RESUMEN

Benzoic acids, which are commonly found in food, are also produced by human microbiota from other dietary phenolics. The aim was to investigate the interactions of 8 food-related benzoic acids with the physiological metals iron and copper under different (patho)physiologically relevant pH conditions in terms of chelation, reduction, impact on the metal-based Fenton chemistry, and copper-based hemolysis. Only 3,4-dihydroxybenzoic acid behaved as a protective substance under all conditions. It chelated iron, reduced both iron and copper, and protected against the iron and copper-based Fenton reaction. Conversely, 2,4,6-trihydroxybenzoic acid did not chelate iron and copper, reduced both metals, potentiated the Fenton reaction, and worsened copper-based hemolysis of rat red blood cells. The other tested compounds showed variable effects on the Fenton reaction. Interestingly, prooxidative benzoic acids mildly protected human erythrocytes against Cu-induced lysis. In conclusion, 3,4-dihydroxybenzoic acid seems to have a protective effect against copper and iron-based toxicity under different conditions.

Asunto(s)

Benzoatos , Cobre , Eritrocitos , Hierro , Cobre/química , Hierro/química , Humanos , Ratas , Animales , Eritrocitos/efectos de los fármacos , Eritrocitos/química , Eritrocitos/metabolismo , Benzoatos/química , Hemólisis/efectos de los fármacos , Quelantes/química , Quelantes/farmacología

RESUMEN

Context In vitro embryo production in pigs is an important tool for advancing biomedical research. Intracytoplasmic sperm injection (ICSI) circumvents the polyspermy problems associated with conventional IVF in porcine. However, the suboptimal efficiency for ICSI in pigs requires new strategies to increase blastocyst formation rates. Aim To investigate novel methods for assisted activation using the zinc chelator 1,10-phenanthroline (PHEN), and to improve embryo developmental competence and quality of ICSI porcine blastocyst. Methods ICSI embryos were treated with PHEN after or before sperm injection, recording pronuclear formation, blastocyst rate and the expression of SMARCA4, OCT4, SOX2 and CDX2. Key results Neither electrical nor PHEN significantly improves pronuclear formation rates before or after ICSI. Following in vitro culture to the blastocyst stage, no significant differences were observed in developmental rates among the groups. Moreover, the use of PHEN did not alter the total cell number or the expression of OCT4, SOX2 and CDX2 in pig ICSI blastocysts. Conclusions Assisted oocyte activation with PHEN does not affect the preimplantation development of ICSI-derived pig embryos. Implications These results hold significance in refining and advancing the application of assisted oocyte activation techniques. They offer insights into addressing fertility issues and propelling advancements in human and animal reproductive medicine.

Asunto(s)

Quelantes , Desarrollo Embrionario , Oocitos , Fenantrolinas , Inyecciones de Esperma Intracitoplasmáticas , Animales , Inyecciones de Esperma Intracitoplasmáticas/veterinaria , Inyecciones de Esperma Intracitoplasmáticas/métodos , Porcinos , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Fenantrolinas/farmacología , Femenino , Quelantes/farmacología , Desarrollo Embrionario/efectos de los fármacos , Blastocisto/efectos de los fármacos , Blastocisto/metabolismo , Zinc/farmacología , Técnicas de Cultivo de Embriones/veterinaria , Masculino

RESUMEN

Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo. These emerging anticancer agents, mixed chelate copper(II) compounds, induce apoptosis by generating reactive oxygen species (ROS) and causing DNA damage. Whole-transcriptome analysis via gene expression arrays indicated that subtoxic concentrations of CasIIIia upregulate genes involved in metal response mechanisms. Casiopeínas® reduced TNBC cell viability dose-dependently and more efficiently than Cisplatin. At subtoxic concentrations (IC20), they inhibited random and chemotactic migration of MDA-MB-231 and 4T1 cells by 50-60%, similar to Cisplatin, as confirmed by transcriptome analysis. In vivo, CasIIIia and Cisplatin significantly reduced tumor growth, volume, and weight in a syngeneic breast cancer model with 4T1 cells. Furthermore, both compounds significantly decreased metastatic foci in treated mice compared to controls. Thus, CasIIIia and CasIIgly are promising chemotherapeutic candidates against TNBC.

Asunto(s)

Antineoplásicos , Cobre , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Humanos , Femenino , Cobre/química , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Quelantes/farmacología , Apoptosis/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/uso terapéutico , Movimiento Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Daño del ADN/efectos de los fármacos

RESUMEN

The by-product of deer skin, which has mostly been used as a decorative material, is rich in collagen and amino acids that could bind to Ca2+. Therefore, the preparation process, stability, antioxidant activity and calcium transport capacity of deer skin collagen peptide calcium chelate (Ca-DSCP) were investigated. In addition, the structure of the new chelate was characterized. The preparation process of Ca-DSCP was optimized using one-way experiments and response surface methodology. The ideal conditions were pH 9, 48 °C, and a peptide-to-calcium mass ratio of 5:1. The chelation rate was (60.73 ± 1.54)%. Zeta potential, XRD, UV-vis and FTIR analyses yielded that deer skin collagen peptides (DSCP) underwent a chelating reaction with calcium ions to form new structures. The stability of Ca-DSCP and the fraction of bioavailability of calcium ions were determined using in vitro gastrointestinal digestion and a Caco-2 cell monolayer model. The results showed that fraction of bioavailability and stability of DSCP were improved by influencing the structural characterization. The antioxidant activities of DSCP and Ca-DSCP were evaluated by measuring relevant oxidative stress indicators, DPPH radical scavenging capacity and hydroxyl radical scavenging capacity. Finally, bioinformatics and molecular docking techniques were utilized to screen and study the antioxidant mechanism of DSCP.

Asunto(s)

Antioxidantes , Calcio , Colágeno , Ciervos , Digestión , Péptidos , Piel , Animales , Humanos , Antioxidantes/farmacología , Células CACO-2 , Colágeno/metabolismo , Calcio/metabolismo , Péptidos/farmacología , Péptidos/química , Piel/metabolismo , Simulación del Acoplamiento Molecular , Disponibilidad Biológica , Tracto Gastrointestinal/metabolismo , Quelantes/farmacología

RESUMEN

Cancer is a serious global health problem, causing the loss of millions of lives each year. Plumbagin, a compound derived from the medicinal plant Plumbago zeylanica, has shown promise in stopping the growth of tumor cells both in laboratory settings and in living organisms. Many plant-based compounds exert their effects through copper's ability to produce reactive oxygen species (ROS). This study aimed to understand how plumbagin, dependent on copper, induces cell death (apoptosis) in human cancer cells through various experiments. The results demonstrate that plumbagin hinders the growth of pancreatic cancer cells PNAC-1 and MIA PaCa-2 by utilizing the copper naturally present in the cells. Unlike metal chelators that remove iron and zinc (desferrioxamine mesylate and histidine), a specific copper chelator called neocuproine lessens the cell death caused by plumbagin. When ROS scavengers are used, plumbagin-induced apoptosis is inhibited, indicating that ROS plays a role in initiating cell death. The study also proves that plumbagin prevents copper from leaving cancer cells by suppressing the expression of specific genes (CTR1 and ATP7A). It is confirmed that plumbagin targets the nuclear copper, leading to signals that promote oxidative stress and, ultimately, cell death. These findings provide valuable insights into the potential of plumbagin as a substance to combat cancer, highlighting the importance of understanding how copper behaves within cancer cells.

Asunto(s)

Apoptosis , Proliferación Celular , Cobre , Naftoquinonas , Especies Reactivas de Oxígeno , Humanos , Naftoquinonas/farmacología , Naftoquinonas/química , Cobre/química , Cobre/farmacología , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quelantes/farmacología , Quelantes/química , Fenantrolinas/química , Fenantrolinas/farmacología , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos/farmacología , Antineoplásicos/química

RESUMEN

Rising concerns about global environmental degradation underscore the pressing need for effective solutions to combat heavy metal pollution. Industries such as semiconductor and steel production discharge vanadium into marine ecosystems, posing significant risks to both marine life and human health. The current study investigates efficacy of utilizing marine thraustochytrid for efficient vanadium removal outcompeting other microbial sources. By optimizing pH and temperature conditions during harvesting, achieved a remarkable 50.80 % enhancement in vanadium removal efficiency, from 19.31 to 29.12 mg/L. Furthermore, chelating agents EDTA and citric acid supplementation demonstrated promising enhancements, reaching up to 31.21 and 32.59 mg/L, respectively. Notably, vanadium-treated biomass supplemented with citric acid exhibited maximum enhancement in lipid content, from 58.47 to 75.34 %, indicating thraustochytrid's potential for biofuel production. This study presents a sustainable approach for industrial-scale vanadium bioremediation, aligning with Sustainable Development Goals focused on dual benefits of environmental protection and renewable energy.

Asunto(s)

Biodegradación Ambiental , Vanadio , Concentración de Iones de Hidrógeno , Contaminantes Químicos del Agua , Biomasa , Temperatura , Ácido Cítrico , Ácido Edético/farmacología , Ácido Edético/química , Quelantes/farmacología , Quelantes/química

RESUMEN

TRPV1 acts as a unique polymodal ion channel having distinct structure and gating properties. In this context, TRPV1-R575D represents a special mutant located at the inner lipid-water-interface (LWI) region that has less possibility of interaction with membrane cholesterol. In control conditions, this lab-generated mutant of TRPV1 shows no "ligand-sensitivity", reduced surface expression, reduced localization in the lipid rafts, yet induces high cellular lethality. Notably, the cellular lethality induced by TRPV1-R575D expression can be rescued by adding 5'I-RTX (a specific inhibitor of TRPV1) or by introducing another mutation in the next position, i.e. in TRPV1-R575D/D576R. In this work we characterized TRPV1-R575D and TRPV1-R575D/D576R mutants in different cellular conditions and compared with the TRPV1-WT. We report that the "ligand-insensitivity" of TRPV1-R575D can be rescued in certain conditions, such as by chelation of extracellular Ca2+, or by reduction of the membrane cholesterol. Here we show that Ca2+ plays an important role in the channel gating of TRPV1-WT as well as LWI mutants (TRPV1-R575D, TRPV1-R575D/D576R). However, chelation of intracellular Ca2+ or depletion of ER Ca2+ did not have a significant effect on the TRPV1-R575D. Certain properties related to channel gating of mutant TRPV1-R575D/D576R can be rescued partially or fully in a context -dependent manner. Cholesterol depletion also alters these properties. Our data suggests that lower intracellular basal Ca2+ acts as a pre-requisite for further opening of TRPV1-R575D. These findings enable better understanding of the structure-function relationship of TRPV1 and may be critical in comprehending the channelopathies induced by other homologous thermosensitive TRPVs.

Asunto(s)

Calcio , Capsaicina , Colesterol , Canales Catiónicos TRPV , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Colesterol/metabolismo , Capsaicina/farmacología , Calcio/metabolismo , Humanos , Células HEK293 , Mutación , Agua/metabolismo , Agua/química , Quelantes/farmacología , Animales

RESUMEN

Monoamine neurotransmitter system dysfunctions lead to behavioral disorders, cognitive metabolic, and other pathological conditions. In this case, different amino acids are precursors of monoamines, while the parenteral path of monoamine administration has pharmacological restrictions. Therefore, intranasal administration one of the most promising methods of delivering an active substance is. The purpose of the work is to study the effect of intranasal administration of a chelate complex of zinc arginyl-glycinate and alpha-glutamyl-tryptophan dipeptide on behavioral and neurochemical changes in acute and chronic experiments. MATERIAL AND METHODS: The studies used outbred Wistar and DAT-KO rats, and inbred C57Bl6 and TAAR1-KO mice. Using intranasal administration of a chelate complex of zinc arginyl-glycinate and alpha-glutamyl-tryptophan dipeptide we tested methods for evaluating different behavioral indicators and the level of cerebral monoamines and their metabolites. RESULTS: An anxiolytic effect of zinc arginyl-glycinate and its combination with alpha-glutamyl-tryptophan was revealed. Both drugs have a physiological effect on the autonomic nervous system, but the determination of their operating mechanisms requires further research. CONCLUSION: Thus, these data indicate that intranasal delivery of the dipeptides is effective during acute and chronic intranasal administration in rodents, the latter showed a change in the anxiety indicator. Acute AG intranasal administration demonstrated signs of lower anxiety and depressive-like behavior in C57Bl6 mice. The acute intranasal administration of a chelate complex zinc arginyl-glycinate and combination with alpha-glutamyl-tryptophan in doses of 50-100 mg/kg of body weight may be used for pre-clinical studies as a new anxiolytic/antidepressant.

Asunto(s)

Administración Intranasal , Dipéptidos , Ratones Noqueados , Ratas Wistar , Animales , Dipéptidos/administración & dosificación , Dipéptidos/farmacología , Ratones , Conducta Animal/efectos de los fármacos , Ratones Endogámicos C57BL , Masculino , Ratas , Quelantes/administración & dosificación , Quelantes/farmacología , Zinc/administración & dosificación , Zinc/farmacología , Ansiedad/tratamiento farmacológico , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Monoaminas Biogénicas/metabolismo

RESUMEN

The design of novel chelators for therapeutic applications has been the subject of extensive research to address various diseases. Many chelators can manipulate the levels of metal ions within cells and effectively modulate the metal excess. In some cases, chelators show significant toxicity to cells. We investigated polyimidazole ligands by potentiometry and UV-Vis spectroscopy for their ability to form copper(II) complexes. We also compared the antiproliferative activity of the polyimidazole ligands and their copper(II) complexes with polypyridine ligands in CaCo-2 (colorectal adenocarcinoma), SH-SY5Y (neuroblastoma) and K562 (chronic myelogenous leukemia) cells and normal HaCaT (keratinocyte) cells. Polyimidazole ligands are less cytotoxic than their analogous polypyridine ligands. All polyimidazole ligands, except the tetraimidazole ligand for K562 cells, did not show any significant effect on the viability of cancer and normal cells. In contrast, the cytotoxic activity of polypiridine ligands was also observed in normal cells with IC50 values similar to those of cancer cells. Tetraimidazole ligand, the only ligand active on the leukemic K562 cell line, induced caspase-dependent apoptosis and increased intracellular reactive oxygen species production with mitochondrial damage. The low cytotoxicity of the polyimidazole ligands, even if it limits their use as anticancer agents, could make them useful in other medical applications, such as in the treatment of metal overload, microbial infections, inflammation or neurodegenerative disorders.

Asunto(s)

Antineoplásicos , Proliferación Celular , Complejos de Coordinación , Cobre , Imidazoles , Humanos , Cobre/química , Cobre/farmacología , Imidazoles/farmacología , Imidazoles/química , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ligandos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células K562 , Línea Celular Tumoral , Células CACO-2 , Quelantes/farmacología , Quelantes/química

RESUMEN

This study focused on exploring the Zn2+ chelating peptide GFLGSP: the characterization of structure/Zn2+ chelating mode and the potential mechanisms for promoting Zn2+ transport in Caco-2 cells. The findings revealed the bidentate chelating between Zn2+ and carboxyl oxygen atom in Pro6 residue. Thereafter, the secondary structure of GFLGSP remained unchanged, but there was an increase in zeta potential and particle size. Notably, the GFLGSP-Zn2+ complex enhanced the Zn2+ transport rate and modulated ZIP4 and ZNT1 expression in a Caco-2 cells monolayer model. As revealed by molecular docking analysis, GFLGSP interacted with ZIP4 through intermolecular hydrogen bonds as well as Van der Waals forces. The Zn2+ transport mechanisms of the GFLGSP-Zn2+ complex encompassed ZIP4 (vital channel), endocytosis (primary pathway) and paracellular transport (supplementary pathway). Based on these results, the tilapia skin collagen-derived GFLGSP hold promise as the potential dietary Zn2+ supplement.

Asunto(s)

Proteínas de Transporte de Catión , Quelantes , Simulación del Acoplamiento Molecular , Péptidos , Zinc , Humanos , Células CACO-2 , Zinc/metabolismo , Zinc/química , Quelantes/química , Quelantes/metabolismo , Quelantes/farmacología , Proteínas de Transporte de Catión/metabolismo , Péptidos/química , Péptidos/metabolismo , Transporte Biológico

RESUMEN

This study investigates the potential of using ionic liquids as cosolvents to enhance the solubility and activity of poorly soluble rhodium(III) complexes, particularly those with diene, pyridine derivatives, and camphor-derived bis-pyrazolylpyridine ligands, in relation to 5'-GMP, CT-DNA, and HSA as well as their biological activity. Findings indicate that ionic liquids significantly increase the substitution activity of these complexes toward 5'-GMP while only marginally affecting DNA/HSA binding affinities with molecular docking, further confirming the experimental results. Lipophilicity assessments indicated good lipophilicity. Notably, cytotoxicity studies show that Rh2 is selectively effective against HeLa cancer cells, with IL1 and IL10 modulating the cytotoxic effects. Redox evaluations indicate that rhodium complexes induce oxidative stress in cancerous cells while maintaining redox balance in noncancerous cells. By elucidating the role of ionic liquids in modulating these effects, the study proposes a promising avenue for augmenting the efficacy and selectivity of cancer treatments, thus opening new horizons in cancer therapeutics.

Asunto(s)

Antineoplásicos , Complejos de Coordinación , Líquidos Iónicos , Rodio , Humanos , Líquidos Iónicos/química , Líquidos Iónicos/farmacología , Líquidos Iónicos/síntesis química , Rodio/química , Rodio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/uso terapéutico , Simulación del Acoplamiento Molecular , Células HeLa , Quelantes/química , Quelantes/farmacología , Quelantes/síntesis química , ADN/metabolismo , ADN/química , Relación Estructura-Actividad , Solubilidad , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ensayos de Selección de Medicamentos Antitumorales , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo

RESUMEN

Environmental or occupational exposure to natural uranium can have adverse health effects, with its chemical toxicity being mainly directed towards the kidneys and skeleton. This has led to the development of chelating agents to remove uranium from the human body, including the ligand 3,4,3-LI(1,2-HOPO). We have developed a new in vitro assay to assess the efficacy of 3,4,3-LI(1,2-HOPO) in attenuating uranium-induced bone cell damage. This approach uses osteoclasts whose formation and function are altered by exposure to uranium. This assay is an interesting and effective alternative to animal methods for assessing the efficacy and safety of new uranium decorporants.

Asunto(s)

Osteoclastos , Uranio , Uranio/toxicidad , Osteoclastos/efectos de los fármacos , Animales , Quelantes/farmacología , Ratones , Línea Celular , Humanos , Supervivencia Celular/efectos de los fármacos , Elementos de Series Actinoides/toxicidad

RESUMEN

OBJECTIVES: To evaluate the mechanical properties of root canal dentin treated with sodium hypochlorite (NaOCl) in combination with hydroxyethylidene diphosphonic acid (HEDP) or ethylenediaminetetraacetic acid (EDTA). METHODS: For testing fracture resistance, 45 single-rooted teeth were instrumented and irrigated with NaOCl/HEDP, NaOCl/EDTA, or distilled water. Fifteen untreated teeth served as control. After obturation, specimens from the experimental groups were thermocycled, dynamically-loaded, and then statically-loaded in a universal testing machine until failure. For flexural strength analysis, 15 teeth were instrumented and irrigated with NaOCl/HEDP or NaOCl/EDTA. Root segments were sectioned into dentin bars and tested for flexural strength using a universal testing machine. For microhardness evaluation, 20 teeth were instrumented and irrigated with NaOCl/HEDP or NaOCl/EDTA. Dentin disks from the coronal-third of each root segment were prepared, one before and one after irrigation, for microhardness testing with a Knoop hardness tester. RESULTS: The highest fracture resistance was recorded in the untreated group, and the lowest in the EDTA group. Although the HEDP group had higher fracture resistance than the EDTA group, the distilled water group demonstrated even greater fracture resistance than the HEDP group. Specimens treated with HEDP had significantly higher flexural strength and microhardness values when compared with those treated with EDTA. CONCLUSION: The fracture resistance, flexural strength, and microhardness of root canal dentin were higher when root canals were irrigated with NaOCl/HEDP, when compared with NaOCl/EDTA. CLINICAL SIGNIFICANCE: Irrigating root canals with NaOCl combined with HEDP significantly improves the mechanical integrity of root canal dentin compared to the use of NaOCl with EDTA.

Asunto(s)

Quelantes , Dentina , Ácido Edético , Dureza , Ensayo de Materiales , Irrigantes del Conducto Radicular , Hipoclorito de Sodio , Dentina/efectos de los fármacos , Hipoclorito de Sodio/farmacología , Humanos , Ácido Edético/farmacología , Irrigantes del Conducto Radicular/farmacología , Quelantes/farmacología , Estrés Mecánico , Ácido Etidrónico/farmacología , Cavidad Pulpar/efectos de los fármacos , Resistencia Flexional , Análisis del Estrés Dental , Preparación del Conducto Radicular/métodos , Fracturas de los Dientes/prevención & control , Raíz del Diente/efectos de los fármacos , Docilidad , Temperatura , Obturación del Conducto Radicular/métodos

RESUMEN

Due to the low permeability characteristics of the deep gas-containing coal seam, the conventional prevention and control measures that cannot solve the problems of gas outbursts are unsatisfactory for the prevention and control of the coal and gas outbursts disaster. Therefore, in this study, a strain of methane-oxidizing bacteria M07 with high-pressure resistance, strong resistance, and high methane degradation rate was selected from coal mines. The growth and degradation abilities of M07 in chelating wetting agent solutions to assess its adaptability and find the optimal agent-to-M07 ratio. It provides a new method for integrating the reduction of impact tendency and gas pressure in deep coal mines. The experimental results show that M07 is a Gram-positive bacterium of the genus Bacillus, which has strong resistance and adaptability to high-pressure water injection. By degrading 70 mol of methane, M07 produces 1 mol of carbon dioxide, which can reduce gas pressure and reduce the risk of gas outbursts in coal mines. As the experiment proves, the best effect was achieved when the M07 concentration of the chelating wetting agent was 0.05%. The methane-oxidizing bacteria based on the chelating wetting agent as carriers prove a new prevention and control method for the integrated prevention and control of coal and gas outbursts in coal mines and also provide a new idea for microbial application in coal mine disaster control.

Asunto(s)

Biodegradación Ambiental , Quelantes , Metano , Metano/metabolismo , Metano/química , Quelantes/química , Quelantes/farmacología , Quelantes/metabolismo , Bacillus/metabolismo , Carbón Mineral , Minas de Carbón

RESUMEN

Recent study showed that zinc (Zn) and amino acid transporters may be involved in enhancing Zn absorption from Zn proteinate with moderate chelation strength (Zn-Prot M) in the duodenum of broilers. However, the specific mechanisms by which Zn-Prot M promotes the above Zn absorption are unknown. Therefore, in this study, 3 experiments were conducted to investigate specific and direct effects of Zn-Prot M and Zn sulfate (ZnS) on Zn absorption and expression of related transporters in primary duodenal epithelial cells of broiler embryos so as to preliminarily address possible mechanisms. In experiment 1, cells were treated with 100 µmol Zn/L as ZnS or Zn-Prot M for 20, 40, 60, 80, 100, or 120 min. Experiment 2 consisted of 3 sub-experiments. In experiment 2A, cells were treated with a Zn-unsupplemented basal medium (Control) or the basal medium supplemented with 100 or 200 µmol Zn/L as ZnS or Zn-Prot M for 60 min; in experiment 2B, cells were treated with a Zn-unsupplemented basal medium (Control) or the basal medium supplemented with 200 µmol Zn/L of as the ZnS or Zn-Prot M for 120 min; in experiment 2C, cells were treated with a Zn-unsupplemented basal medium (Control) or the basal medium supplemented with 400 or 800 µmol Zn/L as ZnS or Zn-Prot M for 120 min. In experiment 3, cells were treated with a Zn-unsupplemented basal medium (Control) or the basal medium supplemented with 400 µmol Zn/L as ZnS or Zn-Prot M for 120 min. The results of experiment 1 indicated that the minimum incubation time for saturable Zn absorption was determined to be 50.83 min using the best fit line. The results in experiment 2 demonstrated that a Zn concentration of 400 µmol/L and an incubation time of 120 min were suitable to increase the absorption of Zn from Zn-Prot M compared to ZnS. In experiment 3, Zn absorption across cell monolayers was significantly increased by Zn addition (P < 0.05), and was significantly greater with Zn-Prot M than with ZnS (P < 0.05). Compared to the control, Zn addition significantly decreased Zn transporter 10 and peptide-transporter 1 mRNA expression levels and increased y + L-type amino transporter 2 (y + LAT2) protein abundance (P < 0.05). Moreover, protein expression levels of zrt/irt-like protein 3 (ZIP3), zrt-irt-like protein 5 (ZIP5), and y + LAT2 were significantly greater for Zn-Prot M than for ZnS (P < 0.05). These findings suggest that Zn-Prot M promote Zn absorption by increasing ZIP3, ZIP5 and y + LAT2 protein expression levels in primary duodenal epithelial cells.

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Our previous studies demonstrated that zinc (Zn) proteinate with moderate chelation strength (Zn-Prot M) exhibited the greatest bioavailability compared to the inorganic Zn sulfate (ZnS) and other organic Zn sources with either weak or strong chelation strength in broilers. Our recent study further showed that Zn and amino acid transporters could be potentially involved in promoting the absorption of Zn as Zn-Prot M in the duodenum of broilers. Nevertheless, further in vitro experiments are required to reveal the specific mechanisms by which Zn-Prot M promotes Zn absorption, where it is necessary first to investigate the specific and direct effect of Zn-Prot M on Zn absorption and the expression of Zn and amino acid transporters compared to that of ZnS. Therefore, we performed an in vitro study and found that Zn-Prot M increased Zn absorption and protein expression levels of the zrt­irt-like protein 3 (ZIP3), zrt­irt-like protein 5 (ZIP5), and y + L-type amino transporter 2 (y + LAT2) compared to ZnS, suggesting that ZIP3, ZIP5, and y + LAT2 might be involved in promoting the absorption of Zn from Zn-Prot M in the primary cultured duodenal epithelial cells of broiler embryos.

Asunto(s)

Sistemas de Transporte de Aminoácidos , Duodeno , Células Epiteliales , Zinc , Animales , Zinc/metabolismo , Duodeno/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Sistemas de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Embrión de Pollo , Pollos , Quelantes/farmacología , Regulación hacia Arriba/efectos de los fármacos , Células Cultivadas , Sulfato de Zinc/farmacología , Proteínas Portadoras

RESUMEN

Essential transition metals have key roles in oxygen transport, neurotransmitter synthesis, nucleic acid repair, cellular structure maintenance and stability, oxidative phosphorylation, and metabolism. The balance between metal deficiency and excess is typically ensured by several extracellular and intracellular mechanisms involved in uptake, distribution, and excretion. However, provoked by either intrinsic or extrinsic factors, excess iron, zinc, copper, or manganese can lead to cellular damage upon chronic or acute exposure, frequently attributed to oxidative stress. Intracellularly, mitochondria are the organelles that require the tightest control concerning reactive oxygen species production, which inevitably leaves them to be one of the most vulnerable targets of metal toxicity. Current therapies to counteract metal overload are focused on chelators, which often cause secondary effects decreasing patients' quality of life. New therapeutic options based on synthetic or natural antioxidants have proven positive effects against metal intoxication. In this review, we briefly address the cellular metabolism of transition metals, consequences of their overload, and current therapies, followed by their potential role in inducing oxidative stress and remedies thereof.

Asunto(s)

Antioxidantes , Estrés Oxidativo , Elementos de Transición , Humanos , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Estrés Oxidativo/efectos de los fármacos , Elementos de Transición/metabolismo , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Hierro/metabolismo , Metales/metabolismo , Quelantes/uso terapéutico , Quelantes/farmacología

RESUMEN

Celastrol (CEL), an active compound isolated from the root of Tripterygium wilfordii, exhibits broad anticancer activities. However, its poor stability, narrow therapeutic window and numerous adverse effects limit its applications in vivo. In this study, an adenosine triphosphate (ATP) activatable CEL-Fe(III) chelate was designed, synthesized, and then encapsulated with a reactive oxygen species (ROS)-responsive polymer to obtain CEL-Fe nanoparticles (CEL-Fe NPs). In normal tissues, CEL-Fe NPs maintain structural stability and exhibit reduced systemic toxicity, while at the tumor site, an ATP-ROS-rich tumor microenvironment, drug release is triggered by ROS, and antitumor potency is restored by competitive binding of ATP. This intelligent CEL delivery system improves the biosafety and bioavailability of CEL for cancer therapy. Such a CEL-metal chelate strategy not only mitigates the challenges associated with CEL but also opens avenues for the generation of CEL derivatives, thereby expanding the therapeutic potential of CEL in clinical settings.

Asunto(s)

Adenosina Trifosfato , Triterpenos Pentacíclicos , Profármacos , Especies Reactivas de Oxígeno , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Profármacos/química , Profármacos/farmacología , Adenosina Trifosfato/metabolismo , Humanos , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Línea Celular Tumoral , Triterpenos/química , Triterpenos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Quelantes/química , Quelantes/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Microambiente Tumoral/efectos de los fármacos , Liberación de Fármacos , Nanopartículas/química , Ensayos Antitumor por Modelo de Xenoinjerto , Compuestos Férricos/química

RESUMEN

Thorium-232 (Th-232) is a promising fuel for advanced nuclear reactors. However, in case of internal human exposure to Th, there is currently no effective modality for its removal from liver and skeleton or for mitigating its effect. The FDA-approved agent, diethylenetriaminepentaacetate (DTPA), can remove Th and other actinides from blood circulation only. For the first time, a rationally-selected polyherbal hepatoprotective i.e. Liv52® (L52S), was evaluated in-combination with DTPA for its Th decorporation ability in Swiss mice. Inductively-coupled plasma mass spectroscopic analysis showed that oral administration of L52S in conjunction with DTPA significantly decreased Th burden from liver (20 %) and skeleton (33 %) as well as enhanced Th excretion (∼2.5 folds) through urine in comparison to DTPA or L52S alone. The combinatorial therapy was found to be complementary in-action, ameliorating Th-induced tissue damage in liver, spleen, and bone more effectively than monotherapy. Furthermore, markers of liver function (alanine transaminase) and liver inflammation and fibrosis (NF-κB & keratin) further validated the beneficial effect of L52S. The human consumption of L52S for various liver disorders further supports its clinical application for Th decorporation and mitigation of its health effects.

Asunto(s)

Hígado , Ácido Pentético , Torio , Animales , Torio/toxicidad , Ácido Pentético/química , Ratones , Hígado/efectos de los fármacos , Hígado/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Masculino , Quelantes/farmacología , Quelantes/química , Bazo/efectos de los fármacos , Bazo/metabolismo

RESUMEN

In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-ß (Aß) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aß-Cu2+ complex as Aß peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aß-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Quelantes , Cobre , Dopamina , Especies Reactivas de Oxígeno , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Dopamina/metabolismo , Cobre/metabolismo , Cobre/química , Humanos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Quelantes/farmacología , Bases de Schiff/farmacología , Bases de Schiff/química

RESUMEN

The new ligand L2Ad, obtained by conjugating the bifunctional species bis(3,5-dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of new Cu complexes 1-5. Their structures were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and by combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modeling. The structure of complex 3 was determined by single-crystal X-ray diffraction analysis. Tested on U87, T98, and U251 glioma cells, Cu(II) complex 3 and Cu(I) complex 5 decreased cell viability with IC50 values significantly lower than cisplatin, affecting cell growth, proliferation, and death. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their cytotoxic activity. Both complexes were able to increase ROS production, leading to DNA damage and death. Interestingly, nontoxic doses of 3 or 5 enhanced the chemosensitivity to Temozolomide.

Asunto(s)

Adamantano , Antineoplásicos , Complejos de Coordinación , Cobre , Glioblastoma , Humanos , Cobre/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Ligandos , Adamantano/farmacología , Adamantano/química , Adamantano/síntesis química , Adamantano/análogos & derivados , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Supervivencia Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Ensayos de Selección de Medicamentos Antitumorales , Especies Reactivas de Oxígeno/metabolismo , Estructura Molecular , Quelantes/química , Quelantes/farmacología , Quelantes/síntesis química , Relación Estructura-Actividad , Acetatos/química , Acetatos/farmacología , Acetatos/síntesis química