Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58.656
Filtrar
1.
Amino Acids ; 54(1): 33-46, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34993628

RESUMO

Sodium chlorate (NaClO3) is a common non-selective herbicide that is also used in paper and pulp mills and is produced as a by-product during drinking water disinfection by chlorine dioxide. Here, we report the effect of dietary antioxidant taurine on NaClO3-induced cytotoxicity in human red blood cells (RBC). RBC were treated with 5 mM NaClO3, either alone or in presence of 1, 2.5 and 5.0 mM taurine. Incubation of RBC with NaClO3 alone caused hemolysis, increased oxidation of lipids and proteins, methemogobin level and decreased total sulfhydryl and glutathione content. It lowered the activities of antioxidant enzymes thioredoxin reductase, glutathione peroxidase, catalase and glutathione reductase, while Cu-Zn superoxide dismutase activity was increased. The antioxidant capacity of RBC was impaired. This strongly suggests that NaClO3 causes the induction of oxidative stress condition in RBC. The specific activities of lactate dehydrogenase, glucose 6-phosphate dehydrogenase and plasma membrane bound enzymes, were also greatly altered. However, prior treatment of RBC with taurine conferred significant protection against NaClO3-induced oxidative damage and also improved the antioxidant defence system of cells. These results were supported by electron microscopy images of RBC. Treatment with NaClO3 alone converted the normal biconcave discoidal RBC to acanthocytes and echinocytes but this transformation was greatly prevented in the presence of taurine. Thus, taurine mitigates the cytotoxicity of NaClO3 in human RBC and can function as an effective chemoprotectant.


Assuntos
Cloratos , Taurina , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cloratos/metabolismo , Cloratos/farmacologia , Eritrócitos , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos , Estresse Oxidativo , Taurina/metabolismo , Taurina/farmacologia
2.
Nanotechnology ; 33(23)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35193121

RESUMO

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Células Endoteliais/patologia , Feminino , Glutationa , Humanos , Isoquinolinas , Nanopartículas/química , Fármacos Fotossensibilizantes , Porfirinas/química , Pirazóis , Pirimidinas
3.
J Toxicol Sci ; 47(5): 169-181, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35527005

RESUMO

Dexmedetomidine (DEX) protects against acute stress-induced liver injury, but what's less clear lies in the specific mechanism. To elucidate the specific mechanism underlying DEX on acute stress-induced liver injury, an in vivo model was constructed on rats with acute stress-induced liver injury by 15 min of exhaustive swimming and 3 hr of immobilization. DEX (30 µg/kg) or miR-34a-5p agomir was injected into model rats. Open field test was used to verify the establishment of the model. Liver injury was observed by hematoxylin-eosin (H&E) staining. Contents of norepinephrine (NE), alanine aminotransfease (ALT) and aspartate aminotransferase (AST) in serum of rats were detected by enzyme-linked immunosorbent assay (ELISA) and those of oxidative stress markers (reactive oxygen species (ROS), Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPX)) were measured using commercial kits. Apoptosis of hepatocytes was detected by Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Western blot was performed to detect the expressions of SOD2, COX-2, cytochrome C, Cleaved caspase 3, Bax, Bcl-2, P-JNK, JNK, P-p38, p38 and c-AMP, p-PKA and PKA in liver tissues. As a result, liver injury in model rat was alleviated by DEX. DEX attenuated the increase in the levels of NE, ALT, AST, MDA, ROS, apoptosis, SOD2, COX-2, Cytochrome C, cleaved caspase 3, Bax, and P-JNK, P-p38, c-AMP, P-PKA and miR-34a-5p, and the decrease in the levels of SOD, GPX, GSH and Bcl-2 in model rats. Furthermore, miR-34a-5p overexpression could partly reverse the effects of DEX. Collectively, DEX could alleviate acute stress-induced liver injury through ROS/JNK/p38 signaling pathway via downregulation of miR-34a-5p.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Dexmedetomidina , MicroRNAs , Monofosfato de Adenosina/farmacologia , Animais , Apoptose , Caspase 3/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocromos c/metabolismo , Dexmedetomidina/farmacologia , Glutationa/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/metabolismo
4.
Biomed Res Int ; 2022: 4359645, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35528170

RESUMO

Vacuole compartmentalization plays an important role in the storage of heavy metals in hyperaccumulators. Is the vacuolar compartmentation a simple shielding process or a dynamic process that continuously consumes cell sap resources? How does glutathione affect the process of vacuolar compartmentalization? These unknown questions are very important to understand the mechanism of vacuole compartmentalization and can provide a guide for the design of hyperaccumulator plants by genetic engineering. Therefore, this study explored the enzyme activities, total cadmium, Cd2+, glutathione, oxidized glutathione, and reactive oxygen species contents in protoplasts and vacuoles of leaf cells in Solanum nigrum L. through subcellular separation. The results showed that vacuolar compartmentalization was a dynamic process that actively induced the related substances produced by cell sap to enter the vacuole for detoxification. When regulating the decreased glutathione content with buthionine sulfoximine, the total cadmium and combined cadmium in protoplasm decreased significantly, but the vacuole still maintained a high proportion of cadmium content and stable ROS content, which indicated that various external resources were preferentially used to maintain cadmium storage and homeostasis in vacuole rather than outside vacuole. These findings could guide the use of genetic engineering to design hyperaccumulator plants.


Assuntos
Poluentes do Solo , Solanum nigrum , Biodegradação Ambiental , Cádmio/análise , Glutationa/farmacologia , Plantas , Poluentes do Solo/análise , Solanum nigrum/genética , Vacúolos
5.
Biomed Res Int ; 2022: 8962149, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35528172

RESUMO

This study examined the protective effect of quercetin against high-altitude-induced brain damage in rats. A molecular docking study was performed to investigate the potential effect of quercetin in reducing brain damages through its ability to target the oxidative stress enzymes. Biomarker assessment screening assays were also performed then followed by in vivo studies. Three groups of rats were divided into the control group, an untreated animal model group with induced brain damage, and finally, the quercetin treated group that received quercetin dose equal to 20 mg/kg of their body weights. Molecular docking studies and biomarker assessment screening assays proved the potential effect of quercetin to affect the level of representative biomarkers glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). Additionally, the protective effect of quercetin against high altitude, low pressure, and low oxygen was also investigated by exploring the brain histopathology of experimental rats. Brain damage was observed in the untreated animal model group. After treatment with quercetin, the cerebral edema in the brain tissues was improved significantly, confirming the protective effects of quercetin. Therefore, quercetin can be used as a natural food additive to protect from the highaltitude-induced brain damage.


Assuntos
Lesões Encefálicas , Quercetina , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Lesões Encefálicas/tratamento farmacológico , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo , Quercetina/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
6.
Acta Cir Bras ; 37(2): e370208, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35507972

RESUMO

PURPOSE: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. METHODS: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). RESULTS: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. CONCLUSIONS: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.


Assuntos
Melatonina , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Caspase 3/metabolismo , Cisplatino/toxicidade , Glutationa/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
7.
Sci Rep ; 12(1): 7336, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513409

RESUMO

Cells are exposed to oxidative stress and reactive metabolites every day. The Nrf2 signaling pathway responds to oxidative stress by upregulation of antioxidants like glutathione (GSH) to compensate the stress insult and re-establish homeostasis. Although mechanisms describing the interaction between the key pathway constituents Nrf2, Keap1 and p62 are widely reviewed and discussed in literature, quantitative dynamic models bringing together these mechanisms with time-resolved data are limited. Here, we present an ordinary differential equation (ODE) based dynamic model to describe the dynamic response of Nrf2, Keap1, Srxn1 and GSH to oxidative stress caused by the soft-electrophile diethyl maleate (DEM). The time-resolved data obtained by single-cell confocal microscopy of green fluorescent protein (GFP) reporters and qPCR of the Nrf2 pathway components complemented with siRNA knock down experiments, is accurately described by the calibrated mathematical model. We show that the quantitative model can describe the activation of the Nrf2 pathway by compounds with a different mechanism of activation, including drugs which are known for their ability to cause drug induced liver-injury (DILI) i.e., diclofenac (DCF) and omeprazole (OMZ). Finally, we show that our model can reveal differences in the processes leading to altered activation dynamics amongst DILI inducing drugs.


Assuntos
Hepatócitos , Fator 2 Relacionado a NF-E2 , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo
8.
Parasite ; 29: 24, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35532265

RESUMO

The thioredoxin (Trx) and the glutathione (GSH) systems represent important antioxidant systems in cells and in particular thioredoxin reductase (TrxR) has been shown to constitute a promising drug target in parasites. For the facultative protozoal pathogen Acanthamoeba, it was demonstrated that a bacterial TrxR as well as a TrxR, characteristic of higher eukaryotes, mammals and humans is expressed on the protein level. However, only bacterial TrxR is strongly induced by oxidative stress in Acanthamoeba castellanii. In this study, the impact of oxidative stress on key enzymes involved in the thioredoxin and the glutathione system of A. castellanii under different culture conditions and of clinical Acanthamoeba isolates was evaluated on the RNA level employing RT-qPCR. Additionally, the effect of auranofin, a thioredoxin reductase inhibitor, already established as a potential drug in other parasites, on target enzymes in A. castellanii was investigated. Oxidative stress induced by hydrogen peroxide led to significant stimulation of bacterial TrxR and thioredoxin, while diamide had a strong impact on all investigated enzymes. Different strains displayed distinct transcriptional responses, rather correlating to sensitivity against the respective stressor than to respective pathogenic potential. Culture conditions appear to have a major effect on transcriptional changes in A. castellanii. Treatment with auranofin led to transcriptional activation of the GSH system, indicating its role as a potential backup for the Trx system. Altogether, our data provide more profound insights into the complex redox system of Acanthamoeba, preparing the ground for further investigations on this topic.


Title: Modifications transcriptionnelles des protéines des système thiorédoxine et glutathion chez Acanthamoeba spp. sous stress oxydatif ­ une approche par l'ARN. Abstract: Les systèmes de la thiorédoxine (Trx) et du glutathion (GSH) représentent des systèmes antioxydants importants dans les cellules et, en particulier, la thiorédoxine réductase (TrxR) s'est avérée constituer une cible médicamenteuse prometteuse chez les parasites. Pour le pathogène protozoaire facultatif Acanthamoeba, il a été démontré qu'une TrxR bactérienne ainsi qu'une TrxR, caractéristique des eucaryotes supérieurs, des mammifères et des humains, s'expriment au niveau protéique. Cependant, seule la TrxR bactérienne est fortement induite par le stress oxydatif chez Acanthamoeba castellanii. Dans cette étude, l'impact du stress oxydatif sur les enzymes clés impliquées dans la thiorédoxine et le système glutathion d'A. castellanii dans différentes conditions de culture et d'isolats cliniques d'Acanthamoeba a été évalué au niveau de l'ARN en utilisant la RT-qPCR. De plus, l'effet de l'auranofine, un inhibiteur de la thiorédoxine réductase déjà établi comme médicament potentiel chez d'autres parasites, a été étudié sur les enzymes cibles chez A. castellanii. Le stress oxydatif induit par le peroxyde d'hydrogène a conduit à une stimulation significative du TrxR bactérien et de la thiorédoxine tandis que le diamide a eu un fort impact sur toutes les enzymes étudiées. Différentes souches ont affiché des réponses transcriptionnelles distinctes, plutôt corrélées à la sensibilité contre le facteur de stress respectif qu'à leur potentiel pathogène respectif. Les conditions de culture semblent avoir un effet majeur sur les changements transcriptionnels chez A. castellanii. Le traitement à l'auranofine a conduit à une activation transcriptionnelle du système GSH, indiquant son rôle de sauvegarde potentielle pour le système Trx. Dans l'ensemble, nos données fournissent des informations plus approfondies sur le système redox complexe d'Acanthamoeba, préparant le terrain pour de nouvelles investigations sur ce sujet.


Assuntos
Acanthamoeba , Tiorredoxina Dissulfeto Redutase , Acanthamoeba/genética , Animais , Auranofina/farmacologia , Glutationa , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Estresse Oxidativo , RNA , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxina Dissulfeto Redutase/farmacologia , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Tiorredoxinas/farmacologia
9.
Redox Rep ; 27(1): 111-118, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35535549

RESUMO

Objectives: This study investigated the impact of rohypnol on gastric tissue integrity.Methods: Forty male Wistar rats were randomized into control, low dose rohypnol-treated, high dose rohypnol-treated, low dose rohypnol-treated recovery and high dose rohypnol-treated recovery groups.Results: Rohypnol caused significant rise in gastric malondialdehyde (MDA), oxidized glutathione (GSSG), nitric oxide (NO), tumour necrotic factor-α (TNF-α), and interleukin-6 (IL-6) levels. Also, rohypnol caused reductions in gastric reduced glutathione (GSH) (as well as GSH/GSSG), and activities of superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), glutathione peroxidase (GPx), cyclo-oxygenase (COX-2). Furthermore, rohypnol upregulated caspase 3 activity and induced gastric DNA damage, evident by a rise in 8-hydroxydeoxyguanosine (8-OHdG) and DNA fragmentation index (DFI) in gastric tissue. These alterations were coupled with reduced gastric weight and distorted gastric cytoarchitecture. Cessation of rohypnol caused a significant but not complete reversal of rohypnol-induced gastric damage.Conclusion: This study revealed that rohypnol induced gastric injury by suppressing glutathione content and COX-2 activity, and upregulating caspase 3-dependent apoptosis, which was partly reversed by rohypnol withdrawal.


Assuntos
Flunitrazepam , Glutationa , Animais , Apoptose , Caspase 3/metabolismo , Ciclo-Oxigenase 2/genética , Glutationa/metabolismo , Dissulfeto de Glutationa , Glutationa Peroxidase/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Regulação para Cima
10.
Artigo em Chinês | MEDLINE | ID: mdl-35545590

RESUMO

Objective: To explore the expulsion effect of sodium dimercaptopropanesulfonate (DMPS) on mercury in different organs of mercury poisoning and the therapeutic effect of glutathione (GSH) combined with antioxidant therapy on mercury poisoning. Methods: In February 2019, 50 SPF male SD rats were randomly divided into 5 groups, 10 rats in each group: A (saline negative control group) , B (HgCL2 positive control group) , treatment group (C: intramuscular injection of DMPS 15 mg/kg treatment, D: intramuscular injection of DMPS30 mg/kg treatment, E: intramuscular injection of DMPS 15 mg/kg and intraperitoneal injection of GSH200 mg/kg treatment) . Rats in group B, C, D and E were subcutaneously injected with mercury chloride solution (1 mg/kg) to establish a rat model of subacute mercury poisoning kidney injury. Rats in group A were subcutaneously injected with normal saline. After the establishment of the model, rats in the treatment group were injected with DMPS and GSH. Rats in group A and group B were injected with normal saline. At 21 d (treatment 7 d) and 28 d (treatment 14 d) after exposure, urine and blood samples of 5 rats in each group were collected. Blood biochemistry, urine mercury, urine microalbumin and mercury content in renal cortex, cerebral cortex and cerebellum were detected. Results: After exposure to mercury, the contents of mercury in renal cortex, cerebrum and cerebellum of rats in group B, C, D and E increased, and urine microalbumin increased. Pathology showed renal tubular injury and renal interstitial inflammation. Compared with group B, urinary mercury and renal cortex mercury in group C, D and E decreased rapidly after DMPS treatment, and there was no significant decrease in mercury levels in cerebellum and cerebral cortex of rats, accompanied by transient increase in urinary albumin after DMPS treatment (P<0.05) ; the renal interstitial inflammation in group E was improved after GSH treatment. There was a positive correlation between urinary mercury and the contents of mercury in renal cortex, cerebral cortex and cerebellum (r=0.61, 0.47, 0.48, P<0.05) . Conclusion: DMPS mercury expulsion treatment can significantly reduce the level of metal mercury in the kidney, and there is no significant change in the level of metal mercury in the cortex and cerebellum.


Assuntos
Nefropatias , Intoxicação por Mercúrio , Mercúrio , Animais , Encéfalo , Feminino , Glutationa , Humanos , Inflamação , Rim , Masculino , Cloreto de Mercúrio/farmacologia , Cloreto de Mercúrio/uso terapêutico , Mercúrio/urina , Intoxicação por Mercúrio/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Solução Salina/farmacologia , Solução Salina/uso terapêutico , Unitiol/farmacologia , Unitiol/uso terapêutico
11.
Cell Death Dis ; 13(5): 440, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35523788

RESUMO

The activation of pancreatic stellate cells (PSCs) is the key mechanism of pancreatic fibrosis, which can lead to ß-cell failure. Oxidative stress is an important risk factor for PSC activation. There is no direct evidence proving if administration of glutathione can inhibit fibrosis and ß-cell failure. To explore the role of glutathione in pancreatic fibrosis and ß-cell failure induced by hyperglycaemia, we established a rat model of pancreatic fibrosis and ß-cell failure. The model was founded through long-term oscillating glucose (LOsG) intake and the setup of a sham group and a glutathione intervention group. In vitro, rat PSCs were treated with low glucose, high glucose, or high glucose plus glutathione to explore the mechanism of high glucose-induced PSC activation and the downstream effects of glutathione. Compared with sham rats, LOsG-treated rats had higher reactive oxygen species (ROS) levels in peripheral leukocytes and pancreatic tissue while TGFß signalling was upregulated. In addition, as the number of PSCs and pancreatic fibrosis increased, ß-cell function was significantly impaired. Glutathione evidently inhibited the upregulation of TGFß signalling and several unfavourable outcomes caused by LOsG. In vitro treatment of high glucose for 72 h resulted in higher ROS accumulation and potentiated TGFß pathway activation in PSCs. PSCs showed myofibroblast phenotype transformation with upregulation of α-SMA expression and increased cell proliferation and migration. Treatment with either glutathione or TGFß pathway inhibitors alleviated these changes. Together, our findings suggest that glutathione can inhibit PSC activation-induced pancreatic fibrosis via blocking ROS/TGFß/SMAD signalling in vivo and in vitro.


Assuntos
Células Estreladas do Pâncreas , Fator de Crescimento Transformador beta , Animais , Células Cultivadas , Fibrose , Glucose/metabolismo , Glucose/toxicidade , Glutationa/metabolismo , Pâncreas/patologia , Células Estreladas do Pâncreas/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo
12.
Eur Rev Med Pharmacol Sci ; 26(8): 2794-2801, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35503624

RESUMO

OBJECTIVE: The nitric oxide (NO) metabolite nitrite has been shown to attenuate hyperglycemia via its increase in insulin sensitivity and glucose uptake. However, the oral use of nitrite is limited due to its potential formation of the carcinogenic N-nitrosamines via reaction of acidic nitrite and the secondary amines. We investigated the anti-diabetic effect of sodium nitrite (SN) combined with glutathione (GSH) in streptozotocin (STZ)-induced diabetic mice for potential use of GSH as a protective agent in future nitrite therapy. MATERIALS AND METHODS: STZ-induced diabetic mice were orally treated for 5 weeks with vehicle, SN, GSH or SN + GSH. Oral glucose tolerance test and the measurement of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were carried out to evaluate anti-diabetic effects of SN and SN + GSH. Plasma levels of total NO metabolites (NOx) were measured to confirm nitrite absorption. RESULTS: SN and SN + GSH significantly improved the glucose tolerance (p < 0.05), but GSH alone did not. The efficacy of combination treatment with SN and GSH in improving the glucose tolerance was higher than that of SN alone. Oral treatment with SN or SN + GSH significant reduced FBG and HbA1c levels (p < 0.05). Interestingly, daily oral administration of SN + GSH was more effective in reducing FBG and HbA1c levels than that of SN alone. Administration of SN or SN + GSH significantly increased plasma NOx levels (p < 0.05), and combination treatment with SN + GSH was more effective in increasing plasma NOx levels than that with SN alone. CONCLUSIONS: Combination treatment with SN and GSH is more effective in controlling hyperglycemia and increasing the plasma NOx levels in an experimental mouse model of diabetes. Since oral administration of GSH has been shown to be non-toxic in humans, the combination of SN and GSH may be important in potential future nitrite therapy.


Assuntos
Diabetes Mellitus Experimental , Glutationa , Hiperglicemia , Nitrito de Sódio , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Glutationa/administração & dosagem , Hemoglobina A Glicada/metabolismo , Hiperglicemia/tratamento farmacológico , Camundongos , Óxido Nítrico/metabolismo , Nitrito de Sódio/administração & dosagem , Estreptozocina
13.
Zhongguo Zhong Yao Za Zhi ; 47(8): 2049-2055, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35531720

RESUMO

The present study investigated the mechanism of the Tibetan medicine Ershiwuwei Songshi Pills(ESP) against the liver injury induced by acetaminophen(APAP) in mice based on the kelch-like ECH-associated protein 1(Keap1)/nuclear transcription factor E2 related factor 2(Nrf2) and Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) p65 signaling pathways. Kunming mice were randomly divided into a blank control group, a model group, an N-acetyl-L-cysteine(NAC) group, and high-(400 mg·kg~(-1)), medium-(200 mg·kg~(-1)), and low-dose(100 mg·kg~(-1)) ESP groups. After 14 days of continuous administration, except for those in the control group, the mice were intraperitoneally injected with 200 mg·kg~(-1) APAP. After 12 h, the serum and liver tissues of mice were collected. Hematoxylin-eosin(HE) staining was performed on pathological sections of the liver, and the levels of aspartate aminotransferase(AST) and alanine aminotransferase(ALT) in the serum and the levels of glutathione(GSH), malondialdehyde(MDA), superoxide dismutase(SOD), catalase(CAT), myeloperoxidase(MPO), and total antioxidant capacity(T-AOC) in liver tissue homogenate were detected to observe and analyze the protective effect of ESP on APAP-induced liver injury in mice. The serum levels of tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1ß), and interleukin-6(IL-6) were determined by enzyme-linked immunosorbent assay(ELISA). The protein expression of Nrf2, Keap1, TLR4, and NF-κB p65 in the liver was determined by Western blot. Quantitative real-time was used to determine the mRNA expression of glutamate-cysteine ligase catalytic subunit(GCLC), glutamate-cysteine ligase regulatory subunit(GCLM), heme oxygenase-1(HO-1), and NAD(P)H dehydrogenase quinone 1(NQO-1) in the liver to explore the mechanism of ESP in improving APAP-induced liver damage in mice. As revealed by results, compared with the model group, the ESP groups showed improved liver pathological damage, decreased ALT and AST levels in the serum and MDA and MPO content in the liver, increased GSH, SOD, CAT, and T-AOC in the liver, reduced TNF-α and IL-6 levels in the serum, down-regulated expression of Keap1 in the liver cytoplasm and NF-κB p65 in the liver nucleus, up-regulated expression of Nrf2 in the liver nucleus, insignificant change in TLR4 expression, and elevated relative mRNA expression levels of antioxidant genes GCLC, GCLM, HO-1, and NQO-1. ESP can reduce the oxidative damage and inflammation caused by APAP, and the mechanism may be related to the Keap1/Nrf2 signaling pathway and the signal transduction factors on the TLR4/NF-κB p65 pathway.


Assuntos
Acetaminofen , Fator 2 Relacionado a NF-E2 , Acetaminofen/toxicidade , Animais , Antioxidantes/farmacologia , Glutamato-Cisteína Ligase/metabolismo , Glutamato-Cisteína Ligase/farmacologia , Glutationa , Interleucina-6/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fígado , Medicina Tradicional Tibetana , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(3): 271-279, 2022 Mar 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-35545319

RESUMO

OBJECTIVES: Liver disease is the most common extra-intestinal manifestation of ulcerative colitis (UC), but the underlying pathogenesis is still not clarified. It is well accepted that the occurrence of UC-related liver disease has close correlation with immune activation, intestinal bacterial liver translocation, inflammatory cytokine storm, and the disturbance of bile acid circulation. The occurrence of UC-related liver disease makes the therapy difficult, therefor study on the pathogenesis of UC-related liver injury is of great significance for its prevention and treatment. Glutathione (GSH) shows multiple physiological activities, such as free radical scavenging, detoxification metabolism and immune defense. The synthesis and the oxidation-reduction all contribute to GSH antioxidant function. It is reported that the deficiency in hepatic GSH antioxidant function participates in multiple liver diseases, but whether it participates in the pathogenesis of UC-related liver injury is still not clear. This study aims to investigate the feature and underlying mechanism of GSH synthesis and oxidation-reduction function during the development of UC, which will provide useful information for the pathogenesis study on UC-related liver injury. METHODS: UC model was induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS)-ethanol solution (5 mg/0.8 mL per rat, 50% ethanol) via intra-colonic administration in rats, and the samples of serum, liver, and colon tissue of rats were collected at the 3rd, 5th, and 7th days post TNBS. The severity degree of colitis was evaluated by measuring the disease activity index, colonic myeloperoxidase activity, and histopathological score, and the degree of liver injury was evaluated by histopathological score and the serum content of alanine aminotransferase. Spearman correlation analysis was also conducted between the degree of colonic lesions and index of hepatic histopathological score as well as serum aspartate aminotransferase level to clarify the correlation between liver injury and colitis. To evaluate the hepatic antioxidant function of GSH in UC rats, hepatic GSH content, enzyme activity of GSH peroxidase (GSH-Px), and GSH reductase (GR) were determined in rats at the 3rd, 5th, and 7th days post TNBS, and the protein expressions of glutamine cysteine ligase (GCL), GSH synthase, GSH-Px, and GR in the liver of UC rats were also examined by Western blotting. RESULTS: Compared with the control, the disease activity index, colonic myeloperoxidase activity, and histopathological score were all significantly increased at the 3rd, 5th, and 7th days post TNBS (all P<0.01), the serum aspartate aminotransferase level and hepatic histopathologic score were also obviously elevated at the 7th day post TNBS (all P<0.05). There was a significant positive correlation between the degree of liver injury and the severity of colonic lesions (P=0.000 1). Moreover, compared with the control, hepatic GSH content and the activity of GSH-Px and GR were all significantly decreased at the 3rd and 5th days post TNBS (P<0.05 or P<0.01), and the protein expressions of GCL, GSH-Px, and GR were all obviously down-regulated at the 3rd, 5th, and 7th days post TNBS (P<0.05 or P<0.01). CONCLUSIONS: There is a significant positive correlation between the degree of liver injury and the severity of colonic lesions, and the occurrence of reduced hepatic GSH synthesis and decreased GSH reduction function is obviously earlier than that of the liver injury in UC rats. The reduced hepatic expression of enzymes that responsible for GSH synthesis and reduction may contribute to the deficiency of GSH synthesis and oxidation-reduction function, indicating that the deficiency in GSH antioxidant function may participate in the pathogenesis of UC related liver injury.


Assuntos
Colite Ulcerativa , Colite , Animais , Antioxidantes , Aspartato Aminotransferases , Colite/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/patologia , Etanol/efeitos adversos , Etanol/metabolismo , Glutationa/efeitos adversos , Glutationa/metabolismo , Fígado/metabolismo , Peroxidase/metabolismo , Ratos , Ácido Trinitrobenzenossulfônico/efeitos adversos , Ácido Trinitrobenzenossulfônico/metabolismo
15.
J Oleo Sci ; 71(5): 709-720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35491096

RESUMO

Current time obesity is the major challenges globally and the incidence of the obesity has raised dramatically in current years. The obesity enhanced the various metabolic diseases such as diabetes, cardiac, cancer and steatohepatitis. Natural drug having the long history to ameliorate the obesity and its related metabolic disorder. In this experimental study, we scrutinized the anti-obesity effect of nimbolide against high fat diet (HFD) induced obesity in rats. Wistar rats were divided into 5 groups and each group contains 10 rats. The body weight, tissue weight was estimated at regular time. Carbohydrate, lipid, hepatic, inflammatory cytokines, antioxidant and inflammatory parameters were estimated. The mRNA expression was also estimated. Nimbolide treated groups significantly (p < 0.001) suppressed the body weight at dose dependent manner. Nimbolide significantly (p < 0.001) reduced the hepatic parameters and altered the antioxidant parameters such as thiobarbituric acid reactive substances (TBARS), glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), superoxide mutase (SOD), glutathione S transferase (GST); decreased the level of inflammatory cytokines (IL-1ß, IL-6, TNF-α). Nimbolide suppressed the mRNA expression of glucose-6-phosphatase HO-1 and nuclear factor erythroid-2 related factor-2 (Nrf2). Collectively, we can say that nimbolide having the capability to suppressed the HFD induced obesity via Nrf2/HO-1 pathway.


Assuntos
Dieta Hiperlipídica , Fator 2 Relacionado a NF-E2 , Animais , Antioxidantes/uso terapêutico , Citocinas , Dieta Hiperlipídica/efeitos adversos , Glutationa/metabolismo , Limoninas , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , RNA Mensageiro , Ratos , Ratos Wistar
16.
Biomed Res Int ; 2022: 4122166, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35496049

RESUMO

Drug-induced liver injury (DILI) is the main cause of liver damage mediated by the excretion of toxic active drug metabolites. Omega-3 fatty acids and vitamin C have potent antioxidant, anti-inflammatory, and antiapoptotic effects that could offer protection against oxidative stress and liver damage. This study evaluated the hepatoprotective effect of omega-3 and vitamin C alone as well as in a combined form in methotrexate- (MTX-) induced acute liver injury in mice. Male ICR mice of seven groups (7 mice per group) were used. Groups 1 (control group) and 2 (MTX) received 0.9% saline/day (po) for 9 days. Groups 3 and 4 received 100 and 200 mg/kg bw/day omega-3 (po), respectively, for 9 days. Groups 5 and 6 received 100 and 200 mg/kg bw/day vitamin C (po), respectively, for 9 days, while group 7 received omega-3 (100 mg/kg bw/day) and vitamin C (100 mg/kg bw/day) (po) for 9 days. All animals in groups 2 to 7 received 20 mg/kg/day MTX (I.P.) once on the 10th day. Our results revealed that MTX significantly induced the elevation of transaminases, alkaline phosphates (ALP), lactate dehydrogenase (LDH), and malonaldehyde (MDA) while depleting the levels of superoxide dismutase (SOD) and glutathione (GSH) when compared to the control group. Treatment with omega-3 fatty acids or vitamin C significantly attenuated the antioxidants and biochemical alterations in a dose-independent manner. Our molecular docking study of ligand-receptor interaction revealed that both ascorbic acid and omega-3 docked well to the binding cavity of LDH with high binding affinities of -5.20 and -4.50 kcal/mol, respectively. The histopathological features were also improved by treatment with omega-3 and vitamin C. The combined form of omega-3 and vitamin C showed a remarkable improvement in the liver enzymes, oxidative stress biomarkers, and the histopathological architecture of the mice. Conclusively, the combination of omega-3 and vitamin C demonstrated a synergistic therapeutic effect against MTX-intoxicated mice, hence representing a potential novel strategy for the management of drug-induced liver disorders.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Ácidos Graxos Ômega-3 , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Glutationa/metabolismo , Masculino , Metotrexato/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estresse Oxidativo , Vitaminas/farmacologia
17.
Biochemistry (Mosc) ; 87(2): 91-105, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35508905

RESUMO

The study was aimed to evaluate the impact of peroxynitrite (PON, oxidative stress agent in diabetes), methylglyoxal (MGO, diabetes-associated reactive carbonyl compound), and their simultaneous application on the structural and functional features of human αA-crystallin (αA-Cry) using various spectroscopy techniques. Additionally, the surface tension and oligomer size distribution of the treated and untreated protein were tested using tensiometric analysis and dynamic light scattering, respectively. Our results indicated that the reaction of PON and MGO with human αA-Cry leads to the formation of new chromophores, alterations in the secondary to quaternary protein structure, reduction in the size of protein oligomers, and significant enhancement in the chaperone activity of αA-Cry. To reverse the effects of the tested compounds, ascorbic acid and glutathione (main components of lens antioxidant defense system) were applied. As expected, the two antioxidant compounds significantly prevented formation of high molecular weight aggregates of αA-Cry (according to SDS-PAGE). Our results suggest that the lens antioxidant defense system, in particular, glutathione, may provide a strong protection against rapid incidence and progression of diabetic cataract by preventing the destructive reactions of highly reactive DM-associated metabolites.


Assuntos
Cristalinas , Diabetes Mellitus , Cadeia A de alfa-Cristalina , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cristalinas/química , Cristalinas/metabolismo , Glutationa/metabolismo , Humanos , Óxido de Magnésio , Estresse Oxidativo , Cadeia A de alfa-Cristalina/química
18.
Food Chem ; 386: 132756, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35509159

RESUMO

A fast, sensitive and reproducible method using LC-MS/MS for simultaneous quantification of glutathione (GSH), glutathione disulfide (GSSG) and glutathione-S-sulfonate (GSSO3H) was developed, optimised and applied in analysis of grape juice and wine samples. The results show that only GSH (10-60 mg·L-1) and GSSG (2-11 mg·L-1) are found in grape juice when SO2 is not added. GSSO3H was detected in must samples treated with SO2 but only at a low concentration (<1 mg L-1). In the wine samples, the dominant form of glutathione was GSSO3H (5-11 mg L-1), followed by GSH (0-5 mg L-1) and GSSG (0-6 mg L-1), underscoring the importance of GSSO3H quantification. GSSO3H formation in wine was correlated with the total SO2 level in the wine. We believe this is the first report on GSSO3H quantification in wine.


Assuntos
Vitis , Vinho , Cromatografia Líquida , Glutationa/análise , Dissulfeto de Glutationa/análise , Espectrometria de Massas em Tandem , Vinho/análise
19.
Nat Commun ; 13(1): 2483, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513392

RESUMO

The SLC25 carrier family consists of 53 transporters that shuttle nutrients and co-factors across mitochondrial membranes. The family is highly redundant and their transport activities coupled to metabolic state. Here, we use a pooled, dual CRISPR screening strategy that knocks out pairs of transporters in four metabolic states - glucose, galactose, OXPHOS inhibition, and absence of pyruvate - designed to unmask the inter-dependence of these genes. In total, we screen 63 genes in four metabolic states, corresponding to 2016 single and pair-wise genetic perturbations. We recover 19 gene-by-environment (GxE) interactions and 9 gene-by-gene (GxG) interactions. One GxE interaction hit illustrates that the fitness defect in the mitochondrial folate carrier (SLC25A32) KO cells is genetically buffered in galactose due to a lack of substrate in de novo purine biosynthesis. GxG analysis highlights a buffering interaction between the iron transporter SLC25A37 (A37) and the poorly characterized SLC25A39 (A39). Mitochondrial metabolite profiling, organelle transport assays, and structure-guided mutagenesis identify A39 as critical for mitochondrial glutathione (GSH) import. Functional studies reveal that A39-mediated glutathione homeostasis and A37-mediated mitochondrial iron uptake operate jointly to support mitochondrial OXPHOS. Our work underscores the value of studying family-wide genetic interactions across different metabolic environments.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Galactose , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Glutationa , Homeostase , Ferro , Proteínas de Membrana Transportadoras/genética
20.
Sci Rep ; 12(1): 7266, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508557

RESUMO

Soil salinization is a growing problem for agriculture worldwide and carrot is one the most salt-sensitive vegetable species. However, some varieties are capable of withstanding high salt concentrations due to unknown genetic and physiological mechanisms. The aim of this work was to reveal protecting mechanisms against osmotic and ionic stresses that contribute to salt tolerance in carrot. For this purpose, changes in biochemical traits due to soil salinity occurring in the salt-tolerant and salt-sensitive plants were determined. The obtained results showed that the tolerance of the salt-tolerant variety was partially determined constitutively, however, the exposition to saline soil triggered a physiological response that was more evident in the root than in the leaves. The most noticeable changes were the high increase in the content of osmoprotective proline and other low molecular antioxidants such as glutathione and ascorbic acid, and the decrease in the ratio of reduced to oxidized glutathione forms. These changes imply an efficient operation of the ascorbate-glutathione cycle that together with a high activity of antioxidative enzymes such as peroxidases, indicate on the induction of mechanisms associated mainly with protection against excessive reactive oxygen species.


Assuntos
Daucus carota , Salinidade , Antioxidantes , Daucus carota/genética , Glutationa , Solo/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...