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1.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(8. Vyp. 2): 17-23, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33016672

RESUMO

OBJECTIVE: To evaluate the hemostasis of plasma aminothiols in different subtypes of ischemic stroke (IS). MATERIAL AND METHODS: The study included 177 patients, aged 62 (55-68) years, admitted in the first 8-24 hours since IS onset. The pathogenetic subtype of IS was clarified according to the results of clinical and instrumental examination by the Trial of ORG 10172 in Acute Stroke Treatment criteria. Determination of the total plasma aminothiols levels, their reduced forms and redox status was performed using the ultra-efficient Acquity H-Class UPLC liquid chromatograph (Waters, CSHA). RESULTS: Large-artery atherosclerosis was diagnosed in 24.3% patients, cardioembolic stroke in 20.3%, lacunar stroke in 55.4%. Significant differences in total levels of cysteine (Cys), glutathione (Gsh) and homocysteine (Hcy) were identified in patients with different IS subtypes. Patients with large-artery atherosclerosis and lacunar stroke showed the highest level of Hcy, patients with cardioembolic stroke had the lowest levels of Cys and Gsh. CONCLUSION: Total levels of plasma aminothiols are associated with different subtypes of IS.


Assuntos
Aterosclerose , Isquemia Encefálica/complicações , Cisteína , Glutationa , Homocisteína , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/sangue , Cisteína/sangue , Glutationa/sangue , Homocisteína/sangue , Humanos , Pessoa de Meia-Idade , Oxirredução
2.
Clín. investig. arterioscler. (Ed. impr.) ; 32(3): 87-93, mayo-jun. 2020. tab
Artigo em Inglês | IBECS | ID: ibc-193352

RESUMO

OBJECTIVE: Post-prandial lipaemia (PL), oxidative stress (OS), and complement component C3 (C3) values are related to the atherosclerosis process. The post-prandial response of C3 after an oral fat load test (OFLT) using unsaturated fat is poorly addressed. The aim of this study was to analyze and compare the post-prandial response of OS markers and C3 values in men and women after an OFLT using unsaturated fat. METHODS: The study included a total of 22 healthy subjects with normal lipids and normal blood glucose (11 men and 11 pre-menopausal women). An oral unsaturated fat load test (OFLT: 50g fat per m2 body surface) was performed using a commercial liquid preparation of long chain triglycerides (Supracal®). OS markers and C3 were measured using standardized methods at fasting state and every 2h up to 8h after the OFLT. RESULTS: Men showed statistically significant higher C3, oxidized glutathione (GSSG), and oxidized-reduced glutathione (GSSG/GSH) ratio values at fasting state compared to that obtained in women. In addition, post-prandial C3 values and GSSG/GSH ratios were significantly higher in men compared to women. The GSSG value and GSSG/GSH ratio significantly decreased in men after the OFLT compared to fasting values. In contrast, the post-prandial OS markers decrease observed in women was not statistically significant. CONCLUSIONS: In fasting state, men showed higher statistically significant C3 values and OS markers than women. The post-prandial OS markers (GSSG and GSSG/GSH ratio) significantly decrease after the OFLT with unsaturated fat in men compared to women


OBJETIVO: Los valores de lipemia postprandial (PL), estrés oxidativo (OS) y componente C3 del complemento (C3) están relacionados con el proceso de aterosclerosis. La respuesta postprandial de C3 tras una sobrecarga oral de grasa (OFLT) utilizando grasa insaturada no es completamente conocida. Nuestro objetivo fue analizar y comparar la respuesta postprandial de los marcadores de OS y los valores de C3 en hombres y mujeres después de una OFLT utilizando grasa insaturada. MÉTODOS: Estudiamos 22 sujetos normolipidémicos y normoglicémicos (11 hombres y 11 mujeres premenopáusicas). Se realizó una sobrecarga oral con grasa insaturada (OFLT: 50g de grasa por m2 de superficie corporal) utilizando una preparación líquida comercial de triglicéridos de cadena larga (Supracal®). Los marcadores OS y C3 se midieron utilizando métodos estandarizados en estado de ayuno y cada 2 horas hasta 8 horas después de OFLT. RESULTADOS: Los hombres mostraron valores significativamente mayores de C3, glutatión oxidado (GSSG) y glutatión reducido (GSSG/GSH) en estado de ayuno en comparación con los obtenidos en mujeres. Además, los valores de C3 postprandiales y la relación GSSG/GSH fueron significativamente más altos en los hombres que en las mujeres. El valor GSSG y la relación GSSG/GSH disminuyeron significativamente en los hombres después de OFLT en comparación con los valores de ayuno. En contraste, la disminución de marcadores postprandiales de OS observada en mujeres no fue estadísticamente significativa. CONCLUSIONES: En ayunas, los hombres muestran valores estadísticamente mayores de C3 y marcadores OS que las mujeres. Los marcadores OS postprandial (GSSG y GSSG/GSH ratio) disminuyen significativamente tras OFLT con grasa insaturada en los hombres en comparación con las mujeres


Assuntos
Humanos , Masculino , Feminino , Adulto , Estresse Oxidativo/efeitos dos fármacos , Complemento C3/efeitos dos fármacos , Aterosclerose/diagnóstico , Gorduras Insaturadas/administração & dosagem , Biomarcadores , Glutationa/sangue , Gorduras Insaturadas/farmacologia , Glutationa/análise , Glutationa Peroxidase/análise , Pré-Menopausa/sangue , Índice de Massa Corporal , Antropometria , Lipoproteínas/análise , Lipídeos/análise , Gorduras na Dieta/administração & dosagem
3.
J Clin Virol ; 128: 104431, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442756

RESUMO

BACKGROUND: Despite the death rate of COVID-19 is less than 3%, the fatality rate of severe/critical cases is high, according to World Health Organization (WHO). Thus, screening the severe/critical cases before symptom occurs effectively saves medical resources. METHODS AND MATERIALS: In this study, all 336 cases of patients infected COVID-19 in Shanghai to March 12th, were retrospectively enrolled, and divided in to training and test datasets. In addition, 220 clinical and laboratory observations/records were also collected. Clinical indicators were associated with severe/critical symptoms were identified and a model for severe/critical symptom prediction was developed. RESULTS: Totally, 36 clinical indicators significantly associated with severe/critical symptom were identified. The clinical indicators are mainly thyroxine, immune related cells and products. Support Vector Machine (SVM) and optimized combination of age, GSH, CD3 ratio and total protein has a good performance in discriminating the mild and severe/critical cases. The area under receiving operating curve (AUROC) reached 0.9996 and 0.9757 in the training and testing dataset, respectively. When the using cut-off value as 0.0667, the recall rate was 93.33 % and 100 % in the training and testing datasets, separately. Cox multivariate regression and survival analyses revealed that the model significantly discriminated the severe/critical cases and used the information of the selected clinical indicators. CONCLUSION: The model was robust and effective in predicting the severe/critical COVID cases.


Assuntos
Doença das Coronárias/diagnóstico , Infecções por Coronavirus/diagnóstico , Complicações do Diabetes/diagnóstico , Diabetes Mellitus/diagnóstico , Surtos de Doenças , Hipertensão/diagnóstico , Pneumonia Viral/diagnóstico , Adulto , Fatores Etários , Idoso , Área Sob a Curva , Betacoronavirus , Biomarcadores/sangue , Complexo CD3/sangue , Estudos de Coortes , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Doença das Coronárias/mortalidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Complicações do Diabetes/sangue , Complicações do Diabetes/mortalidade , Diabetes Mellitus/sangue , Diabetes Mellitus/mortalidade , Feminino , Glutationa/sangue , Humanos , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/mortalidade , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Prognóstico , Curva ROC , Índice de Gravidade de Doença , Máquina de Vetores de Suporte , Análise de Sobrevida , Tiroxina/sangue
4.
ACS Infect Dis ; 6(7): 1558-1562, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32463221

RESUMO

Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. The hypothesis that glutathione deficiency is the most plausible explanation for serious manifestation and death in COVID-19 patients was proposed on the basis of an exhaustive literature analysis and observations. The hypothesis unravels the mysteries of epidemiological data on the risk factors determining serious manifestations of COVID-19 infection and the high risk of death and opens real opportunities for effective treatment and prevention of the disease.


Assuntos
Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Glutationa/deficiência , Glutationa/farmacologia , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Adulto , Anti-Inflamatórios/sangue , Anticoagulantes/sangue , Antivirais/sangue , Betacoronavirus/fisiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Estudos de Viabilidade , Feminino , Glutationa/sangue , Humanos , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Prognóstico , Espécies Reativas de Oxigênio/sangue , Fatores de Risco , Índice de Gravidade de Doença , Replicação Viral/efeitos dos fármacos , Deficiência de Vitamina D/complicações
5.
Arch Med Res ; 51(3): 204-214, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111490

RESUMO

BACKGROUND: Oxidative and endoplasmic reticulum stresses contribute to the pathogenesis of ß-cell dysfunction in diabetes mellitus. This study investigates the effect of isopulegol on the above stresses in HFD/STZ induced diabetic rats. METHODS: Animals in group I and II were placed in normal pellet diet and group II was treated with isopulegol at 200 mg/kg b.w. Animals in groups III-V were placed in HFD for 4 weeks and made diabetic with single intraperitoneal injection of STZ (35 mg/kg b.w) in 0.1 M citrate buffer (pH 4.5). Group III served as diabetic control while animals in group IV and V were treated with isopulegol (100 mg/kg b.w) and metformin (25 mg/kg b.w) respectively for 28 d. RESULTS: The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione sulphur transferase (GST), glutathione reductase (GR) and the levels of vitamin-E, vitamin-C, reduced glutathione (GSH) were significantly (p <0.05) decreased in plasma and tissues of diabetic rats. Thiobarbituric acid reactive acid substances (TBARS) and lipid hydroperoxides (LHP), indices of lipid peroxidation were also significantly (p <0.05) increased in diabetic rats. In pancreatic tissue ER stress markers PERK, elf2α, ATF4 and in hepatic tissue oxidative stress marker UCP-2 expression was significantly (p <1.0) increased in diabetic rats. Administration of isopulegol significantly improved antioxidant status and decreased oxidative and ER stress markers in diabetic treated rats. Histopathological studies on liver and kidney supported the above findings. The results are comparable with the standard drug metformin. CONCLUSIONS: Isopulegol a naturally occurring monoterpene alcohol attenuated oxidative and ER stress in HFD/STZ induced diabetic rats.


Assuntos
Antioxidantes/farmacologia , Monoterpenos Cicloexânicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Ascórbico/sangue , Glicemia/metabolismo , Catalase/metabolismo , Glutationa/sangue , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Hiperglicemia/patologia , Insulina/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/sangue , Masculino , Ratos , Ratos Wistar , Estreptozocina , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Vitamina E/sangue
6.
Oxid Med Cell Longev ; 2020: 1079129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32064020

RESUMO

Inflammation and oxidative stress are pivotal mechanisms for the pathogenesis of ischemia and reperfusion injury (IRI). Vagus nerve stimulation (VNS) may participate in maintaining oxidative homeostasis and response to external stimulus or injury. We investigated whether the in vivo VNS can protect the liver from IRI. In this study, hepatic IRI were induced by ligating the vessels supplying the left and middle lobes of the liver, which underwent 1 h occlusion followed with 24 h reperfusion. VNS was initiated 15 min after ischemia and continued 30 min. Hepatic function, histology, and apoptosis rates were evaluated after 24 h reperfusion. Compared with the IRI group, VNS significantly improved hepatic function. The protective effect was accompanied by a reduction in histological damage in the ischemic area, and the apoptosis rate of hepatocytes has considerable reduction. To find the underlying mechanism, proteomic analysis was performed and differential expression of glutathione synthetase (GSS) and glutathione S-transferase (GST) was observed. Subsequently, test results indicated that VNS upregulated the expression of mRNA and protein of GSS and GST. Meanwhile, VNS increased the plasma levels of glutathione and glutathione peroxidases. We found that VNS alleviated hepatic IRI by upregulating the antioxidant glutathione via the GSS/glutathione/GST signaling pathway.


Assuntos
Glutationa/sangue , Hepatócitos/metabolismo , Hepatopatias/terapia , Traumatismo por Reperfusão/terapia , Estimulação do Nervo Vago , Animais , Antioxidantes/metabolismo , Apoptose/genética , Citocinas/metabolismo , Glutationa/biossíntese , Glutationa/metabolismo , Glutationa Peroxidase/sangue , Glutationa Sintase/genética , Glutationa Sintase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Hepatócitos/enzimologia , Fígado/enzimologia , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Estresse Oxidativo , Proteômica , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/genética
7.
Oxid Med Cell Longev ; 2020: 5478708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082479

RESUMO

Kidney disease represents a serious global health problem. One of the main concerns is its late diagnosis, only feasible in a progressed disease state. The lack of a clinical manifestation in the early stages and the fact that the commonly measured parameters of renal function are markedly reduced only during advanced stages of the disease are the main cause. Changes at the molecular level of the kidney tissue occur even before nitrogenous substances, such as creatinine and urea, start to accumulate in the blood. Renal proximal tubules contain a large number of mitochondria and are critical for the energy-demanding process of reabsorption of water and solutes. Mitochondria are the largest producers of oxygen radicals, which, in turn, increase the susceptibility of kidneys to oxidative stress-induced damage. Free radicals and prooxidants produced during acute or chronic kidney injury may further aggravate the course of the disease and play a role in the pathogenesis of subsequent complications. Prevention might be the solution in CKD, but patients are often reluctant to undergo preventive examinations. Noninvasive markers and the possibility to obtain samples at home might help to increase compliance. This review will provide an overview of the possible uses of markers of oxidative status in noninvasive biofluids in patients with renal disease.


Assuntos
Lesão Renal Aguda/metabolismo , Biomarcadores/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/fisiopatologia , Animais , Citocinas/metabolismo , Glutationa/sangue , Humanos , Inflamação/metabolismo , Túbulos Renais Proximais/metabolismo , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/urina , Ureia/sangue
8.
Adv Clin Exp Med ; 29(1): 135-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011832

RESUMO

BACKGROUND: Anesthetics, such as isoflurane, sevoflurane, ketamine, and desflurane, are commonly used in clinics. Specifically, isoflurane is one of the most commonly used inhalational anesthetics, which can be used in surgery patients of all ages, including children. OBJECTIVES: The aim of the study was to investigate the mechanisms of vitexin against isoflurane-induced neurotoxicity. MATERIAL AND METHODS: Reference memory testing was performed for 5 days (4 trials, 2 per day) before anesthesia. Reversal testing was performed on the 3rd day after anesthesia. The cell viability and apoptosis of PC-12 cells were detected using MTT and TUNEL assays, respectively. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure serum tumor necrosis factor α (TNF­α), interleukin 6 (IL­6), glutathione (GSH), and superoxide dismutase (SOD) concentrations. The concentration of reactive oxygen species (ROS) was detected using ROS measurement. Expression of miR-409 was determined using quantitative reverse-transcription polymerase chain reaction (qPT-PCR). Protein expression levels were detected using western blotting. RESULTS: Rats treated with isoflurane showed significant increases in the escape latency periods (ELP) and the apoptosis of hippocampus neuron cells; this effect was reversed by 3 mg/kg or 10 mg/kg of vitexin (p < 0.05). Further testing showed that isoflurane could significantly decrease the cell viability and increase the apoptosis of PC-12, the expression of inflammatory cytokines (TNF­α and IL­6) and ROS (p < 0.05). However, these results were reversed by 10/100 µM of vitexin. In addition, vitexin could significantly increase the expression of miR-409 (p < 0.05). Further studies showed that overexpression of miR-409 could significantly promote the effect of vitexin on isoflurane-induced neurotoxicity (p < 0.05). Finally, overexpression miR-409 could significantly increase the expression of p-AMPK/t-AMPK and p-GSK3ß/t-GSK3ß. CONCLUSIONS: Vitexin has protective effects against isoflurane-induced neurotoxicity by targeting miR-409 and the AMPK/GSK3ß pathway.


Assuntos
Anestésicos Inalatórios , Apigenina/farmacologia , Isoflurano/farmacologia , MicroRNAs/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP , Animais , Apoptose/efeitos dos fármacos , Criança , Ensaio de Imunoadsorção Enzimática , Glutationa/sangue , Glicogênio Sintase Quinase 3 beta , Humanos , Interleucina-6/sangue , MicroRNAs/genética , Ratos , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangue
9.
Sci Rep ; 10(1): 1478, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001745

RESUMO

As a neurotologic disorder of persistent non-vertiginous dizziness, chronic subjective dizziness (CSD) arises unsteadily by psychological and physiological imbalance. The CSD is hypersensitivity reaction due to exposure to complex motions visual stimuli. However, the pathophysiological features and mechanism of the CSD still remains unclearly. The present study was purposed to establish possible endogenous contributors of the CSD using serum samples from patients with the CSD. A total 199 participants were gathered and divided into two groups; healthy (n = 152, male for 61, and female for 91) and CSD (n = 47, male for 5, female for 42), respectively. Oxidative stress parameters such as, hydrogen peroxide and reactive substances were significantly elevated (p < 0.01 or p < 0.001), whereas endogenous antioxidant components including total glutathione contents, and activities of catalase and superoxide dismutase were significantly deteriorated in the CSD group (p < 0.01 or p < 0.001) as comparing to the healthy group, respectively. Serum levels of tumor necrosis factor -α and interferon-γ were significantly increased in the CSD participants (p < 0.001). Additionally, emotional stress related hormones including cortisol, adrenaline, and serotonin were abnormally observed in the serum levels of the CSD group (p < 0.01 or p < 0.001). Our results confirmed that oxidative stress and antioxidants are a critical contributor of pathophysiology of the CSD, and that is first explored to establish features of redox system in the CSD subjects compared to a healthy population.


Assuntos
Antioxidantes/metabolismo , Tontura/sangue , Estresse Oxidativo , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Catalase/sangue , Doença Crônica , Citocinas/sangue , Feminino , Glutationa/sangue , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Superóxido Dismutase/sangue , Adulto Jovem
10.
Mater Sci Eng C Mater Biol Appl ; 108: 110456, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924021

RESUMO

Under different pathological conditions, high levels of reactive oxygen species (ROS) cause substantial damage to multiple organs. To counter these ROS levels in multiple organs, we have engineered highly potent novel terpolymers. We found that combination of FDA-approved polyethylene glycol, fumaric acid moieties and electroactive tetra(aniline) by varying the content of tetra(aniline) results into a novel drug composition with biologically active and tunable intrinsic antioxidant properties. To test the intrinsic antioxidative properties of these novel terpolymers, we used alloxan to induce diabetes in rats where ROS generation is known to be higher. The systemic administration of terpolymers to the diabetic rats showed strong electroactive antioxidant behavior which not only normalized ROS levels, but also improved the levels of enzymatic antioxidants including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). As a proof-of-principle, we here show TANI based novel drug composition of terpolymers with tunable intrinsic antioxidant properties in multiple organs.


Assuntos
Compostos de Anilina , Antioxidantes , Diabetes Mellitus Experimental/tratamento farmacológico , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Catalase/sangue , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Glutationa/sangue , Humanos , Masculino , Ratos , Espécies Reativas de Oxigênio , Superóxido Dismutase/sangue
11.
Mol Cell Biol ; 40(6)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31932477

RESUMO

Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer's disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF ) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF ::Keap1FA/FA mice. Matrix-assisted laser desorption ionization-mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF ::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/fisiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Glutationa/sangue , Inflamação/patologia , Isotiocianatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidiletanolaminas/metabolismo , Placa Amiloide/genética , Placa Amiloide/patologia , Plasmalogênios/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
J Biochem Mol Toxicol ; 34(2): e22425, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729815

RESUMO

The effect of combined administration of calcium (Ca), iron (Fe), zinc (Zn), chrysanthemum flavonoids, and meso-2,3-dimercaptosuccinic acid (DMSA) on the treatment of lead (Pb) intoxication in mice was studied. One hundred ninety female mice (SPF level, aged 18-22 days) were randomly divided into two groups as experimental animals. Mice in group I (10 mice) served as normal control animals, and were administered deionized water containing 12.5 µL/L acetate acid for 6 weeks, whereas mice in group II (180 mice) were exposed to 0.1% (wt/vol) of lead acetate in deionized water for 6 weeks and served as experimental animals. After 6 weeks of successful modeling, 180 mice from group II (lead-exposed) were divided into 18 groups of 10 mice each, 16 of which were treated by the combined administration of Ca, Fe, Zn, chrysanthemum flavonoids, and DMSA by L16 (215 ) orthogonal design. The remaining two groups were given treatment with low and high doses of DMSA, respectively. After three weeks of intervention (ig), the optimal treatment group was identified according to its blood lead level, as well as some antioxidant indices in the blood, liver, and hippocampus. The results indicated that the combined administration of Fe, Zn, chrysanthemum flavonoids, and DMSA with low dosage had the most significant effect on increasing the activities of blood delta-aminolevulinic acid dehydratase and superoxide dismutase (SOD), hepatic SOD and hippocampus nitric oxide synthase while decreasing the blood lead level, the content of hepatic malondialdehyde and hippocampus nitric oxide; this was considered the optimal treatment group. There was no difference in the level of blood hemoglobin between the optimal treatment group and the model control group (the first group of the orthogonal experiment). The activities of blood glutathione (GSH), hepatic GSH and glutathione peroxidase of the optimal treatment group were the same as other groups', and the recovery of the related indexes in the optimal effect group closely resembled the high dosage DMSA group. It can be concluded that the coadministration of Fe, Zn, and chrysanthemum flavonoids along with a low-dose DMSA effectively reduces Pb poisoning and lead-induced oxidative damage in lead-exposed mice; the result may provide a theoretical reference for the treatment of Pb poisoning.


Assuntos
Cálcio/farmacologia , Chrysanthemum/química , Flavonoides/farmacologia , Ferro/farmacologia , Intoxicação por Chumbo/tratamento farmacológico , Extratos Vegetais/farmacologia , Succímero/farmacologia , Zinco/farmacologia , Animais , Cálcio/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Flavonoides/administração & dosagem , Glutationa/sangue , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ferro/administração & dosagem , Chumbo/efeitos adversos , Chumbo/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Malondialdeído/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Sintase do Porfobilinogênio/sangue , Succímero/administração & dosagem , Superóxido Dismutase/sangue , Resultado do Tratamento , Zinco/administração & dosagem
13.
Artigo em Inglês | MEDLINE | ID: mdl-31690176

RESUMO

An adequate level of low molecular weight thiols (LMW-SH, especially glutathione (GSH)) protects cellular macromolecules against toxic agents, and is used as a sensitive biomarker of exposure to toxic compounds. During sample collection, storage and preparation, non-enzymatic and enzymatic oxidation of LMW-SH can occur leading to analytical inaccuracy. The aim of this study was to optimize a fast and reliable screening method for the determination of LMW-SH, mainly GSH, in blood and plasma samples as well as to investigate the impact of storage conditions on the LMW-SH stability. Based on our results, the described spectrophotometric method allows fast and reliable determination of LMW-SH in blood and plasma samples. Results on incubation of samples at 37 °C imply that synthesis of LMW-SH (probably GSH) as well as dynamic interexchange among various thiols forms can be induced in blood cells in in vitro conditions. Importantly, the level of LMW-SH in blood and plasma stored at -20 °C was constant, indicating that they can be stored at -20 °C for at least 30 days. Therefore, the method is suitable for assessment of LMW-SH in long-term human biomonitoring as well as environmental field studies, especially those involving a large number of samples such as epidemiological studies.


Assuntos
Monitoramento Biológico/métodos , Compostos de Sulfidrila/sangue , Biomarcadores/sangue , Biomarcadores/química , Glutationa/sangue , Glutationa/química , Humanos , Peso Molecular , Oxirredução , Manejo de Espécimes , Compostos de Sulfidrila/química , Temperatura
14.
Mol Cell Biochem ; 463(1-2): 147-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31595424

RESUMO

Amalaki rasayana, a traditional preparation, is widely used by Ayurvedic physicians for the treatment of inflammatory conditions, cardiovascular diseases, and cancer. Metabolic alterations induced by Amalaki rasayana intervention are unknown. We investigated the modulations in serum metabolomic profiles in Wistar rats following long-term oral administration of Amalaki rasayana. Global metabolic profiling was performed of the serum of rats administered with either Amalaki rasayana (AR) or ghee + honey (GH) for 18 months and control animals which were left untreated. Amalaki rasayana components were confirmed from AR extract using HR-LCMS analysis. Significant reductions in prostaglandin J2, 11-dehydrothromboxane B2, and higher levels of reduced glutathione and glycitein metabolites were observed in the serum of AR administered rats compared to the control groups. Eleven different metabolites classified as phospholipids, glycerophospholipids, glucoside derivatives, organic acids, and glycosphingolipid were exclusively observed in the AR administered rats. Pathway analysis suggests that altered metabolites in AR administered rats are those associated with different biochemical pathways of arachidonic acid metabolism, fatty acid metabolism, leukotriene metabolism, G-protein mediated events, phospholipid metabolism, and the immune system. Targeted metabolomics confirmed the presence of gallic acid, ellagic acid, and arachidonic acid components in the AR extract. The known activities of these components can be correlated with the altered metabolic profile following long-term AR administration. AR also activates IGF1R-Akt-Foxo3 signaling axis in heart tissues of rats administered with AR. Our study identifies AR components that induce alterations in lipid metabolism and immune pathways in animals which consume AR for an extended period.


Assuntos
Metabolismo dos Lipídeos , Metabolômica , Miocárdio , Extratos Vegetais/farmacologia , Prostaglandina D2/análogos & derivados , Transdução de Sinais , Animais , Glutationa/sangue , Glutationa/imunologia , Isoflavonas/sangue , Isoflavonas/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/imunologia , Masculino , Miocárdio/imunologia , Miocárdio/metabolismo , Prostaglandina D2/biossíntese , Prostaglandina D2/imunologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Tromboxano B2/análogos & derivados , Tromboxano B2/sangue , Tromboxano B2/imunologia
15.
Nephrology (Carlton) ; 25(1): 90-95, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30891869

RESUMO

AIM: The removal of cysteine during a dialysis procedure may affect glutathione (GSH) concentration, allowing haemodialysis (HD) patients to become more susceptible to oxidative damage. This study was performed to determine whether the change of GSH/glutathione disulfide (GSSG) redox state and GSH redox potential were linked with the change of cysteine or oxidative stress in patients receiving HD treatment. METHODS: Sixty-seven HD patients who had received regular HD treatment were recruited. Plasma GSH, GSSG, cysteine and malondialdehyde (MDA) were measured at both pre- and post-HD. RESULTS: Plasma cysteine, GSH and GSSG levels significantly decreased after the completion of HD, compared to the levels at pre-HD. Plasma MDA concentration, GSH/GSSG ratio and GSH redox potential remained constant during the dialysis session. Plasma GSH and GSSG were positively associated with plasma MDA at post-HD, while GSH redox potential was negatively associated with plasma MDA at post-HD. However, plasma GSH, GSSG, GSH/GSSG ratio and GSH redox potential were not associated with plasma cysteine at either pre- or post-HD. CONCLUSION: The GSH and GSSG levels were significantly utilized during a HD session, and their levels were significantly associated with increased oxidative stress. HD patients may require higher GSH demands to cope with increased oxidative stress during an HD session.


Assuntos
Glutationa/sangue , Estresse Oxidativo , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/terapia , Idoso , Biomarcadores/sangue , Estudos Transversais , Cisteína/sangue , Feminino , Dissulfeto de Glutationa/sangue , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Oxirredução , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Fatores de Tempo , Resultado do Tratamento
16.
Biosens Bioelectron ; 148: 111829, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31710959

RESUMO

Glutathione (GSH) plays a variety of vital functions in biological systems. Growth-associated change of GSH level in cells might be critical for cell survival and monitoring of GSH in living cells are of great significance for understanding the dynamic link between GSH and some diseases. In this work, chitason micelles templated gold nanoclusters (CM-Au NCs) emitting red fluorescence were prepared with a simple and rapid method, which shows interesting phenomenon of aggregation induced emission (AIE) affected by the size of the chitosan micelles. The unique CM-Au NCs can be used to develop turn-off fluorescent probe for detecting GSH in human serum and living cells based on the reverse process of AIE of CM-Au NCs, completely different from the principle of aggregation caused quenching (ACQ) effect, which can distinguish GSH from other biothiols (cysteine and homocysteine) and quantitatively detect GSH concentration of human serum in healthy people and cancer patients with high sensitivity. The practical application of fluorescent CM-Au NCs for cellular imaging and detecting GSH level indicates ultra-trace changes of GSH levels in normal and cancer cells could be monitored at different growth stages, which reveals that the levels of GSH in cancer cells was always higher than that of normal cells. Compared with commercial GSH assay kits for detection GSH in human serum and living cells, the proposed method was verified to be accuracy and precision. The results not only reflect the changes of GSH during cell growth at different stages, but also demonstrate the feasibility of reverse process of AIE of CM-Au NCs for detection GSH. This strategy would provide a platform to understand the dynamic link between GSH and disease to clarify the disease mechanism.


Assuntos
Corantes Fluorescentes/química , Glutationa/análise , Glutationa/sangue , Ouro/química , Nanopartículas Metálicas/química , Técnicas Biossensoriais/métodos , Linhagem Celular , Humanos , Limite de Detecção , Nanopartículas Metálicas/ultraestrutura , Micelas , Microscopia Confocal/métodos , Imagem Óptica/métodos
17.
J Pharm Biomed Anal ; 177: 112871, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31539712

RESUMO

Osimertinib is a "third-generation'' oral, irreversible, tyrosine kinase inhibitor. It is used in the treatment of non-small cellular lung carcinoma and spares wild-type EGFR. Due to its reactive nature, osimertinib is, in addition to oxidative routes, metabolized through GSH coupling and subsequent further metabolism of these conjugates. The extent of the non-oxidative metabolism of osimertinib is unknown, and methods to quantify this metabolic route have not been reported yet. To gain insight into this metabolic route, a sensitive bioanalytical assay was developed for osimertinib, the active desmethyl metabolite AZ5104, and the thio-metabolites osimertinibs glutathione, cysteinylglycine, and cysteine conjugates was developed. The ease of synthesis of these metabolites was a key-part in the development of this assay. This was done through simple one-step synthesis and subsequent LC-purification. The compounds were characterized by NMR and high-resolution mass spectrometry. Sample preparation was done by a simple protein crash with acetonitrile containing the stable isotopically labeled internal standards for osimertinib and the thio-metabolites, partial evaporation of solvents, and reconstitution in eluent, followed by UHPLC-MS/MS quantification. The assay was successfully validated in a 2-2000 nM calibration range for all compounds except the glutathione metabolite, where the LLOQ was set at 6 nM due to low accuracy at 2 nM. Limited stability was observed for osimertinib, AZ5104, and the glutathione metabolite. The clinical applicability of the assay was demonstrated in samples of patients treated with 80 mg osimertinib once daily, containing all investigated compounds at detectable and quantifiable levels.


Assuntos
Acrilamidas/farmacocinética , Compostos de Anilina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Acrilamidas/administração & dosagem , Acrilamidas/sangue , Acrilamidas/metabolismo , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/sangue , Compostos de Anilina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Cromatografia Líquida de Alta Pressão/métodos , Dipeptídeos/sangue , Dipeptídeos/síntese química , Dipeptídeos/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Glutationa/sangue , Glutationa/síntese química , Glutationa/metabolismo , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/metabolismo , Espectrometria de Massas em Tandem/métodos
18.
Talanta ; 207: 120294, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594563

RESUMO

Dual-functional nanosensors based on small molecule regulation can be widely used due to their simplicity, high sensitivity and selectivity. Herein, glutathione (GSH) calibrated dual-functional system for GSH and cadmium ions (Cd2+) detection based on fluorescence resonance energy transfer (FRET) between NH2-NaYF4:Yb,Er/NaYF4@SiO2 upconversion nanoparticles (UCNPs) and gold nanoparticles (AuNPs) is designed. Unmodified AuNPs are easy to aggregate in high-salt solution and thereby quenching the red emission of UCNPs. The presence of GSH prevents the aggregation of AuNPs, so GSH can be detected by the changes in the color of solution and the recovery of red emission of UCNPs. However, Cd2+ can interact with GSH, which makes AuNPs easy to aggregate, resulting in a gradual decrease in red emission of UCNPs. The fluorescence response of the system is linear with the concentrations of GSH and Cd2+ in a wide range of concentrations, with low detection limits of 0.016 µM and 0.059 µM, respectively. Furthermore, the nanosensor demonstrates high selectivity for GSH and Cd2+ detection and can be applied for the detection of GSH in human plasma and Cd2+ in drinking water.


Assuntos
Cádmio/análise , Transferência Ressonante de Energia de Fluorescência , Fluoretos/química , Glutationa/análise , Ouro/química , Nanopartículas Metálicas/química , Dióxido de Silício/química , Ítrio/química , Água Potável/química , Glutationa/sangue , Humanos
19.
Talanta ; 207: 120349, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594572

RESUMO

In this work, for the first time, the direct usability of natural products, catechins (CT) and cocoa powder (CO), as electrochemical mediators able to modify a carbon black modified screen-printed electrode (SPE-CB) is proved, and, as proof of applicability, free (GSH) and total glutathione (GSH + GSSG) in blood samples is successfully determined. Noteworthy, the cocoa powder (naturally rich in catechins), dissolved in DMSO, was able to give rise to a useful highly redox-active catechol-quinone surface-confined system onto a carbon black nanoparticles modified screen-printed electrode (SPE-CB-CO - Cocoatrode), giving rise to a similar behaviour obtained with pure catechins (SPE-CB-CT). The electrodeposition process has been carefully studied, the resulting immobilized natural mediator (obtained using both CT and CO) features investigated, and the performance of the resulting sensors (SPE-CB-CT and Cocoatrode) tested and compared. Both modified electrodes (SPE-CB-CT and Cocoatrode) have a good inter-electrodes precision (RSD ip,a ≤ 4.2%, n = 3) and intra-electrodes repeatability (RSD ip,a ≤ 3.9%, n = 20), indicating a robust and stable 'fabrication' strategy. Finally, SPE-CB-CT and Cocoatrode have been employed for the detection of free (GSH) and total (GSH+GSSG) glutathione in blood samples, using differential pulse voltammetry decrease in the mediator's reduction peak (Δi %), as analytical signal. Analytical curves (R2 ≥ 0.998), for the GSH detection, have been determined both with SPE-CB-CT and Cocoatrode in the 2.5 × 10-8-6.0 × 10-5 M and 5.0 × 10-8-1.0 × 10-4 M concentration ranges, respectively. Limits of detections (LODs) were ≤2.6 × 10-8 M. GSH (free and total) determined in blood samples, by the proposed CT and CO sensors, showed a good intra-electrode repeatability (RSD ip,a ≤ 9.0%, n = 3), with good recoveries (from 88.3% to 117.7%). The values obtained were in agreement with a classical spectrophotometric method (GSH and GSSG concentration relative error between -4.7 and +9.8%). The SPE-CB-CT and the Cocoatrode platforms demonstrated high potentiality in sensing and biosensing scenario, opening new gates to the natural/food products employment as unconventional, eco-friendly and economically affordable analytical active tools.


Assuntos
Análise Química do Sangue/instrumentação , Catequina/química , Chocolate , Glutationa/sangue , Impressão , Fuligem/química , Eletroquímica , Eletrodos , Glutationa/química
20.
Talanta ; 207: 120311, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594615

RESUMO

Detection of glutathione in human serum is of great importance for clinical diagnosis of various diseases, such as AIDS, diabetes mellitus, Alzheimer disease and cancer. In this work, a new water-soluble bismacrocyclic polyamine-derived compound, namely L, which contains two molecules of 4-nitro-1,2,3-benzoxa-diazole as the fluorophores, was designed and prepared. The experiments of selectivity of L toward metal ions showed it could rapidly and sensitively detect Hg2+ with a detection limit of 27 nM. Furthermore, the cell imaging and co-staining experiments in HeLa cells demonstrated that the L-Hg2+ probe had selectivity for the Golgi apparatus to a certain degree. Moreover, it had excellent selectivity for biothiols, especially for glutathione. Finally, the probe was successfully applied to sensitively detect glutathione (GSH) in human serum and fetal bovine serum.


Assuntos
Corantes Fluorescentes/química , Glutationa/sangue , Limite de Detecção , Compostos Macrocíclicos/química , Mercúrio/sangue , Poliaminas/química , Glutationa/química , Humanos , Mercúrio/química , Imagem Óptica
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