Hernández García, Samanta

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Hernández García, Samanta

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Novel organo-osmium(II) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans
(Royal Society of Chemistry, 2020-10-27) Ortega, Enrique; Ballester, Francisco J.; Hernández García, Alba; Guerrero Rubio, M. Alejandra; Bautista, Delia; Santana, M. Dolores; Ruiz, José; Gandía Herrero, Fernando; Hernández García, Samanta; Bioquímica y Biología Molecular A; SAI, Universidad de Murcia,
This work reports the synthesis and characterization of some novel osmium(II) complexes with potential as anticancer drugs tested in vitro and in vivo. The complexes have a structure [(η6 -p-cym)Os(C^N)(X)]0/+, where the C^N ligand is deprotonated 2-phenylpyridine (ppy) or 4-(2-pyridin)benzaldehyde (ppy-CHO) and X is chloride, pyridine (py) or the pyridine derivative 4-NMe2-py. The in vitro cytotoxic studies showed that complexes [(η6 -p-cym)Os(C^N)(4-NMe2-py)]+ (C^N = ppy 2a and ppy-CHO 5a) exerted effective antiproliferative activity towards both cisplatin-sensitive ovarian cancer cells (A2780) and cisplatin-resistant cells (A2780cis). The mechanism underlying the antiproliferative effects in vitro was studied showing a reduction of proteosynthesis up to 58% and an increase of apoptosis modulated by caspase-3. Model animal Caenorhabditis elegans was used to estimate the effects of 2a and 5a and the in-house 4-NMe2-py Ru(II) analogue 5b in vivo. Compounds 2a, 5a and 5b were able to reduce tumor growth up 32.2%, 19% and 30%, respectively in the tumoral strain JK1466 and presented low toxicity in both tumoral and wild-type strains. The mechanistic study using reporter gene expression showed that 2a, 5a and 5b were able to maintain the reactive oxygen species (ROS) levels in the animals by increased expression of the mitochondrial superoxide dismutase 3 (SOD-3), an indication that they were able to regulate oxidative stress genes specifically. Interestingly the three complexes showed a similar mechanism of action, suggesting that the identity of the metal ion does not matter and the effect is more related to the whole structure of the complex. Worthy of note, cisplatin treatment produced elevated ROS levels in the animals and induced the expression of glutathione transferase 4 (GST-4) suggesting different mechanisms of action for the two complexes. Altogether the results showed that osmium(II) complexes can be potential candidates in the search for novel chemotherapeutic drugs.
Open Access
Exploring in the classroom the relationship between alcohol intake and behavioral disorders through an animal model
(Wiley, International Union of Biochemistry and Molecular Biology (IUBMB), 2024-03-19) Guerrero-Rubio, M. Alejandra; Henarejos Escudero, Paula; Martínez Rodríguez, Pedro; Gandía Herrero, Fernando; Hernández García, Samanta; Bioquímica y Biología Molecular A
Alcohol consumption has profound effects on behavior, such as impaired judg-ment, addiction or even death. It is estimated that alcohol contributes to around three million deaths worldwide, 13.5% of them in young people with ages between 20 and 39 years. Consequently, it is necessary to raise awareness among college and high school students of the risk related to alcohol drinking. The small nematode Caenorhabditis elegans is an animal widely used as amodel organism to study nearly all aspects of Biochemistry. It is a powerfultool to test the potential bioactivity and molecular mechanisms of natural com-pounds and drugs in vivo. Therefore, it is an interesting topic to include in an undergraduate course of Biotechnology, Biochemistry or Biology students among other scientific vocations. C. elegans is also used as a neurobiological model to evaluate substances´ neurotoxicity and behavioral effects. The pro-posed experiment introduces students to the handling of this preclinical modeland to the evaluation of behavioral alterations induced by chemicals in scien-tific research. The effects of different doses of ethanol on C. elegans behavior are studied using a versatile chemotaxis assay. This laboratory experiment issuitable for an undergraduate course. The practical session can be used in theglobal strategies of information and awareness of educational centres to miti-gate the impact of alcohol abuse among students, both in formal courses or inScience fairs or exhibitions
Open Access
Potent anticancer activity of a novel iridium metallodrug via oncosis
(Springer, 2022-09-06) Ortega Forte, Enrique; Vigueras, Gloria; Henarejos Escudero, Paula; Cutillas, Natalia; Ruiz, José; Gandía Herrero, Fernando; Hernández García, Samanta; Bioquímica y Biología Molecular A
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 mitochondriatargeted 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 nonconventional modes of action such as oncosis, which could be of particular interest for the treatment of apoptosis-resistant cancers.
Open Access
Consumption of commonly used artificial food dyes increases activity and oxidative stress in the animal model Caenorhabditis elegans
(Elsevier, 2023-05-02) Guerrero Rubio, M. Alejandra; Gandía Herrero, Fernando; García Carmona, Francisco; Hernández García, Samanta; Bioquímica y Biología Molecular A
In recent decades, the consumption of artificial colorants in foods and beverages has increased despite of concerns in the general population raised by studies that have shown possible injurious effects. In this study, tartrazine, sunset yellow, quinoline yellow, ponceau 4R, carmoisine and allura red were employed as pure compounds to explore their effects in vivo in the animal model Caenorhabditis elegans. The exposition of C. elegans to these artificial dyes produced damage related with aging such as oxidative stress and lipofuscin accumulation, as well as a heavy shortening of lifespan, alterations in movement patterns and alterations in the production of dopamine receptors. Besides, microarray analysis performed with worms treated with tartrazine and ponceau 4R showed how the consumption of synthetic colorants is able to alter the expression of genes involved in resistance to oxidative stress and neurodegeneration.
Open Access
A way to increase the bioaccesibility and photostability of roflumilast, a COPD treatment, by cyclodextrin monomers
(MDPI, 2019-05-04) Matencio Durán, Adrián; López Nicolás, José Manuel; García Carmona, Francisco; Hernández García, Samanta; Bioquímica y Biología Molecular A; Facultad de Biología
Roflumilast is an orally available inhibitor of phosphodiesterase (PDE) type 4, which is widely used in chronic obstructive pulmonary diseases. However, it has low solubility and adverse effects include diarrhea and nausea. Since its solubilization may improve treatment and, dismissing any adverse effects, its interaction with cyclodextrins (CDs) was studied. The Higuchi-Connors method was used to determine the complexation constant with different CDs, pH values and temperatures. Molecular docking was used to predict interaction between the complexes. An in vitro digestion experiment was carried out to test roflumilast protection. Finally, the photostability of the complex was evaluated. The complex formed with β-CD had the highest K11 value (646 ± 34 M−1), although this value decreased with increasing temperature. Similarly, K11 decreased as the pH increased. In vitro digestion showed that CDs protect the drug during digestion and even improve its bioaccessibility. Finally, CDs reduced the drug’s extreme photosensitivity, originating a fluorescence signal, which is described for first time. The kinetic parameters of the reaction were obtained. This study not only completes the complexation study of roflumilast-CD, but also points to the need to protect roflumilast from light, suggesting that tablets containing the drug might be reformulated.
Open Access
Antitumoral drug potential of tryptophan betaxanthin and related plant betalains in the Caenorhabditis elegans tumoral model
(MDPI, 2020-07-22) Henarejos Escudero, Paula; Guerrero Rubio, M. Alejandra; Gandía Herrero, Fernando; García Carmona, Francisco; Hernández García, Samanta; Bioquímica y Biología Molecular A
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.
Open Access
Modifying the chromophoric ring of betalamic acid in plant pigments. Synthesis and characterization of methylated betalains
(Elsevier, 2025-05-23) Martínez-Rodríguez, Pedro; Contreras-Llano, Luis Eduardo; Pagán-López, Diego José; Guerrero-Rubio, María Alejandra; Lozada-Ramírez, José Daniel; Gandía Herrero, Fernando; Hernández García, Samanta; Bioquímica y Biología Molecular "A"
The recent discovery of decarboxylated betalains, derived from dopamine, in nature has expanded the number of chemical modifications possible in these plant pigments. Alternative starting materials in biochemical rocesses can yield novel molecules with modifications in the betalamic ring. For the first time, a functional group has been incorporated into the betalamic acid structure of betalains, thus creating a novel family of methylated pigments. A synthetic pathway starting from α-methyl-DOPA yields 6-methyl-betalamic acid. The process is enzymatic and kinetic characterization reveals that the formation of 6-methyl-betalamic acid is favored over the formation of 6- methyl-dopaxanthin, as a further condensation reaction can be hindered. Starting from the methylated betalamic acid, a novel family of methylated betalains has been biotechnologically produced comprising ten yellow and violet molecules. The novel compounds were characterized by using HPLC-ESI-Q-TOF-MS, spectrophotometry, and spectrofluorometry. Potential antioxidant capacity was measured using the ORAC assay, demonstrating the molecules’ effectiveness against peroxyl radicals, with indoline-6-methyl-betacyanin identified as the most antioxidant. This study shows the venue for the chemical modification of the betalamic ring in pigments and thus represents the beginning of the era of betalain core chemistry. This opens new fields for future research to explore novel structures and their potential bioactive effects.
Open Access
In vitro, in vivo, and in silico evidence for the use of plant pigments betalains as potential nutraceuticals against Alzheimer’s disease
(Wiley, 2024-07-24) Martínez-Rodriguez, Pedro; Henarejos Escudero, Paula; Gandía Herrero, Fernando; Sánchez Ferrer, Álvaro; Hernández García, Samanta; Bioquímica y Biología Molecular A
Anti-amyloidogenic properties of plant pigments betalains as potential nutraceuticals against Alzheimer’s disease have been screened using 24 pure molecules. Twenty-two betalains reduced amyloid aggregation in vitro, eight of them up to 100%, with IC 50values in the micromolar range. Atomic force and transmission electron microscopy images showed the typical fibrils associated with Alzheimer’s disease and how beta-lains avoid its formation. Neuroprotection after ingestion was supported by in vivo experiments with Caenorhabditis elegans. Indoline-betacyanin was the most effective molecule by significantly improving the chemotactic behavior of the CL2355 strain,a model of Alzheimer’s disease. Furthermore, in-depth molecular docking analyses revealed that the pigments interact with the N-terminal region of the amyloid pep-tide. This work is the most comprehensive study in the field and provides in vitro, in vivo, and in silico evidence for the use of betalains as nutraceuticals of relevance in theprevention of Alzheimer’s disease
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Polyphenols from traditional Chinese medicine and Mediterranean diet are effective against Aβ toxicity in vitro and in vivo in Caenorhabditis elegans
(Royal Society of Chemistry, 2021-12-15) Gea-González, Adriana; Henarejos Escudero, Paula; Martínez-Rodríguez, Pedro; Gandía Herrero, Fernando; García Carmona, Francisco; Hernández García, Samanta; Bioquímica y Biología Molecular "A"
The potential of naturally occurring polyphenols as nutraceuticals to prevent and/or treat Alzheimer’s disease is studied. Five structurally related flavones and four tyrosols were tested in vitro in human amyloid-β peptide aggregation assays. The most promising compounds were two flavones, scutellarein and baicalein, and two tyrosols hydroxytyrosol and hydroxytyrosol acetate. These compounds caused a dose-dependent reduction of Aβ-peptide aggregation up to 90% for the flavones and 100% for the tyrosols, at concentrations of 83.3 µM and 33.3 mM, respectively. The IC50 value obtained for scutellarein was 22.5 µM, and was slightly higher for baicalein, 25.9 µM, while for hydroxytyrosol and hydroxytyrosol acetate they were 0.57 mM and 0.62 mM. Given these results, the compounds were selected to conduct in vivo assays with the Caenorhabditis elegans animal model of Alzheimer’s disease. The amyloid antiaggregation ability of these polyphenols was demonstrated in in vivo aggregation assays in which 1 mM hydroxytyrosol reduced the amyloid plaques in the mutant strain CL2331 by 43%. The neuroprotective effect was evaluated in chemotaxis experiments carried out with transgenic strain CL2355 that expresses the human amyloid-β peptide in the neurons. The chemotaxis index was improved by 240% when the neuron-impaired animals were treated with 1 mM hydroxytyrosol. The results indicate that the four molecules would be viable candidates to develop nutraceuticals that interfere in amyloid-β peptide aggregation and, consequently, prevent and/or treat Alzheimer’s disease.
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Biosynthesis of a novel polymeric chitosan-betaxanthin and characterization of the first sugar-derived betalains and their effects in the in vivo model Caenorhabditis elegans
(Elsevier, 2020-09-28) Guerrero Rubio, María Alejandra; Gandía Herrero, Fernando; García Carmona, Francisco; Hernández García, Samanta; Bioquímica y Biología Molecular "A"
Betaxanthins are nitrogenous plant pigments belonging to the family of betalains and they are known for their health-promoting effects and fluorescent properties. A novel biotechnological approach in the synthesis of these compounds has allowed the synthesis of high amounts of known betalains and of novel, tailor-made betalains through the condensation of the structural unit - betalamic acid - with amine groups of different compounds. Here we describe the synthesis and characterization of chitosan-betaxanthin, the first fluorescent polymeric betaxanthin which forms nanoparticles and that might combine the fluorescent properties of betalains and the properties of chitosan, a sugar polymer widely used with medical purposes. In addition, glucosamine, the structural unit of chitosan, and its stereoisomer galactosamine were shown to condense in solution with betalamic acid. This produced novel molecules with spectral and in vivo antioxidant and anti-aging properties similar to those of biological betaxanthins, which are the first sugar-derived betaxanthins described.