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1.
Front Immunol ; 12: 598601, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815361

RESUMO

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.


Assuntos
/metabolismo , Ferroptose , Ferro/metabolismo , Peroxidação de Lipídeos , Meningite Criptocócica/metabolismo , Tuberculose/metabolismo , /imunologia , Ferroptose/imunologia , Glutationa/metabolismo , Humanos , Inflamação/imunologia , Metabolismo dos Lipídeos , Meningite Criptocócica/imunologia , Meningite Criptocócica/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Tuberculose/imunologia , Tuberculose/patologia
2.
Biomed Khim ; 67(2): 162-168, 2021 Mar.
Artigo em Russo | MEDLINE | ID: mdl-33860774

RESUMO

The antioxidant effect of dinitrosyl iron complexes (DNICs) was studied in various model systems. DNICs with glutathione ligands effectively inhibited Cu2+-induced peroxidation of low density lipoproteins (LDL). The antioxidant effect of DNICs with phosphate ligands and free reduced glutathione (GSH) was less pronounced. In addition, DNICs with glutathione suppressed the formation of reactive oxygen species during co-oxidation of lecithin liposomes and glucose. Free radical oxidation in this system was induced with a lipophilic azo initiator and evaluated by luminol-dependent chemiluminescence. NO sharply stimulated chemiluminescence during co-oxidation of glucose and liposomes, thus suggesting the formation of potent oxidants under these conditions. Glutathione DNICs scavenge the superoxide radical anion generated in the xanthine-xanthine oxidase system. Superoxide production was assessed by lucigenin-dependent chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy. Chemiluminescence revealed the dose-dependent character of antiradical effect of glutathione DNICs; moreover, these complexes turned out to be more efficient than GSH. EPR spectra of the adducts of the DEPMPO spin trap with free radicals suggest that the interaction of glutathione DNICs and superoxide does not result in the formation of the thiyl radical of glutathione. Here we propose a mechanism of the antioxidant action of glutathione DNICs, suggesting that unstable intermediate complexes are formed upon their interaction with superoxide or lipid radicals. Further, as a result of intramolecular rearrangement, these intermediates decompose without the free radical as the by-products.


Assuntos
Antioxidantes , Óxidos de Nitrogênio , Antioxidantes/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa , Ferro , Superóxidos
3.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802702

RESUMO

Our previous study demonstrated that the glutathione S-transferase Mu 5 (GSTM5) gene is highly CpG-methylated in bladder cancer cells and that demethylation by 5-aza-dC activates GSTM5 gene expression. The aim of the present study was to investigate the role of GSTM5 in bladder cancer. The levels of GSTM5 gene expression and DNA methylation were analyzed in patients with bladder cancer, and functional studies of GSTM5 were conducted using GSTM5 overexpression in cultured bladder cancer cells. Clinical analysis revealed that the GSTM5 mRNA expression was lower in bladder cancer tissues than in normal tissues and that the level of GSTM5 DNA methylation was higher in bladder cancer tissues than in normal urine pellets. Overexpression of GSTM5 decreased cell proliferation, migration and colony formation capacity. Glutathione (GSH) assay results indicated that cellular GSH concentration was decreased by GSTM5 expression and that GSH supplementation reversed the decrease in proliferation and migration of cells overexpressing GSTM5. By contrast, a GSH synthesis inhibitor significantly decreased 5637 cell GSH levels, survival and migration. Furthermore, GSTM5 overexpression inhibited the adhesion of cells to the extracellular matrix protein fibronectin. To elucidate the effect of GSTM5 on anticancer drugs used to treat bladder cancer, cellular viability was compared between cells with or without GSTM5 overexpression. GSTM5-overexpressed cells showed no significant change in the cytotoxicity of cisplatin or mitomycin C in 5637, RT4 and BFTC 905 cells. Though a degree of resistance to doxorubicin was noted in 5637 cells overexpressing GSTM5, no such resistance was observed in RT4 and BFTC 905 cells. In summary, GSTM5 plays a tumor suppressor role in bladder cancer cells without significantly affecting chemoresistance to cisplatin and mitomycin C, and the cellular GSH levels highlight a key mechanism underlying the cancer inhibition effect of GSTM5. These findings suggest that low gene expression and high DNA methylation levels of GSTM5 may act as tumor markers for bladder cancer.


Assuntos
Antineoplásicos/metabolismo , Biomarcadores Tumorais/metabolismo , Glutationa Transferase/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Butionina Sulfoximina/farmacologia , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/farmacologia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Neoplasias da Bexiga Urinária/genética
4.
Molecules ; 26(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804228

RESUMO

Sophora flavescens, also known as Kushen, has traditionally been used as a herbal medicine. In the present study we evaluated the ameliorative effects of kushenol C (KC) from S. flavescens against tBHP (tert-Butyl hydroperoxide)-induced oxidative stress in hepatocellular carcinoma (HEPG2) cells and acetaminophen (APAP)-induced hepatotoxicity in mice. KC pretreatment protected the HEPG2 cells against oxidative stress by reducing cell death, apoptosis and reactive oxygen species (ROS) generation. KC pretreatment also upregulated pro-caspase 3 and GSH (glutathione) as well as expression of 8-Oxoguanine DNA Glycosylase (OGG1) in the HEPG2 cells. The mechanism of action was partly related by KC's activation of Akt (Protein kinase B (PKB)) and Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) in the HepG2 cells. In in vivo investigations, coadministration of mice with KC and APAP significantly attenuated APAP-induced hepatotoxicity and liver damage, as the serum enzymatic activity of aspartate aminotransferase and alanine aminotransferase, as well as liver lipid peroxidation and cleaved caspase 3 expression, were reduced in APAP-treated mice. Coadministration with KC also up-regulated antioxidant enzyme expression and prevented the production of proinflammatory mediators in APAP-treated mice. Taken together, these results showed that KC treatment has potential as a therapeutic agent against liver injury through the suppression of oxidative stress.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sophora/química , terc-Butil Hidroperóxido/efeitos adversos , Alanina Transaminase/metabolismo , Animais , Antioxidantes/fisiologia , Aspartato Aminotransferases/metabolismo , Linhagem Celular Tumoral , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Células Hep G2 , Medicina Herbária/métodos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
J Appl Oral Sci ; 29: e20200859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886942

RESUMO

INTRODUCTION: Due to its ability to arrest untreated dental caries, silver diamine fluoride (SDF) has been advocated for indirect pulp capping procedures. However, the high concentrations of silver and fluoride in SDF raise concerns about its biocompatibility to pulpal tissues. OBJECTIVES: This study aimed to investigate the effect of SDF on the viability, alkaline phosphatase (ALP) activity, and morphology of pulpal-like cells (RPC-C2A) and to evaluate the influence of reduced glutathione (GSH) on SDF-induced cytotoxicity and deposit formation on dentin. METHODOLOGY: The cytotoxicity of diluted 38% SDF solutions (10-4 and 10-5), with or without the addition of 5 mM or 50 mM GSH, was evaluated at 6 and 24 hours. Cell viability was detected using WST-8 and the effect on ALP activity was performed using an ALP assay kit. Cell morphology was observed using a phase-contrast microscope. Scanning electron microscopy analysis was conducted to evaluate the effect of GSH incorporation or conditioning on SDF-induced deposit formation on dentin discs. Cytotoxicity data were analyzed by two-way analysis of variance (ANOVA) and Tukey post hoc tests (p<0.05). RESULTS: There were significant differences between the groups. The results demonstrated that all tested SDF dilutions caused a remarkable cytotoxic effect, while the addition of GSH prevented SDF-induced damage at 6-hour exposure time in the higher dilution of SDF. Dentin treated with plain SDF or GSH-incorporated SDF solution showed deposit formation with occluded dentinal tubules, unlike the other groups. CONCLUSION: SDF severely disturbed the viability, mineralization-ability, and morphology of pulpal-like cells, while controlled concentrations of GSH had a short-term protective effect against SDF-induced damage. GSH showed an inhibitory effect on SDF-induced dentinal deposit formation. Further research is warranted to evaluate the effect of GSH on caries-arresting, anti-hypersensitivity, and antibacterial functions of SDF.


Assuntos
Cárie Dentária , Animais , Cariostáticos/toxicidade , Dentina , Fluoretos Tópicos/toxicidade , Glutationa , Compostos de Amônio Quaternário , Ratos , Compostos de Prata
6.
Med Hypotheses ; 149: 110543, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33657459

RESUMO

The socio-economic implications of COVID-19 are devastating. Considerable morbidity is attributed to 'long-COVID' - an increasingly recognized complication of infection. Its diverse symptoms are reminiscent of vitamin B12 deficiency, a condition in which methylation status is compromised. We suggest why SARS-CoV-2 infection likely leads to increased methyl-group requirements and other disturbances of one-carbon metabolism. We propose these might explain the varied symptoms of long-COVID. Our suggested mechanismmight also apply to similar conditions such as myalgic encephalomyelitis/chronic fatigue syndrome. The hypothesis is evaluable by detailed determination of vitamin B12and folate status, including serum formate as well as homocysteine and methylmalonic acid, and correlation with viral and host RNA methylation and symptomatology. If confirmed, methyl-group support should prove beneficial in such individuals.


Assuntos
/complicações , Ácido Fólico/sangue , Deficiência de Vitamina B 12/diagnóstico , Adenosina/análogos & derivados , Adenosina/química , /fisiopatologia , Deficiência de Ácido Fólico , Formiatos/sangue , Genoma Viral , Glutationa/sangue , Homocisteína/sangue , Hospitalização , Humanos , Metilação , Ácido Metilmalônico/sangue , Estresse Oxidativo , RNA/química , Serina/sangue , Vitamina B 12/sangue
7.
Int J Nanomedicine ; 16: 2071-2085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727814

RESUMO

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.


Assuntos
Ligas/farmacologia , Transportador de Cobre 1/metabolismo , Ferro/farmacologia , Nanopartículas Metálicas/química , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Platina/farmacologia , Tolerância a Radiação , Aerobiose , Animais , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Modelos Biológicos , Tolerância a Radiação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento , Raios X
8.
Nat Commun ; 12(1): 1827, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758187

RESUMO

Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.


Assuntos
Acetilcisteína/farmacologia , Proteínas Amiloidogênicas/metabolismo , Angiopatia Amiloide Cerebral Familiar/dietoterapia , Cistatina C/metabolismo , Cistatinas/metabolismo , Acetilcisteína/administração & dosagem , Acetilcisteína/análogos & derivados , Acetilcisteína/química , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/genética , Biópsia , Angiopatia Amiloide Cerebral Familiar/tratamento farmacológico , Angiopatia Amiloide Cerebral Familiar/genética , Cistatina C/química , Cistatina C/genética , Cistatinas/química , Cistatinas/genética , Expressão Gênica , Glutationa/química , Glutationa/farmacologia , Células HEK293 , Humanos , Pele/efeitos dos fármacos , Pele/metabolismo , Adulto Jovem
9.
Life Sci ; 276: 119429, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785333

RESUMO

AIM: The therapeutic expediency of cisplatin was limited due to its nephrotoxic side effects, so this study planned to assess the nephrotic and neuroprotective impact of metformin (MET) and low-dose radiation (LDR) in cisplatin-prompted kidney injury and uremic encephalopathy (UE). METHODS: The effect of the 10-day MET treatment (200 mg/kg, orally) and/or fractionated LDR (0.25 Gy, of the total dose of 0.5 Gy, 1st and 7th day, respectively) on (5 mg/kg, intraperitoneally) cisplatin as a single dose was administered at the 5th day. Serum urea, creatinine and renal kidney injury molecule-1 were measured for the assessment of kidney function. Furthermore, the antioxidant potential in the renal and brain tissues was evaluated through, malondialdehyde and reduced glutathione estimation. Moreover, renal apoptotic markers: AMP-activated protein kinase, lipocalin, B-cell lymphoma 2 associated X protein, B-cell lymphoma 2, P53 and beclin 1 were estimated. UE was evaluated through the determination of serum inflammatory markers: nuclear factor kappa B, tumor-necrosis factor-α and interleukin 1 beta likewise, the cognitive deficits were assessed via forced swimming test, gamma-aminobutyric acid, n-methyl-d-aspartate and neuronal nitric oxide synthases besides AMP-activated protein kinase, light chain 3 and caspase3 levels in rats' cerebella. KEY FINDINGS: The obtained results revealed a noticeable improvement in the previously mentioned biochemical factors and behavioral tasks that was reinforced by histopathological examination when using the present remedy. SIGNIFICANCE: metformin and low doses of radiation afforded renoprotection and neuroprotection against cisplatin-induced acute uremic encephalopathy.


Assuntos
Biomarcadores/metabolismo , Encefalopatias/prevenção & controle , Cisplatino/toxicidade , Raios gama , Metformina/farmacologia , Fármacos Neuroprotetores/farmacologia , Uremia/prevenção & controle , Animais , Antineoplásicos/toxicidade , Encefalopatias/induzido quimicamente , Encefalopatias/metabolismo , Encefalopatias/patologia , Relação Dose-Resposta à Radiação , Glutationa/metabolismo , Hipoglicemiantes/farmacologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Uremia/induzido quimicamente , Uremia/metabolismo , Uremia/patologia
10.
Life Sci ; 276: 119420, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785340

RESUMO

Quercetin (Q) is formulated into oil-in-water F127 microemulsions to improve its bioavailability. The size of the Q-loaded microemulsions system was about 8 nm by dynamic light scattering analysis. To compare antioxidant activity of bulk solution and microemulsion of Q, free radical scavenging activity was evaluated against 2,2-diphenyl-1-picrylhydrazyl (DPPH). The IC50 values were 56.77 and 187.68 µM, respectively. The drug in the bulk form released 16.34 times faster than microemulsion form. Although gentamicin (GM) has potent efficacy against gram-negative bacteria, it induces renal toxicity. Poor solubility and low bioavailability of Q as a bioflavonoid with potent antioxidant activity, limit its therapeutic application. We aimed to compare the effect of free Q and nanoencapsulated (NEQ) against GM-induced renal damage in Wistar rats. Forty-two animals were divided into six groups. Control and GM groups received apo-nanomicelles and GM (100 mg/kg) for 10 days. Two groups received Q (50 mg/kg, i.g.) and NEQ (50 mg/kg, i.g.) respectively for 10 days. Remaining two groups received Q and NEQ (50 mg/kg, i.g.) plus GM (100 mg/kg, i.p.) simultaneously for 10 days. After the experiments, serum and kidneys were used for biochemical, molecular and histological examinations. Immunohistochemical analysis was performed to explore kidney injury molecule-1 (KIM-1) expression as a specific protein biomarker of renal injury. Our findings indicated oxidative stress and altered histological features in renal tissue with deviated serum renal biomarkers in GM-treated rats. Although Q treatment in GM group tried to protect against GM-induced nephrotoxicity, but there were still differences compared to control rats. However, NEQ administration corrected elevations in the levels of urea, creatinine, uric acid and decrements in serum total proteins of GM group. Meanwhile, NEQ restored renal oxidative injury in GM rats through attenuation of lipid peroxidation and enhancement of antioxidant defense systems, glutathione, catalase and superoxide dismutase. NEQ could also normalize GM-induced abnormal renal histology features including fibrosis. Furthermore, the result of immunohistochemistry study confirmed these findings by undetecting KIM-1 expression in NEQ treated GM group, meanwhile showing this renal biomarker in GM and Q treated GM groups. Therefore, NEQ seems to be useful in protecting against renal oxidative stress and kidney damage in a rat model of GM nephrotoxicity which deserve further evaluations.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Antioxidantes/farmacologia , Gentamicinas/toxicidade , Polietilenos/química , Polipropilenos/química , Substâncias Protetoras/farmacologia , Quercetina/farmacologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Biomarcadores/análise , Nitrogênio da Ureia Sanguínea , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Quercetina/administração & dosagem , Quercetina/química , Ratos , Ratos Wistar
11.
Food Chem ; 352: 129458, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33714166

RESUMO

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.


Assuntos
Ácido Ascórbico/metabolismo , Capsicum/efeitos dos fármacos , Capsicum/metabolismo , Temperatura Baixa , Glutationa/farmacologia , Frutas/efeitos dos fármacos , Frutas/metabolismo , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Plântula/efeitos dos fármacos , Plântula/metabolismo
12.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672046

RESUMO

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.


Assuntos
Cinamatos/farmacologia , Citoproteção/efeitos dos fármacos , Glutationa/biossíntese , Hepatócitos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Morte Celular/efeitos dos fármacos , Cinamatos/química , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Luciferases/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Substâncias Protetoras/farmacologia , terc-Butil Hidroperóxido
13.
ACS Appl Mater Interfaces ; 13(11): 12912-12927, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33715350

RESUMO

The current pandemic caused by SARS-CoV-2 has seen a widespread use of personal protective equipment, especially face masks. This has created the need to develop better and reusable protective masks with built-in antimicrobial, self-cleaning, and aerosol filtration properties to prevent the transmission of air-borne pathogens such as the coronaviruses. Herein, molybdenum disulfide (MoS2) nanosheets are used to prepare modified polycotton fabrics having excellent antibacterial activity and photothermal properties. Upon sunlight irradiation, the nanosheet-modified fabrics rapidly increased the surface temperature to ∼77 °C, making them ideal for sunlight-mediated self-disinfection. Complete self-disinfection of the nanosheet-modified fabric was achieved within 3 min of irradiation, making the fabrics favorably reusable upon self-disinfection. The nanosheet-modified fabrics maintained the antibacterial efficiency even after 60 washing cycles. Furthermore, the particle filtration efficiency of three-layered surgical masks was found to be significantly improved through incorporation of the MoS2-modified fabric as an additional layer of protective clothing, without compromising the breathability of the masks. The repurposed surgical masks could filter out around 97% of 200 nm particles and 96% of 100 nm particles, thus making them potentially useful for preventing the spread of coronaviruses (120 nm) by trapping them along with antibacterial protection against other airborne pathogens.


Assuntos
Anti-Infecciosos/química , Dissulfetos/química , Molibdênio/química , Nanoestruturas/química , Equipamento de Proteção Individual , Reciclagem , Anti-Infecciosos/farmacologia , /virologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Glutationa/química , Humanos , Nanoestruturas/toxicidade , Oxirredução , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Luz Solar , Temperatura
14.
Nat Commun ; 12(1): 1589, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707434

RESUMO

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.


Assuntos
Cisteína/metabolismo , Cistina/metabolismo , Ferroptose/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Glutationa/metabolismo , Células HEK293 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Neoplasias/patologia
15.
Nat Commun ; 12(1): 1345, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649319

RESUMO

Drug therapy unavoidably brings toxic side effects and drug content-limited therapeutic efficacy although many nanocarriers have been developed to improve them to a certain extent. In this work, a concept of drug-free therapeutics is proposed and defined as a therapeutic methodology without the use of traditional toxic drugs, without the consumption of therapeutic agents during treatment but with the inexhaustible therapeutic capability to maximize the benefit of treatment, and a Z-scheme SnS1.68-WO2.41 nanocatalyst is developed to achieve near infrared (NIR)-photocatalytic generation of oxidative holes and hydrogen molecules for realizing combined hole/hydrogen therapy by the drug-free therapeutic strategy. Without the need of any drug and other therapeutic agent assistance, the nanocatalyst oxidizes/consumes intratumoral over-expressed glutathione (GSH) by holes and simultaneously generates hydrogen molecules in a lasting and controllable way under NIR irradiation. Mechanistically, generated hydrogen molecules and GSH consumption inhibit cancer cell energy and destroy intratumoral redox balance, respectively, to synergistically damage DNA and induce tumor cell apoptosis. High efficacy and biosafety of combined hole/hydrogen therapy of tumors are achieved by the nanocatalyst. The proposed catalysis-based drug-free therapeutic strategy breaks a pathway to realize high efficacy and low toxicity of cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Fototerapia , Animais , Catálise/efeitos da radiação , Linhagem Celular Tumoral , Glutationa/química , Humanos , Hidrogênio/química , Raios Infravermelhos , Antígeno Ki-67/metabolismo , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Análise Espectral , Carga Tumoral , Microambiente Tumoral
16.
Environ Pollut ; 276: 116725, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33631691

RESUMO

Ionic liquids (ILs), also known as green solvents, are widely acknowledged in several fields, such as chemical separation, synthesis, and electrochemistry, owing to their excellent physiochemical properties. However, their poor biodegradability may lead to environmental and health risks, posing a severe threat to humans, thus requiring further research. In this study, the biotoxicities of the imidazolium-based ILs were evaluated in Tetrahymena pyriformis. Moreover, IL detoxification was investigated by addition of glutathione (GSH), cysteine, and nicotinamide adenine dinucleotide (NADH). Reactive oxygen species (ROS) initiated by different IL types caused damage to Tetrahymena, while glutathione, cysteine, and NADH eliminated ROS, achieving the detoxification purposes. Detoxification results showed that NADH exhibited the best detoxification ability, followed by glutathione and cysteine. Finally, RT-PCR results suggested that metallothionein might have participated in IL detoxification.


Assuntos
Líquidos Iônicos , Tetrahymena pyriformis , Cisteína , Glutationa , Humanos , Líquidos Iônicos/toxicidade , NAD
17.
Chem Biol Interact ; 338: 109402, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33587916

RESUMO

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.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/efeitos adversos , Inflamação/patologia , Ovário/patologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Útero/patologia , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Catalase/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Malondialdeído/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ovário/efeitos dos fármacos , Progesterona/sangue , Prolactina/sangue , Carbonilação Proteica/efeitos dos fármacos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/metabolismo
18.
J Dairy Sci ; 104(4): 3990-4001, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33589257

RESUMO

Streptococcus thermophilus is widely used as a starter culture in the fermentation of yogurt. Glutathione (GSH; γ-glutamyl-cysteinyl-glycine), as a tripeptide, has an important physiological role for Strep. thermophilus. However, the scope of the GSH transport proteins is still unexplored in this species. In the present study, 5 peptide transporter-related proteins (Ptrp) of Strep. thermophilus strain ST-1 were selected and then inactivated by gene insertion, respectively. Through detection and comparison of intracellular GSH content of mutant strain and wild strain, we identified 2 proteins, named Ptrp-2 and Ptrp-4, that might be related to GSH transport. Reverse-transcriptase quantitative PCR was performed to verify the gene expressions of these 2 possible GSH transport-related proteins, and it was finally determined that Ptrp-2 plays an important role in GSH transport of Strep. thermophilus. Milk fermentation experiments were further conducted to test the effect of Ptrp-2 on the characteristics of yogurt. The results showed that the fermented milk hardly curds using the mutant strain, indicating that Ptrp-2 is important for Strep. thermophilus as a yogurt starter.


Assuntos
Streptococcus thermophilus , Iogurte , Animais , Proteínas de Transporte , Fermentação , Glutationa , Proteínas de Membrana Transportadoras , Leite , Streptococcus thermophilus/genética
19.
Molecules ; 26(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562280

RESUMO

Oxidative protein folding is a biological process to obtain a native conformation of a protein through disulfide-bond formation between cysteine residues. In a cell, disulfide-catalysts such as protein disulfide isomerase promote the oxidative protein folding. Inspired by the active sites of the disulfide-catalysts, synthetic redox-active thiol compounds have been developed, which have shown significant promotion of the folding processes. In our previous study, coupling effects of a thiol group and guanidyl unit on the folding promotion were reported. Herein, we investigated the influences of a spacer between the thiol group and guanidyl unit. A conjugate between thiol and guanidyl units with a diethylene glycol spacer (GdnDEG-SH) showed lower folding promotion effect compared to the thiol-guanidyl conjugate without the spacer (GdnSH). Lower acidity and a more reductive property of the thiol group of GdnDEG-SH compared to those of GdnSH likely resulted in the reduced efficiency of the folding promotion. Thus, the spacer between the thiol and guanidyl groups is critical for the promotion of oxidative protein folding.


Assuntos
Etilenoglicol/química , Estresse Oxidativo/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/química , Compostos de Sulfidrila/química , Catálise , Cisteína/química , Dissulfetos/química , Etilenoglicol/farmacologia , Glutationa/química , Cinética , Oxirredução/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos , Compostos de Sulfidrila/farmacologia
20.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567754

RESUMO

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.


Assuntos
Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Compostos de Metilmercúrio/análise , Compostos de Metilmercúrio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Apoptose , Sobrevivência Celular , Células Cultivadas , Feminino , Glutationa/metabolismo , Humanos , Placenta/metabolismo , Placenta/patologia , Gravidez , Substâncias Protetoras/análise
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