 g), and AOX (2.0 and 8.1 mM Trolox equivalent/100 g for FPA and BPA, respectively) were also detected with elevated TAC levels (274 mg C3G/kg dw) and AOX activity (3.1 mM Trolox equivalent/100 g). This is the first study to characterize Blue × Yellow maize hybrids that adapt to subtropical environments.

Grain and tortilla quality in landraces and improved maize grown in the highlands of Mexico.

The maize produced in the highlands of Mexico (>2,400 masl) is generally not accepted by the flour and masa and tortilla industry. The objective of this work was to evaluate the grain quality and tortilla properties of maize landraces commonly grown in the highlands of Mexico and compare them with improved germplasm (hybrids). Germplasm analysis included 11 landraces, 32 white hybrids, and six yellow hybrids. Grain quality was analyzed for a range of physical and chemical factors, as well as for alkaline cooking quality. Landrace grains tended to be heterogeneous in terms of size, hardness and color. All landraces had soft-intermediate grains with an average flotation index (FI) of 61%. In contrast, hybrid grains were homogenous in size and color, and harder than landrace grains, with a FI of 38%. Protein, free sugars, oil and phenolic content in landraces were higher than in the hybrids. Significant correlations were found between phenolic content and tortilla color (r= -0.60; p<0.001). Three landraces were identified as appropriate for the masa and tortilla industry, while all the hybrids evaluated fulfilled the requirements of this industry.

Effects of saline elicitors on saponin production in Agave salmiana plants grown in vitro.

Agave plants are natives of Mexico and have an important role in the functional food industry. Agave salmiana grows in dry and desert soils, which are high in salt content; however, little is known about its response to saline conditions. In this study, A. salmiana plants grown in vitro were exposed to 0.1, 0.5, and 1.0 mM of salt elicitors, including AlCl3, NaCl, and CoCl2, and saponin synthesis and morphological characteristics were examined. Saponins were identified and quantified in ethanolic extracts using HPLC-ELSD. Root length and number, leaf length and number, and plant fresh weight were evaluated to determine the phenological condition of the plant. The presence of salts at various concentrations did not affect the physiological characteristics of the plant. Moreover, 0.5 mM NaCl induced a higher production of total saponin. Chlorogenin glycoside 1 (CG1) and hecogenin glycoside 1 (HG1) content remained unchanged across treatments. By contrast, CG2 and HG2 concentrations tended to decrease in response to increased concentrations of AlCl3, NaCl, or CoCl2. In vitro salt elicitors could be a feasible tool in the synthesis of specific saponins, without compromising on plant biomass. Our findings can be used in further generation of low saponin agave plants in field for the improvement of fermentation yield.

Effect of the Addition of Different Vegetal Mixtures on the Nutritional, Functional, and Sensorial Properties of Snacks Based on Pseudocereals.

Quick meals available in markets are popular among consumers. Generally, these products are not recognized as functional foods owing to nutrient-poor composition. In this study, energy snack bars were developed with different formulations, using puffed quinoa, amaranth, cacao liquor, and coconut oil, and the effects of the addition of commercial vegetal mixtures (VM) on nutritional and functional properties were assessed. VM addition showed significant effects on the protein, lipid, and fiber contents, phenolic compounds (PHC) content, and antioxidant activity of the snacks. The control snack showed higher levels of free and bound PHC. The oxygen radical absorbance capacity (ORAC) analyses recorded highest values of free PHC (9392.7 µmol TE/100 g dry weight) in PC65 (concentrate based on a combination of vegetal proteins), whereas the highest bound PHC levels of 47,087 and 46,531 µmol TE/100 g dry weight were observed in PC65 and the control snacks, respectively. Sensorial attributes assessment provided a high score on the hedonic scale, wherein panelists detected no differences among the samples. Altogether, the selection of non-conventional ingredients with high antioxidant activities emerged as a successful strategy to produce sensory acceptable meals.