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1.
Int J Nanomedicine ; 19: 5045-5056, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38832334

RESUMO

Background: Chemodynamic therapy (CDT) is a new treatment approach that is triggered by endogenous stimuli in specific intracellular conditions for generating hydroxyl radicals. However, the efficiency of CDT is severely limited by Fenton reaction agents and harsh reaction conditions. Methods: Bimetallic PtMn nanocubes were rationally designed and simply synthesized through a one-step high-temperature pyrolysis process by controlling both the nucleation process and the subsequent crystal growth stage. The polyethylene glycol was modified to enhance biocompatibility. Results: Benefiting from the alloying of Pt nanocubes with Mn doping, the structure of the electron cloud has changed, resulting in different degrees of the shift in electron binding energy, resulting in the increasing of Fenton reaction activity. The PtMn nanocubes could catalyze endogenous hydrogen peroxide to toxic hydroxyl radicals in mild acid. Meanwhile, the intrinsic glutathione (GSH) depletion activity of PtMn nanocubes consumed GSH with the assistance of Mn3+/Mn2+. Upon 808 nm laser irradiation, mild temperature due to the surface plasmon resonance effect of Pt metal can also enhance the Fenton reaction. Conclusion: PtMn nanocubes can not only destroy the antioxidant system via efficient reactive oxygen species generation and continuous GSH consumption but also propose the photothermal effect of noble metal for enhanced Fenton reaction activity.


Assuntos
Glutationa , Manganês , Platina , Espécies Reativas de Oxigênio , Animais , Platina/química , Platina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Glutationa/química , Humanos , Manganês/química , Manganês/farmacologia , Terapia Fototérmica/métodos , Camundongos , Nanopartículas Metálicas/química , Peróxido de Hidrogênio/química , Linhagem Celular Tumoral , Radical Hidroxila/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ferro/química
2.
PLoS One ; 19(6): e0303374, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38843156

RESUMO

The objective of this study is to investigate the effects of a moderate intensity physical training protocol, on alveolar bone morphology of rats submitted to ligature-induced periodontitis. Twenty-eight male Wistar rats were divided into four groups, considering the presence/absence of periodontitis and presence/absence of training. The training protocol was performed on a treadmill, 30 min/day, 5 days a week, for 4 weeks. In the experimental periodontal breakdown, with/without training, ligatures were placed on the lower first molars on the 14th day of the experiment, and were followed until the end of the protocol. At the end of the experiment, animals were euthanized and samples of plasma and mandibles were collected for immunoenzymatic evaluation of interleukins (IL)-1ß, IL-6, TNF-α and IL-10, evaluation of serum concentrations of C-reactive protein, analysis of lipid peroxidation (LPO) and reduced glutathione, histological and microtomographic analyses were performed. Physical training resulted in a reduced levels of IL-1ß, IL-6, TNF-α C-reactive protein and LPO and an increase in the levels of IL-10 in rats with periodontitis (p<0.05); a reduction in the inflammatory infiltrate and decreased fiber degradation was identified in histological analysis. Additionally, it was shown a decrease in vertical bone loss and an increase in the bone volume/trabecular volume ratio was identified in periodontitis+physical training group (p<0.05). Based on the results, the practice of frequent physical exercise, at moderate intensity, can contribute to the reduction of damage related to the disproportionate inflammatory response in periodontitis.


Assuntos
Peroxidação de Lipídeos , Estresse Oxidativo , Periodontite , Condicionamento Físico Animal , Ratos Wistar , Animais , Periodontite/metabolismo , Periodontite/patologia , Masculino , Ratos , Proteína C-Reativa/metabolismo , Perda do Osso Alveolar/patologia , Perda do Osso Alveolar/metabolismo , Glutationa/metabolismo , Modelos Animais de Doenças , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Citocinas/metabolismo , Citocinas/sangue
3.
Mikrochim Acta ; 191(7): 365, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38831060

RESUMO

Copper-cobalt bimetallic nitrogen-doped carbon-based nanoenzymatic materials (CuCo@NC) were synthesized using a one-step pyrolysis process. A three-channel colorimetric sensor array was constructed for the detection of seven antioxidants, including cysteine (Cys), uric acid (UA), tea polyphenols (TP), lysine (Lys), ascorbic acid (AA), glutathione (GSH), and dopamine (DA). CuCo@NC with peroxidase activity was used to catalyze the oxidation of TMB by H2O2 at three different ratios of metal sites. The ability of various antioxidants to reduce the oxidation products of TMB (ox TMB) varied, leading to distinct absorbance changes. Linear discriminant analysis (LDA) results showed that the sensor array was capable of detecting seven antioxidants in buffer and serum samples. It could successfully discriminate antioxidants with a minimum concentration of 10 nM. Thus, multifunctional sensor arrays based on CuCo@NC bimetallic nanoenzymes not only offer a promising strategy for identifying various antioxidants but also expand their applications in medical diagnostics and environmental analysis of food.


Assuntos
Antioxidantes , Carbono , Colorimetria , Cobre , Nitrogênio , Nitrogênio/química , Colorimetria/métodos , Carbono/química , Antioxidantes/química , Antioxidantes/análise , Cobre/química , Cobalto/química , Peróxido de Hidrogênio/química , Humanos , Catálise , Limite de Detecção , Glutationa/química , Glutationa/sangue , Dopamina/sangue , Dopamina/análise , Dopamina/química , Benzidinas/química , Polifenóis/química , Polifenóis/análise , Ácido Ascórbico/química , Ácido Ascórbico/sangue , Ácido Ascórbico/análise , Oxirredução , Ácido Úrico/sangue , Ácido Úrico/química , Ácido Úrico/análise , Cisteína/química , Cisteína/sangue
4.
BMC Vet Res ; 20(1): 248, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849865

RESUMO

BACKGROUND: Periodontal diseases are the most frequently diagnosed problem in cats. It has been well-established that periodontal diseases could not only cause various oral health issues but could also contribute to systemic diseases. Oxidative stress is a possible link between systemic diseases and periodontitis. Our study aimed to illustrate the influence of periodontitis on oxidative stress development in cats. Furthermore, the changes in the bacterial flora of the gums were investigated. METHODS: Based on the clinical and laboratory examinations, fifty cats were divided into two groups normal (n = 25) and moderate to advanced periodontitis (n = 25). Serum total antioxidant capacity (TAC), total oxidant status (TOS), reduced (GSH) and oxidized glutathione (GSSG) were measured. In addition, samples were taken from the subgingival plaques of all cats for bacterial culture. RESULTS: Serum TOS, GSSG, GSSG to GSH ratio, and oxidative stress index (OSI), calculated as the ratio of TOS to TAC in cats with periodontal disease were significantly higher, and TAC was significantly lower (p < 0.05) compared with controls. The results of bacterial culture indicated that the number of isolated bacterial colonies is higher in patients than in the control group. Additionally, the analysis of these data showed a positive association between periodontal index and oxidative stress. CONCLUSIONS: Our results revealed that periodontitis in cats is related to a main oxidative stress. Furthermore, oxidant factors such as TOS and OSI, compared to antioxidant factors, may better indicate the presence of oxidative stress conditions in patients with periodontitis.


Assuntos
Antioxidantes , Doenças do Gato , Glutationa , Estresse Oxidativo , Periodontite , Animais , Gatos , Doenças do Gato/microbiologia , Doenças do Gato/sangue , Doenças do Gato/metabolismo , Estudos de Casos e Controles , Periodontite/veterinária , Periodontite/microbiologia , Feminino , Masculino , Antioxidantes/metabolismo , Glutationa/sangue , Glutationa/metabolismo , Dissulfeto de Glutationa/sangue , Dissulfeto de Glutationa/metabolismo , Oxidantes/metabolismo , Oxidantes/sangue
5.
Brain Behav ; 14(6): e3539, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38849974

RESUMO

BACKGROUND AND OBJECTIVES: Maternal hypoxia disrupts neural development and subsequently leads to cerebral palsy and epilepsy in newborns. Hypoxia plays a role in neurodegeneration by increasing oxidative stress. Pistacia atlantica is known as an important antioxidant, and its anti-inflammatory and antioxidant effects have been shown in various studies. This study aims to investigate the effects of methanolic extract of P. atlantica leaves (MEPaLs) on the oxidative parameters in the serum of rats affected by maternal hypoxia. MATERIAL AND METHODS: In this study, eight pregnant rats were used. The newborns were divided into four groups, including the control and the hypoxia groups, which are affected by maternal hypoxia, hypoxia + MEPaL 100 mg/kg, and hypoxia + MEPaL 150 mg/kg. MEPaL was injected (i.p) for 21 days into the neonatal rats after the lactation period. Hypoxia was induced by keeping pregnant rats in a hypoxic chamber with 7% oxygen and 93% nitrogen intensity for 3 h on the 20th day of pregnancy. Behavioral changes were measured using open-field and rotarod tests. Finally, biomarkers of oxidative stress, nitric oxide (NO), glutathione (GSH), GSSG, TAS, TOS, and oxidative stress index (OSI) were measured in the experimental groups. RESULTS: Behavioral results showed that the anxiety behavior in the hypoxia group increased, but the motor activity (moved distance and movement speed) decreased. Moreover, the amount of time spent maintaining balance on the rotarod rod was significantly decreased in the hypoxia group. The concentration of NO in the group of hypoxia + MEPaL 100 mg/kg showed a significant decrease, and MEPaL 100, and 150 mg/kg + hypoxia also increased the concentration of GSH and decreased GSSG. In addition, MEPaL100 and 150 mg/kg caused a significant increase in the ratio of GSH to GSSG and decreased OSI and total oxidant capacity. CONCLUSIONS: Oxidative stress increased in the rats affected by maternal hypoxia and may be the main mechanism for motor activity impairment and balance disturbance, whereas MELaL improved motor performance by decreasing oxidative stress.


Assuntos
Antioxidantes , Estresse Oxidativo , Extratos Vegetais , Animais , Estresse Oxidativo/efeitos dos fármacos , Feminino , Gravidez , Ratos , Antioxidantes/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Hipóxia/fisiopatologia , Ratos Wistar , Animais Recém-Nascidos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Glutationa/metabolismo , Glutationa/sangue , Masculino , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico/sangue
6.
Food Res Int ; 188: 114433, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823827

RESUMO

Whey derived peptides have shown potential activity improving brain function in pathological condition. However, there is little information about their mechanism of action on glial cells, which have important immune functions in brain. Astrocytes and microglia are essential in inflammatory and oxidative defense that take place in neurodegenerative disease. In this work we evaluate antioxidant and anti-inflammatory potential bioactivity of whey peptide in glial cells. Peptides were formed during simulated gastrointestinal digestion (Infogest protocol), and low molecular weight (<5kDA) peptides (WPHf) attenuated reactive oxygen species (ROS) production induced by hydrogen peroxide stimulus in both cells in dose-dependent manner. WPHf induced an increase in the antioxidant glutathione (GSH) content and prevented GSH reduction induced by lipopolysaccharides (LPS) stimulus in astrocytes cells in a cell specific form. An increase in cytokine mRNA expression (TNFα and IL6) and nitric oxide secretion induced by LPS was attenuated by WPHf pre-treatment in both cells. The inflammatory pathway was dependent on NFκB activation. Bioactive peptide ranking analysis showed positive correlation with hydrophobicity and negative correlation with high molecular weights. The sequence identification revealed 19 peptides cross-referred with bioactive database. Whey peptides were rich in leucine, valine and tyrosine in the C-terminal region and lysine in the N-terminal region. The anti-inflammatory and antioxidant potential of whey peptides were assessed in glia cells and its mechanisms of action were related, such as modulation of antioxidant enzymes and anti-inflammatory pathways. Features of the peptide structure, such as molecular size, hydrophobicity and types of amino acids present in the terminal region are associated to bioactivity.


Assuntos
Anti-Inflamatórios , Antioxidantes , Neuroglia , Proteínas do Soro do Leite , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Proteínas do Soro do Leite/farmacologia , Proteínas do Soro do Leite/química , Proteínas do Soro do Leite/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Animais , Espécies Reativas de Oxigênio/metabolismo , Lipopolissacarídeos/farmacologia , Glutationa/metabolismo , Peptídeos/farmacologia , Óxido Nítrico/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo
7.
Chem Commun (Camb) ; 60(48): 6134-6137, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38829522

RESUMO

Compounds harboring high acidity and oxidizability of thiol groups permit tuning the redox equilibrium constants of CxxC sites of members of the protein disulphide isomerase (PDI) family and thus can be used to accelerate folding processes and increase the production of native proteins by minimal loading in comparison to glutathione.


Assuntos
Isomerases de Dissulfetos de Proteínas , Isomerases de Dissulfetos de Proteínas/metabolismo , Isomerases de Dissulfetos de Proteínas/química , Oxirredução , Dobramento de Proteína , Motivos de Aminoácidos , Humanos , Glutationa/metabolismo , Glutationa/química
8.
Nat Commun ; 15(1): 4751, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834573

RESUMO

Intracellular potassium (K+) homeostasis is fundamental to cell viability. In addition to channels, K+ levels are maintained by various ion transporters. One major family is the proton-driven K+ efflux transporters, which in gram-negative bacteria is important for detoxification and in plants is critical for efficient photosynthesis and growth. Despite their importance, the structure and molecular basis for K+-selectivity is poorly understood. Here, we report ~3.1 Å resolution cryo-EM structures of the Escherichia coli glutathione (GSH)-gated K+ efflux transporter KefC in complex with AMP, AMP/GSH and an ion-binding variant. KefC forms a homodimer similar to the inward-facing conformation of Na+/H+ antiporter NapA. By structural assignment of a coordinated K+ ion, MD simulations, and SSM-based electrophysiology, we demonstrate how ion-binding in KefC is adapted for binding a dehydrated K+ ion. KefC harbors C-terminal regulator of K+ conductance (RCK) domains, as present in some bacterial K+-ion channels. The domain-swapped helices in the RCK domains bind AMP and GSH and they inhibit transport by directly interacting with the ion-transporter module. Taken together, we propose that KefC is activated by detachment of the RCK domains and that ion selectivity exploits the biophysical properties likewise adapted by K+-ion-channels.


Assuntos
Microscopia Crioeletrônica , Proteínas de Escherichia coli , Escherichia coli , Potássio , Escherichia coli/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Glutationa/metabolismo , Simulação de Dinâmica Molecular , Potássio/metabolismo , Antiportadores de Potássio-Hidrogênio/metabolismo , Antiportadores de Potássio-Hidrogênio/química , Antiportadores de Potássio-Hidrogênio/genética , Domínios Proteicos
9.
Plant Physiol Biochem ; 212: 108789, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38850727

RESUMO

Role of redox homeostasis in fruit ripening of Capsicum annuum L. with oxidative metabolism was studied. The research aims the ability to reduce agents during postharvest storage on fruit for delayed ripening with the regulation of oxidative stress. Thus, we applied 10 mM reduced glutathione (GSH) to fruit as pretreatment followed by 1 mM hydrogen peroxide (H2O2) as ripening-inducing treatment and observed during 7 days of storage at 25 °C. A decrease in total soluble solid and firmness under H2O2, was increased while dehydration in tissue was decreased by GSH pretreatment. Glutathione regulated the turnover of organic acids to reducing sugars with higher activity of NADP malic enzyme that sustained the fruit coat photosynthesis through chlorophyll fluorescence, pigment composition, and photosystem II activity. Malondialdehyde accumulation was inversely correlated with GSH content and antioxidative enzyme activity that reduced loss of cell viability. Conclusively, regulation of oxidative stress with GSH may be effective in the extension of shelf life under postharvest storage.


Assuntos
Capsicum , Frutas , Glutationa , Oxirredução , Capsicum/metabolismo , Capsicum/efeitos dos fármacos , Glutationa/metabolismo , Frutas/metabolismo , Frutas/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Metabolismo Secundário/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Armazenamento de Alimentos/métodos , Malondialdeído/metabolismo , Fotossíntese/efeitos dos fármacos , Antioxidantes/metabolismo
10.
Int J Oncol ; 65(1)2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847236

RESUMO

Glutathione (GSH)­degrading enzymes are essential for starting the first stages of GSH degradation. These enzymes include extracellular γ­glutamyl transpeptidase (GGT) and intracellular GSH­specific γ­glutamylcyclotransferase 1 (ChaC1) and 2. These enzymes are essential for cellular activities, such as immune response, differentiation, proliferation, homeostasis regulation and programmed cell death. Tumor tissue frequently exhibits abnormal expression of GSH­degrading enzymes, which has a key impact on the development and spread of malignancies. The present review summarizes gene and protein structure, catalytic activity and regulation of GSH­degrading enzymes, their vital roles in tumor development (including regulation of oxidative and endoplasmic reticulum stress, control of programmed cell death, promotion of inflammation and tumorigenesis and modulation of drug resistance in tumor cells) and potential role as diagnostic biomarkers and therapeutic targets.


Assuntos
Glutationa , Neoplasias , gama-Glutamilciclotransferase , gama-Glutamiltransferase , Humanos , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/enzimologia , Glutationa/metabolismo , gama-Glutamilciclotransferase/metabolismo , gama-Glutamilciclotransferase/genética , gama-Glutamiltransferase/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Animais , Regulação Neoplásica da Expressão Gênica , Estresse Oxidativo , Estresse do Retículo Endoplasmático
11.
Mikrochim Acta ; 191(7): 389, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871997

RESUMO

A novel photoelectrochemical sensor, employing an S-scheme heterojunction of phthalocyanine and TiO2 nanoparticles, has been developed to enable highly sensitive determination of glutathione. By integrating the favorable stability, environmental benignity, and electronic properties of the TiO2 matrix with the unique photoactivity of phthalocyanine species, the designed sensor presents a substantial linear dynamic range and a low detection limit for the quantification of glutathione. The sensitivity is attributed to efficient charge transfer and separation across the staggered heterojunction energy levels, which generates measurable photocurrent signals. Systematic variation of phthalocyanine content reveals an optimal composition that balances light harvesting capacity and electron-hole recombination rates. The incorporation of phosphotungstic acid (PTA) in sample preparation effectively minimizes interference from compounds like L-cysteine and others. Consequently, this leads to an improvement in accuracy through the reduction of impurity levels. Appreciable photocurrent enhancements are observed upon introduction of both oxidized and reduced glutathione at the optimized composite photoanode. Coupled with advantageous features of photoelectrochemical transduction such as simplicity, cost-effectiveness, and resistance to fouling, this sensor holds great promise for practical applications in complex biological media.


Assuntos
Técnicas Eletroquímicas , Glutationa , Indóis , Isoindóis , Titânio , Titânio/química , Glutationa/química , Glutationa/análise , Indóis/química , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Limite de Detecção , Processos Fotoquímicos , Eletrodos
12.
Mol Biol Rep ; 51(1): 744, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38874632

RESUMO

BACKGROUND: Vanillic acid (VA; 4-hydroxy-3-methoxybenzoic acid) is a flavouring agent found in various natural sources such as olives, fruits, and green tea. While VA exhibits numerous pharmacological effects, its potential protective effects against gastric injury warrants further investigation. Therefore, the primary objective of this study is to elucidate investigate the gastroprotective properties of VA against ethanol-induced gastric injury. METHODS AND RESULTS: Rats were orally administered either saline or VA at different doses (50, 100, and 200 mg/kg/day), with omeprazole (20 mg/kg) serving as a positive control, for fourteen consecutive days before ethanol administration. Blood and gastric tissue samples were collected one hour after ethanol administration for biochemical, molecular, and histological analyses. Pre-treatment with VA before ulcer induction alleviated both macroscopic and microscopic damage. It also increased antioxidant glutathione levels and decreased malondialdehyde and myeloperoxidase activity, along with reducing inflammatory markers such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, and nuclear factor kappa B (NF-κB). Additionally, VA pre-treatment reversed the elevation of Bax mRNA expression and gastric caspase-3 levels induced by gastric damage. It also mitigated the reduction in Bcl-2 mRNA expression. CONCLUSION: These findings suggest that VA exerts protective effects against ethanol-induced gastric injury in rats. It achieves this by augmenting gastric antioxidant capacity and mitigating oxidative, inflammatory, and apoptotic damage.


Assuntos
Apoptose , Etanol , NF-kappa B , Transdução de Sinais , Úlcera Gástrica , Ácido Vanílico , Animais , NF-kappa B/metabolismo , Etanol/toxicidade , Etanol/efeitos adversos , Ratos , Apoptose/efeitos dos fármacos , Ácido Vanílico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/lesões , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Substâncias Protetoras/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Glutationa/metabolismo
13.
Proc Natl Acad Sci U S A ; 121(24): e2404668121, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38833473

RESUMO

Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.


Assuntos
Cobre , Glutationa , Homeostase , Oxirredução , Animais , Camundongos , Humanos , Glutationa/metabolismo , Camundongos Endogâmicos C57BL , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Estresse Oxidativo/efeitos dos fármacos , Sinergismo Farmacológico , Morte Celular Imunogênica/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Ferroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo
14.
Anal Chem ; 96(24): 9885-9893, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38848670

RESUMO

Glutathione (GSH) redox control and arginine metabolism are critical in regulating the physiological response to injury and oxidative stress. Quantification assessment of the GSH/arginine redox metabolism supports monitoring metabolic pathway shifts during pathological processes and their linkages to redox regulation. However, assessing the redox status of organisms with complex matrices is challenging, and single redox molecule analysis may not be accurate for interrogating the redox status in cells and in vivo. Herein, guided by a paired derivatization strategy, we present a new ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based approach for the functional assessment of biological redox status. Two structurally analogous probes, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and newly synthesized 2-methyl-6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (MeAQC), were set for paired derivatization. The developed approach was successfully applied to LPS-stimulated RAW 264.7 cells and HDM-induced asthma mice to obtain quantitative information on GSH/arginine redox metabolism. The results suggest that the redox status was remarkably altered upon LPS and HDM stimulation. We expect that this approach will be of good use in a clinical biomarker assay and potential drug screening associated with redox metabolism, oxidative damage, and redox signaling.


Assuntos
Arginina , Glutationa , Oxirredução , Espectrometria de Massas em Tandem , Animais , Arginina/metabolismo , Arginina/análise , Arginina/química , Glutationa/metabolismo , Glutationa/análise , Camundongos , Espectrometria de Massas em Tandem/métodos , Células RAW 264.7 , Carbamatos/metabolismo , Carbamatos/química , Cromatografia Líquida de Alta Pressão , Lipopolissacarídeos/farmacologia , Aminoquinolinas/química
15.
Mol Biol Rep ; 51(1): 729, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38862809

RESUMO

BACKGROUND: Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells. METHODS AND RESULTS: The cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase. CONCLUSION: Our findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.


Assuntos
Sobrevivência Celular , Metformina , Estresse Oxidativo , Neoplasias da Próstata , Espécies Reativas de Oxigênio , Metformina/farmacologia , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Oxirredução/efeitos dos fármacos , Glutationa/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético/efeitos dos fármacos
16.
Biotechnol J ; 19(6): e2300662, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863126

RESUMO

Alzheimer's disease (AD), the most common form of dementia, has gotten considerable attention. Previous studies have demonstrated that clioquinol (CQ) as a metal chelator is a potential drug for the treatment of AD. However, the mode of action of CQ in AD is still unclear. In our study, the antioxidant effects of CQ on yeast cells expressing Aß42 were investigated. We found that CQ could reduce Aß42 toxicity by alleviating reactive oxygen species (ROS) generation and lipid peroxidation level in yeast cells. These alterations were mainly attributable to the increased reduced glutathione (GSH) content and independent of activities of superoxide dismutase (SOD) and/or catalase (CAT). CQ could affect antioxidant enzyme activity by altering the transcription level of related genes. Interestingly, it was noted for the first time that CQ could combine with antioxidant enzymes to reduce their enzymatic activities by molecular docking and circular dichroism spectroscopy. In addition, CQ restored Aß42-mediated disruption of GSH homeostasis via regulating YAP1 expression to protect cells against oxidative stress. Our findings not only improve the current understanding of the mechanism of CQ as a potential drug for AD treatment but also provide ideas for subsequent drug research and development.


Assuntos
Peptídeos beta-Amiloides , Antioxidantes , Clioquinol , Glutationa , Estresse Oxidativo , Espécies Reativas de Oxigênio , Saccharomyces cerevisiae , Estresse Oxidativo/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Clioquinol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Glutationa/metabolismo , Antioxidantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Fragmentos de Peptídeos/metabolismo , Simulação de Acoplamento Molecular , Catalase/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo
17.
Anal Chim Acta ; 1312: 342768, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38834271

RESUMO

A novel biothiols-sensitive near-infrared (NIR) fluorescent probe RhDN based on a rhodamine skeleton was developed for early detection of drug-induced hepatotoxicity in living mice. RhDN can be used not only as a conventional large stokes shift fluorescent (FL) probe, but also as a kind of anti-Stokes frequency upconversion luminescence (FUCL) molecular probe, which represents a long wavelength excitation (808 nm) to short wavelength emission (760 nm), and response to Cys/Hcy/GSH with high sensitivity. Compared with traditional FL methods, the FUCL method exhibited a lower detection limit of Cys, Hcy, and GSH in 75.1 nM, 101.8 nM, and 84.9 nM, respectively. We exemplify RhDN for tracking endogenously biothiols distribution in living cells and further realize real-time in vivo bioimaging of biothiols activity in mice with dual-mode luminescence system. Moreover, RhDN has been successfully applied to visualize the detection of drug-induced hepatotoxicity in living mice. Overall, this report presents a unique approach to the development of large stokes shift NIR FUCL molecular probes for in vitro and in vivo biothiols biosensing.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Corantes Fluorescentes , Animais , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Camundongos , Humanos , Raios Infravermelhos , Imagem Óptica , Glutationa/análise , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/química , Cisteína/análise , Rodaminas/química , Rodaminas/toxicidade , Homocisteína/análise , Luminescência
18.
PeerJ ; 12: e17541, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38832034

RESUMO

Introduction: Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. Methods: CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. Results: Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. Discussion: The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.


Assuntos
Astrócitos , Etanol , Glutationa , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Animais , Etanol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Glutationa/metabolismo , Hidroquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Malondialdeído/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Células Cultivadas
19.
J Nanobiotechnology ; 22(1): 324, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858692

RESUMO

Breast cancer remains a malignancy that poses a serious threat to human health worldwide. Chemotherapy is one of the most widely effective cancer treatments in clinical practice, but it has some drawbacks such as poor targeting, high toxicity, numerous side effects, and susceptibility to drug resistance. For auto-amplified tumor therapy, a nanoparticle designated GDTF is prepared by wrapping gambogic acid (GA)-loaded dendritic porous silica nanoparticles (DPSNs) with a tannic acid (TA)-Fe(III) coating layer. GDTF possesses the properties of near-infrared (NIR)-enhanced and pH/glutathione (GSH) dual-responsive drug release, photothermal conversion, GSH depletion and hydroxyl radical (·OH) production. When GDTF is exposed to NIR laser irradiation, it can effectively inhibit cell proliferation and tumor growth both in vitro and in vivo with limited toxicity. This may be due to the synergistic effect of enhanced tumor accumulation, and elevated reactive oxygen species (ROS) production, GSH depletion, and TrxR activity reduction. This study highlights the enormous potential of auto-amplified tumor therapy.


Assuntos
Neoplasias da Mama , Glutationa , Nanopartículas , Espécies Reativas de Oxigênio , Dióxido de Silício , Neoplasias da Mama/tratamento farmacológico , Feminino , Nanopartículas/química , Animais , Glutationa/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Dióxido de Silício/química , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Xantonas/química , Xantonas/farmacologia , Taninos/química , Taninos/farmacologia , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Liberação Controlada de Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química
20.
Clin Exp Dent Res ; 10(3): e907, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38881240

RESUMO

OBJECTIVE: The present systematic review explored the involvement of enzymatic and nonenzymatic antioxidants in periodontitis, drawing from established literature. MATERIALS AND METHODS: The research approach encompassed an extensive electronic search from 2000 to 2023 across databases such as PubMed, Science Direct, and Wiley Online Library and cross-referencing using specific keywords. RESULTS: The initial literature exploration generated a total of 766 articles. After thoroughly examining the abstracts, 693 articles were excluded from consideration due to duplication and lack of relevance to the central research inquiry. Following that, 73 articles were left for in-depth evaluation. Following a qualitative assessment, 35 studies that satisfied the inclusion criteria were chosen, while 38 were removed for not meeting the necessary standards. Within this selection, a meta-analysis was conducted on 11 articles that provided consistent data for quantitative synthesis. Specifically, the analysis of glutathione (GSH) levels in serum samples revealed a standardized mean difference (SMD) of -5.552 µg/mL (CI 95%: -9.078 to -2.026; P-0.002). In contrast, the analysis of glutathione peroxidase (GPx) enzymes in gingival crevicular fluid (GCF) samples displayed an overall SMD of 2.918 ng/µL (CI 95%: 0.372-5.465; P-0.025), while salivary samples exhibited an overall SMD value of 0.709 U/l (95% CI: -1.907-3.325; P-0.596) which is of insignificant. CONCLUSION: The systematic review findings suggest a notable decrease in antioxidant enzymes across various systemic biological samples among patients with periodontitis, contrasting with the results from gingival tissue samples meta-analysis of GPx enzyme.


Assuntos
Glutationa Peroxidase , Glutationa Redutase , Glutationa , Periodontite , Humanos , Periodontite/diagnóstico , Periodontite/sangue , Periodontite/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa/metabolismo , Glutationa Redutase/metabolismo , Dissulfeto de Glutationa/metabolismo , Dissulfeto de Glutationa/sangue , Líquido do Sulco Gengival/química , Antioxidantes/metabolismo , Antioxidantes/análise
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