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1.
Int J Nanomedicine ; 16: 2071-2085, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727814

RESUMEN

Background: Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells. Materials and Methods: Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer. Results: These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using hCtr1-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors. Conclusion: These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.


Asunto(s)
Aleaciones/farmacología , Transportador de Cobre 1/metabolismo , Hierro/farmacología , Nanopartículas del Metal/química , Mitocondrias/metabolismo , Neoplasias/metabolismo , Platino (Metal)/farmacología , Tolerancia a Radiación , Aerobiosis , Animales , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , Glutatión/metabolismo , Humanos , Nanopartículas del Metal/ultraestructura , Ratones SCID , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Modelos Biológicos , Tolerancia a Radiación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Resultado del Tratamiento , Rayos X
2.
Molecules ; 26(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672046

RESUMEN

Substituted N-phenyl cinnamamide derivatives were designed and synthesized to confirm activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway by the electronic effect on beta-position of Michael acceptor according to introducing the R1 and R2 group. Compounds were screened using the Nrf2/antioxidant response element (ARE)-driven luciferase reporter assay. Compound 1g showed desirable luciferase activity in HepG2 cells without cell toxicity. mRNA and protein expression of Nrf2/ARE target genes such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase catalytic subunit (GCLC) were upregulated by compound 1g in a concentration-dependent manner. Treatment with 1g resulted in increased endogenous antioxidant glutathione, showing strong correlation with enhanced GCLC expression for synthesis of glutathione. In addition, tert-butyl hydroperoxide (t-BHP)-generated reactive oxygen species were significantly removed by 1g, and the results of a cell survival assay in a t-BHP-induced oxidative cell injury model showed a cytoprotective effect of 1g in a concentration dependent manner. In conclusion, the novel compound 1g can be utilized as an Nrf2/ARE activator in antioxidative therapy.


Asunto(s)
Cinamatos/farmacología , Citoprotección/efectos de los fármacos , Glutatión/biosíntesis , Hepatocitos/patología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Elementos de Respuesta Antioxidante/genética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Muerte Celular/efectos de los fármacos , Cinamatos/química , Glutatión/metabolismo , Células Hep G2 , Hepatocitos/efectos de los fármacos , Humanos , Luciferasas/metabolismo , Factor 2 Relacionado con NF-E2/agonistas , Sustancias Protectoras/farmacología , terc-Butilhidroperóxido
3.
Nat Commun ; 12(1): 1589, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33707434

RESUMEN

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.


Asunto(s)
Cisteína/metabolismo , Cistina/metabolismo , Ferroptosis/fisiología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Línea Celular Tumoral , Técnicas de Inactivación de Genes , Glutatión/metabolismo , Células HEK293 , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Neoplasias/patología
4.
Food Chem ; 352: 129458, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33714166

RESUMEN

We investigated the effect of exogenous glutathione (GSH) on chilling injury (CI) in postharvest bell pepper fruits stored at low temperature and explored the mechanism of this treatment from the perspective of the ascorbate-glutathione (AsA-GSH) cycle. Compared with the control, fruits treated with exogenous GSH before refrigeration displayed only slight CI symptoms and mitigated CI-induced cell damage after 10 d. Moreover, the treated peppers had lower lipid peroxidation product, H2O2, and O2- content than those did the control. Glutathione treatment enhanced the ascorbate-glutathione cycle by upregulating CaAPX1, CaGR2, CaMDHAR1, and CaDHAR1 and the antioxidant enzymes APX, GR, and MDHAR associated with the ascorbate-glutathione cycle. Glutathione treatment also increased ascorbate and glutathione concentrations. Taken together, our results showed that exogenous GSH treatment could alleviate CI in pepper fruits during cold storage by triggering the AsA-GSH cycle and improving antioxidant capacity.


Asunto(s)
Ácido Ascórbico/metabolismo , Capsicum/efectos de los fármacos , Capsicum/metabolismo , Frío , Glutatión/farmacología , Frutas/efectos de los fármacos , Frutas/metabolismo , Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Plantones/efectos de los fármacos , Plantones/metabolismo
5.
Life Sci ; 272: 119194, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33609541

RESUMEN

AIM: The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. MATERIAL AND METHODS: After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-ß) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. RESULTS: Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. CONCLUSION: The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.


Asunto(s)
Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/metabolismo , Animales , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Dexametasona/farmacología , Modelos Animales de Enfermedad , Glutatión/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Agonistas Muscarínicos/farmacología , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptor Muscarínico M1 , Factor de Necrosis Tumoral alfa/metabolismo
6.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33567754

RESUMEN

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.


Asunto(s)
Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Compuestos de Metilmercurio/análisis , Compuestos de Metilmercurio/farmacología , Estrés Oxidativo/efectos de los fármacos , Placenta/efectos de los fármacos , Sustancias Protectoras/farmacología , Apoptosis , Supervivencia Celular , Células Cultivadas , Femenino , Glutatión/metabolismo , Humanos , Placenta/metabolismo , Placenta/patología , Embarazo , Sustancias Protectoras/análisis
7.
Toxicol Lett ; 341: 94-106, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33539969

RESUMEN

Enzymatic conjugation of glutathione (GSH) to trichloroethylene (TCE) followed by catabolism to the corresponding cysteine-conjugate, S-(dichlorovinyl)-L-cysteine (DCVC), and subsequent bioactivation by renal cysteine conjugate beta-lyases is considered to play an important role in the nephrotoxic effects observed in TCE-exposed rat and human. In this study, it is shown for the first time that three regioisomers of GSH-conjugates of TCE are formed by rat and human liver fractions, namely S-(1,2-trans-dichlorovinyl)-glutathione (1,2-trans-DCVG), S-(1,2-cis-dichlorovinyl)-glutathione (1,2-cis-DCVG) and S-(2,2-dichlorovinyl)-glutathione (2,2-DCVG). In incubations of TCE with rat liver fractions their amounts decreased in order of 1,2-cis-DCVG > 1,2-trans-DCVG > 2,2-DCVG. Human liver cytosol showed a more than 10-fold lower activity of GSH-conjugation, with amounts of regioisomers decreasing in order 2,2-DCVG > 1,2-trans-DCVG > 1,2-cis-DCVG. Incubations with recombinant human GSTs suggest that GSTA1-1 and GSTA2-2 play the most important role in human liver cytosol. GSTP1-1, which produces regioisomers in order 1,2-trans-DCVG > 2,2-cis-DCVG > 1,2-cis-DCVG, is likely to contribute to extrahepatic GSH-conjugation of TCE. Analysis of the products formed by a beta-lyase mimetic model showed that both 1,2-trans-DCVC and 1,2-cis-DCVC are converted to reactive products that form cross-links between the model nucleophile 4-(4-nitrobenzyl)-pyridine (NBP) and thiol-species. No NBP-alkylation was observed with 2,2-DCVC corresponding to its low cytotoxicity and mutagenicity. The lower activity of GSH-conjugation of TCE by human liver fractions, in combination with the lower fraction of potential nephrotoxic and mutagenic 1,2-DCVG-isomers, suggest that humans are at much lower risk for TCE-associated nephrotoxic effects than rats.


Asunto(s)
Glutatión Transferasa/metabolismo , Glutatión/análogos & derivados , Glutatión/metabolismo , Tricloroetileno/farmacología , Animales , Cromatografía Liquida , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glutatión Transferasa/genética , Humanos , Hígado , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Proteínas Recombinantes , Solventes/farmacología , Especificidad de la Especie
8.
Chem Biol Interact ; 338: 109402, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33587916

RESUMEN

Cisplatin is an important antineoplastic drug used in multiple chemotherapeutic regimens but unfortunately causes serious toxic effects as ovarian and uterine toxicity. This study aimed to investigate the potential protective effect of resveratrol (RSV) against cisplatin-induced ovarian and uterine toxicity in female rats. Thirty-two female Wistar rats were divided randomly into four groups (n = 8 in each). Control group received oral normal saline for 28 days; RSV group received RSV (10 mg/kg; daily) via oral gavage; CIS group received a single dose of CIS (7 mg/kg; i.p.) on the 21st day; (CIS + RSV) group received both RSV and CIS by the same schedules and doses of RSV and CIS groups, respectively. Results demonstrated a significant decrease in MDA level and a significant increase in both glutathione content and activity of the antioxidant enzymes GPx, SOD, and CAT in the tissues of the ovary and uterus of CIS + RSV group in comparison to that of CIS group (P<0.05), also there are significantly decreased tissue levels of the proinflammatory cytokines and enzymes (NF-κB, IL-1ß, IL-6, TNF-α, COX-2, and iNOS), increased estradiol, progesterone, prolactin and decreased FSH serum levels in CIS + RSV group compared to CIS group (P < 0.05). Moreover, there is downregulation of tissues Cleaved Caspase-3, NF-κB and Cox-2 proteins as shown in Western blot analysis, also apoptosis was significantly inhibited, evidenced by downregulation of Bax and upregulation of Bcl-2 proteins, and the ovarian and uterine histological architecture and integrity were maintained in CIS + RSV group compared to CIS group. In conclusion, these findings indicate that RSV has beneficial effects in ameliorating cisplatin-induced oxidative stress, inflammation, and apoptosis in the ovarian and uterine tissues of female rats.


Asunto(s)
Apoptosis/efectos de los fármacos , Cisplatino/efectos adversos , Inflamación/patología , Ovario/patología , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Resveratrol/farmacología , Útero/patología , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Catalasa/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Malondialdehído/metabolismo , Modelos Biológicos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ovario/efectos de los fármacos , Progesterona/sangre , Prolactina/sangre , Carbonilación Proteica/efectos de los fármacos , Ratas Wistar , Superóxido Dismutasa/metabolismo , Proteína X Asociada a bcl-2/metabolismo
9.
Plant Physiol Biochem ; 160: 386-396, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33556754

RESUMEN

Reactive oxygen species (ROS) such as hydrogen peroxide at low concentrations act as signaling of several abiotic stresses. Overproduction of hydrogen peroxide causes the oxidation of plant cell lipid phosphate layer promoting senescence and cell death. To mitigate the effect of ROS, plants develop antioxidant defense mechanisms (superoxide dismutase, catalase, guaiacol peroxidase), ascorbate-glutathione cycle enzymes (ASA-GSH) (ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase and glutathione reductase), which have the function of removing and transforming ROS into non-toxic substances to maintain cellular homeostasis. Foliar or soil application of fertilizers containing B, Cu, Fe, Mn, Mo, Ni, Se and Zn at low concentrations has the ability to elicit and activate antioxidative enzymes, non-oxidizing metabolism, as well as sugar metabolism to mitigate damage by oxidative stress. Plants treated with micronutrients show higher tolerance to abiotic stress and better nutritional status. In this review, we summarized results indicating micronutrient actions in order to reduce ROS resulting the increase of photosynthetic capacity of plants for greater crop yield. This meta-analysis provides information on the mechanism of action of micronutrients in combating ROS, which can make plants more tolerant to several types of abiotic stress such as extreme temperatures, salinity, heavy metals and excess light.


Asunto(s)
Fertilizantes , Micronutrientes , Plantas , Especies Reactivas de Oxígeno/metabolismo , Estrés Fisiológico , Antioxidantes/metabolismo , Ascorbato Peroxidasas/metabolismo , Glutatión/metabolismo , Estrés Oxidativo , Superóxido Dismutasa/metabolismo
10.
Nat Metab ; 3(2): 182-195, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33619381

RESUMEN

Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity.


Asunto(s)
Glucólisis , Neoplasias de Cabeza y Cuello/patología , Células Madre Neoplásicas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Animales , Antioxidantes/metabolismo , Progresión de la Enfermedad , Glutatión/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vía de Pentosa Fosfato , ARN Neoplásico/genética , Análisis de la Célula Individual , Sirtuinas/genética , Sirtuinas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Free Radic Biol Med ; 165: 184-190, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33524532

RESUMEN

Several recent reviews have suggested a role of oxidative stress in the pathophysiology of COVID-19, but its interplay with disease severity has not been revealed yet. In the present study, we aimed to investigate the association between the severity of COVID-19 and oxidative stress parameters. Clinical data of 77 patients with COVID-19 admitted to the hospital were analyzed and divided into moderate (n = 44) and severe (n = 33) groups based on their clinical condition. Production of oxidant (hydrogen peroxide) and defense antioxidants (total antioxidant capacity, reduced and oxidized glutathione, glutathione s-transferase), and oxidative damage (malondialdehyde, carbonyl, and sulfhydryl) were assessed using the serum samples. The results revealed that severe patients who presented high serum leukocyte count and CRP level stayed for a longer period in the hospital. However, there was no correlation observed between the oxidative stress parameters and degree of COVID-19 severity in the present study. In conclusion, these results indicate that the disease severity may not be a detrimental factor contributing to the changes in the redox profile of hospitalized patients with COVID-19.


Asunto(s)
/metabolismo , Estrés Oxidativo/fisiología , /fisiología , Adulto , Anciano , Brasil/epidemiología , Estudios de Cohortes , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Glutatión/metabolismo , Glutatión Transferasa/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos
12.
Nat Commun ; 12(1): 101, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397942

RESUMEN

Western diet (WD) is one of the major culprits of metabolic disease including type 2 diabetes (T2D) with gut microbiota playing an important role in modulating effects of the diet. Herein, we use a data-driven approach (Transkingdom Network analysis) to model host-microbiome interactions under WD to infer which members of microbiota contribute to the altered host metabolism. Interrogation of this network pointed to taxa with potential beneficial or harmful effects on host's metabolism. We then validate the functional role of the predicted bacteria in regulating metabolism and show that they act via different host pathways. Our gene expression and electron microscopy studies show that two species from Lactobacillus genus act upon mitochondria in the liver leading to the improvement of lipid metabolism. Metabolomics analyses revealed that reduced glutathione may mediate these effects. Our study identifies potential probiotic strains for T2D and provides important insights into mechanisms of their action.


Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/microbiología , Dieta Occidental , Lactobacillus/metabolismo , Mitocondrias Hepáticas/metabolismo , Animales , Bilirrubina/sangre , Diabetes Mellitus Tipo 2/genética , Microbioma Gastrointestinal , Regulación de la Expresión Génica , Glucosa/metabolismo , Glutatión/sangre , Glutatión/metabolismo , Humanos , Metabolismo de los Lípidos , Masculino , Metabolómica , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/ultraestructura , Reproducibilidad de los Resultados , Transcriptoma/genética
13.
Nihon Yakurigaku Zasshi ; 156(1): 21-25, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390475

RESUMEN

Ischemic stroke is one of the most prevalent brain disorders and the major cause of long-term disability. In particularly, hippocampal injury after ischemia-reperfusion is a serious problem as it contributes to vascular dementia. Many researches have revealed that ischemia-reperfusion causes increase in reactive oxygen species production and disruption of neuronal Zn2+ homeostasis in the hippocampus, which induces hippocampal neuron death. Glutathione (GSH) is present in all mammalian cells and plays a crucial role in neuronal cell defense against oxidative stress. On the other hand, thiol group of GSH chemically chelates Zn2+ and functions as a regulator of neuronal Zn2+ homeostasis. These evidences suggest that neuronal GSH levels could be an important factor affecting neuronal surviving. The synthesis of GSH is largely influenced by intracellular cysteine availability. In neurons, excitatory amino acid carrier type 1 (EAAC1) acts as a cysteine transporter and provides cysteine substrate for GSH synthesis. Recently, several animal studies have revealed that promotion of neuronal GSH synthesis through EAAC1 reduces ischemia-induced hippocampal neuron death. This review aims to describe neuroprotective role of GSH against hippocampal injury following ischemia-reperfusion, focusing on EAAC1.


Asunto(s)
Fármacos Neuroprotectores , Daño por Reperfusión , Animales , Transportador 3 de Aminoácidos Excitadores/metabolismo , Glutatión/metabolismo , Glutatión/farmacología , Hipocampo/metabolismo , Isquemia , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , Reperfusión
14.
Nihon Yakurigaku Zasshi ; 156(1): 26-30, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390476

RESUMEN

Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine that acts as an important neuroprotective molecule in the central nervous system. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, GSH levels in the brain would be decreased before the onset, and GSH dysregulation is considered to be involved in the development of these neurodegenerative diseases. Cysteine uptake into neurons is the rate-limiting step for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1), which is a glutamate/cysteine cotransporter, is responsible for the neuronal cysteine uptake, and EAAC1 dysfunction reduces GSH levels in the brain and has a significant influence on the process of neurodegeneration. Since miR-96-5p, which is one of microRNAs, suppresses EAAC1 expression, it is conceivable that miR-96-5p inhibitor suppresses the onset or slows the progression of neurodegenerative diseases by increasing EAAC1 levels leading to promoting neuronal GSH production.


Asunto(s)
Glutatión , Enfermedades Neurodegenerativas , Cisteína , Transportador 3 de Aminoácidos Excitadores , Glutatión/metabolismo , Humanos , Neuronas/metabolismo
15.
Ecotoxicol Environ Saf ; 208: 111758, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396081

RESUMEN

The cultivation of leafy vegetables on metal contaminated soil embodies a serious threat to yield and quality. In the present study, the potential role of exogenous jasmonic acid (JA; 0, 5, 10, and 20 µM) on mitigating chromium toxicity (Cr; 0, 150, and 300 µM) was investigated in choysum (Brassica parachinensis L.). With exposure to increasing Cr stress levels, a dose-dependent decline in growth, photosynthesis, and physio-biochemical attributes of choysum plants was observed. An increase in Cr levels also resulted in oxidative stress closely associated with higher lipoxygenase activity (LOX), hydrogen peroxide (H2O2) generation, lipid peroxidation (MDA), and methylglyoxal (MG) levels. Exogenous application of JA alleviated the Cr-induced phytotoxic effects on photosynthetic pigments, gas exchange parameters, and restored growth of choysum plants. While exposed to Cr stress, JA supplementation induced plant defense system via enhanced regulation of antioxidant enzymes, ascorbate and glutathione pool, and the glyoxalase system enzymes. The coordinated regulation of antioxidant and glyoxalase systems expressively suppressed the oxidative and carbonyl stress at both Cr stress levels. More importantly, JA restored the mineral nutrient contents, restricted Cr uptake, and accumulation in roots and shoots of choysum plants when compared to the only Cr-stressed plants. Overall, the application of JA2 treatment (10 µM JA) was more effective and counteracted the detrimental effects of 150 µM Cr stress by restoring the growth and physio-biochemical attributes to the level of control plants, while partially mitigated the detrimental effects of 300 µM Cr stress. Hence, JA application might be considered as an effective approach for minimizing Cr uptake and its detrimental effects in choysum plants grown on contaminated soils.


Asunto(s)
Antioxidantes/farmacología , Brassica/fisiología , Cromo/toxicidad , Ciclopentanos/farmacología , Oxilipinas/farmacología , Contaminantes del Suelo/toxicidad , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Brassica/efectos de los fármacos , Brassica/metabolismo , Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Oxidación-Reducción , Estrés Oxidativo/fisiología , Fotosíntesis/efectos de los fármacos , Hojas de la Planta/metabolismo
16.
Ecotoxicol Environ Saf ; 208: 111589, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396112

RESUMEN

Marine bivalves have been widely applied as environmental contamination bioindicators, although studies concerning tropical species are less available compared to temperate climate species. Assessments regarding Perna perna mytilid mussels, in particular, are scarce, even though this is an extremely important species in economic terms in tropical countries, such as Brazil. To this end, Perna perna mytilids were sampled from two tropical bays in Southeastern Brazil, one anthropogenically impacted and one previously considered a reference site for metal contamination. Gill metallothionein (MT), reduced glutathione (GSH), carboxylesterase (CarbE) and lipid peroxidation (LPO) were determined by UV-vis spectrophotometry, and metal and metalloid contents were determined by inductively coupled plasma mass spectrometry (ICP-MS). Metalloprotein metal detoxification routes in heat-stable cellular gill fractions were assessed by size exclusion high performance chromatography (SEC-HPLC) coupled to an ICP-MS. Several associations between metals and oxidative stress endpoints were observed at all four sampling sites through a Principal Component Analysis. As, Cd, Ni and Se contents, in particular, seem to directly affect CarbE activity. MT is implicated in playing a dual role in both metal detoxification and radical oxygen species scavenging. Differential SEC-HPLC-ICP-MS metal-binding profiles, and, thus, detoxification mechanisms, were observed, with probable As-, Cu- and Ni-GSH complexation and binding to low molecular weight proteins. Perna perna mussels were proven adequate tropical bioindicators, and further monitoring efforts are recommended, due to lack of data regarding biochemical metal effects in tropical species. Integrated assessments, as performed herein demonstrate, are invaluable in evaluating contaminated aquatic environments, resulting in more accurate ecological risk assessments.


Asunto(s)
Metales/toxicidad , Perna/fisiología , Contaminantes Químicos del Agua/toxicidad , Animales , Bahías , Brasil , Monitoreo del Ambiente , Branquias/efectos de los fármacos , Glutatión/metabolismo , Metaloproteínas/metabolismo , Metalotioneína/metabolismo , Metales/análisis , Metales/metabolismo , Perna/efectos de los fármacos , Alimentos Marinos/análisis , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/metabolismo
17.
Ecotoxicol Environ Saf ; 208: 111708, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396039

RESUMEN

In a laboratory based study, Salvinia natans L. was pre-treated with reduced glutathione (GSH) following transfer under 2, 4-Dicholro phenoxy acetic acid (2,4-D), peroxide (H2O2), dark and irradiation. Plants recorded 2, 4-D bio-accumulation and tolerance maximally under 500 µM following absorption kinetics modulated with GSH in changes of relative water content (20.98%), growth rate (3.04%) and net assimilation rate (1.3 fold) over control. GSH pre-treatment minimized the oxidative revelation with reactive oxygen species (ROS) by 5.55% decrease under 2, 4-D and 1.3, 1.2, 0.8 fold increase through the other stresses. Apoplastic NADPH-oxidase expression was moderated by GSH with 11.76% less over the control. Also the activity of alcohol dehydrogenase and glutathione-S-transferase had their altered values by 1.5 and 9.0 fold increases respectively and may serve as biomarkers. The oxidized:reduced glutathione was positively correlated with glutathione-peroxidase (r=+0.99) and negatively with glutathione reductase (r=-0.04). The induced activities sustained oxidized:reduced GSH pool by 1.09 fold and had varied polymorphic gene expression under 2, 4-D and allied stresses. This study may be relevant to consider Salvinia as a potent weed species remediating 2, 4-D toxicity in soil with its wider hyper-accumulating efficiency. The cellular responses in tolerance to oxidative stress and thereby, induced physiological attributes may opt for selection pressures in other weed flora for broader aspects of phytoremediation against xenobiotics like 2, 4-D.


Asunto(s)
Ácido 2,4-Diclorofenoxiacético/metabolismo , Helechos/metabolismo , Glutatión/metabolismo , Estrés Oxidativo , Biodegradación Ambiental/efectos de la radiación , Biomarcadores/metabolismo , Oscuridad , Glutatión/farmacología , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Luz , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Proteínas de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismo
18.
Ecotoxicol Environ Saf ; 208: 111715, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396046

RESUMEN

Metal tolerance in marine diatoms vary between morphotypes, strains, and species due to their long-term adaptations to stochastic environments. The mechanisms underlying this highly variable trait remain a matter of interest in ecotoxicology. In this study, we used several cutting-edge techniques, including a non-invasive micro-test technique, atomic force microscopy, and X-ray photoelectron spectroscopy to examine cadmium (Cd) accumulation and tolerance in the three morphotypes of Phaeodactylum tricornutum. Subcellular Cd distribution, metal transporter expression, and glutathione and phytochelatin activity were also analyzed to characterize the morphology-dependent Cd homeostasis and detoxification. We found that the oval morphotype accumulated more Cd, but was also more Cd tolerant than the other morphotypes. The greater surface binding of Cd to the oval morphotype is attributable to its smaller spherical form, rougher cell surface, and lower surface potential. Moreover, the oval morphotype was less permeable to Cd ions and contained higher phytochelatin and glutathione levels, which explained its higher metal tolerance. Our study offers new explanations for diatom's adaptations to changing environments that may contribute to its evolutionary success.


Asunto(s)
Adaptación Fisiológica , Diatomeas/fisiología , Metales/metabolismo , Proteínas Algáceas/genética , Proteínas Algáceas/metabolismo , Cadmio/metabolismo , Diatomeas/citología , Diatomeas/genética , Diatomeas/metabolismo , Glutatión/metabolismo , Homeostasis , Fenotipo , Fitoquelatinas/metabolismo
19.
Ecotoxicol Environ Saf ; 208: 111616, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396136

RESUMEN

Our previous studies showed that exogenous glutathione (GSH) decreased cadmium (Cd) concentration in shoots and alleviated the growth inhibition in pakchoi (Brassica chinensis L.) under Cd stress. Nevertheless, it is largely unknown how GSH decreases Cd accumulation in edible parts of pakchoi. This experiment mainly explored the mechanisms of GSH-induced reduction of Cd accumulation in shoot of pakchoi. The results showed that compared with sole Cd treatment, Cd + GSH treatment remarkably increased the expression of BcIRT1 and BcIRT2, and further enhanced the concentrations of Cd and Fe in root. By contrast, GSH application declined the concentration of Cd in the xylem sap. However, these results were not caused by xylem loading process because the expression of BcHMA2 and BcHMA4 had not significant difference between sole Cd treatment and Cd + GSH treatment. In addition, exogenous GSH significantly enhanced the expression of BcPCS1 and promoted the synthesis of PC2, PC3 and PC4 under Cd stress. At the same time, exogenous GSH also significantly improved the expression of BcABCC1 and BcABCC2 in the roots of seedling under Cd stress, suggesting that more PCs-Cd complexes may be sequestrated into vacuoles by ABCC1 and ABCC2 transporters. The results showed that exogenous GSH could up-regulate the expression of BcIRT1/2 to increase the Cd accumulation in root, and the improvement of PCs contents and the expression of BcABCC1/2 enhanced the compartmentalization of Cd in root vacuole of pakchoi under Cd stress. To sum up, exogenous GSH reduce the concentration of free Cd2+ in the cytoplast of root cells and then dropped the loading of Cd into the xylem, which eventually given rise to the reduction of Cd accumulation in edible portion of pakchoi.


Asunto(s)
Brassica/metabolismo , Cadmio/metabolismo , Glutatión/metabolismo , Raíces de Plantas/metabolismo , Plantones/metabolismo , Contaminantes del Suelo/metabolismo , Vacuolas/metabolismo , Transporte Biológico , Brassica/efectos de los fármacos , Brassica/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Proteínas de Plantas/genética , Plantones/efectos de los fármacos
20.
Ecotoxicol Environ Saf ; 209: 111820, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33385678

RESUMEN

The objective of this study was to investigate the influence of deltamethrin (DLM)on brain function and to find whether DLM-induced neurotoxicity is prevented by the treatment with cinnamon oil. Four groups of ten Wistar albino male rats each were used. Group I (control) received saline only. Group II received cinnamon oil alone at 0.5 mg/kg B.W. intraperitonally, whereas Group III received orally DLM alone at 6 mg/kg B.W. Groups IV was treated with cinnamon oil plus DLM for 21 days to induce neurotoxicity. Rat behaviour, brain acetylcholine esterase (AChE), serotonin, oxidative stress profile were assessed. Serum sampling for the assessment of corticosterone concentration was also carried out. Finally, we demonstrate the gene expression of CYP1A1 and iNOS and the histological picture of the brain. Considering the behaviour assessment, DLM administration alone caused neurobehavioral deficits manifested by anxiety-like behavior which represented ina marked decrease in the sleeping frequency and duration, and marked increase the digging frequency and a wake non-active behavior duration. Moreover, the open field result showed a significant decrease in central square entries and duration. The neurochemical analysis revealed that DLM significantly suppressed AChE activity and elevated serotonin and corticosterone concentrations. Furthermore, results revealed thatthe brain reduced glutathione (GSH) content, superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were significantly altered in DLM treated rats. Neurochemical disturbances were confirmed by histopathological changes in the brain. Furthermore, DLM up-regulates the mRNA expression of brain CYP1A1 and iNOS. Co-treatment with cinnamon oil exhibited significant improvement in behavioural performance and the brain antioxidant capacities with an increase in AChE activity and diminished the concentration of serotonin, serum corticosterone and MDA. Cinnamon oil treatment resulted in down-regulation of CYP1A1 and iNOS and improve the histologically picture. In conclusion, cinnamon oil ameliorated DLM-induced neurotoxicity through preventing oxidative stress-induced genotoxicity and apoptosis of brain in rats.


Asunto(s)
Cinnamomum zeylanicum , Citocromo P-450 CYP1A1/metabolismo , Insecticidas/toxicidad , Neurotransmisores/farmacología , Nitrilos/toxicidad , Aceites Volátiles/farmacología , Piretrinas/toxicidad , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Glutatión/metabolismo , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
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