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1.
Redox Biol ; 59: 102593, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36608588

RESUMO

Five out of eight human glutathione peroxidases (GPXs) are selenoproteins, representing proteins that contain selenium as part of the amino acid selenocysteine. The GPXs are important for reducing hydroperoxides in a glutathione-consuming manner and thus regulate cellular redox homeostasis. GPX1, GPX2, and GPX4 represent the three main cytosolic GPXs, but they differ in their expression patterns with GPX1 and GPX4 being expressed ubiquitously, whereas GPX2 is mainly expressed in epithelial cells. GPX1 and GPX2 have been described to reduce soluble hydroperoxides, while GPX4 reduces complex lipid hydroperoxides, thus protecting cells from lipid peroxidation and ferroptosis. But most of these data are derived from cells that are devoid of one of the isoforms and thus, compensation or other cellular effects might affect the conclusions. So far, the use of isolated recombinant human selenoprotein glutathione peroxidases in pure enzyme assays has not been employed to study their substrate specificities side by side. Using recombinant GPX1, GPX2, and GPX4 produced in E. coli we here assessed their GPX activities by a NADPH-consuming glutathione reductase-coupled assay with 17 different peroxides (all at 50 µM) as substrates. GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide. In contrast, small soluble hydroperoxides such as H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide were reduced by all three isoforms, but with approximately 10-fold higher efficiency for GPX1 in comparison to GPX2 and GPX4. Also, several fatty acid-derived hydroperoxides were reduced by all three isoforms and again GPX1 had the highest activity. Interestingly, the stereoisomerism of the fatty acid-derived hydroperoxides clearly affected the activity of the GPX enzymes. Overall, distinct substrate specificity is obvious for GPX4, but not so when comparing GPX1 and GPX2. Clearly GPX1 was the most potent isoform of the three GPXs in terms of turnover in reduction of soluble and fatty-acid derived hydroperoxides.


Assuntos
Escherichia coli , Peróxido de Hidrogênio , Humanos , Escherichia coli/genética , Escherichia coli/metabolismo , Ácidos Graxos , Glutationa , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Especificidade por Substrato
2.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674952

RESUMO

Coffee presents beneficial health properties, including antiobesity effects. However, its effects on inflammation are controversial. Hydroxycinnamic acids are the main coffee phenolic bioactive compounds. In human bioavailability studies carried out with coffee, among the most abundant compounds found in urine and plasma were the colonic metabolites, dihydrocaffeic (DHCA), dihydroferulic (DHFA), and hydroxyhippuric (HHA) acids. To understand the hepato-protective potential of these three compounds, we tested whether treatment with realistic concentrations (0.5-10 µM) were effective to counteract inflammatory process and oxidative status induced by tumor necrosis factor α (TNF-α). First, we established a novel model of inflammation/oxidation using TNF-α and HepG2 cells. Afterwards, we evaluated the activity of DHCA, DHFA, and HHA against the inflammatory/oxidative challenge through the determination of the inflammatory mediators, interleukins (IL)-6, and IL-8 and chemokines, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1, as well as the levels of biomarkers of oxidative stress, such as reactive oxygen species, reduced glutathione, and the antioxidant enzymes glutathione peroxidase and reductase. Results showed that all three compounds have a potential hepato-protective effect against the induced inflammatory/oxidative insult.


Assuntos
Café , Fenóis , Humanos , Fenóis/farmacologia , Fenóis/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Hepatócitos/metabolismo , Glutationa Peroxidase/metabolismo , Interleucina-6/metabolismo , Inflamação
3.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675129

RESUMO

Ferroptosis, characterized by excessive iron accumulation and lipid peroxidation, is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other known cell death types, such as apoptosis, necrosis, and autophagy. Emerging evidence shows that glutathione peroxidase 4 (GPX4), a critical core regulator of ferroptosis, plays an essential role in protecting cells from ferroptosis by removing the product of iron-dependent lipid peroxidation. The fast-growing studies on ferroptosis in cancer have boosted a perspective on its use in cancer therapeutics. In addition, significant progress has been made in researching and developing tumor therapeutic drugs targeting GPX4 based on ferroptosis, especially in acquired drug resistance. Selenium modulates GPX4-mediated ferroptosis, and its existing form, selenocysteine (Sec), is the active center of GPX4. This review explored the structure and function of GPX4, with the overarching goal of revealing its mechanism and potential application in tumor therapy through regulating ferroptosis. A deeper understanding of the mechanism and application of GPX4-mediated ferroptosis in cancer therapy will provide new strategies for the research and development of antitumor drugs.


Assuntos
Ferroptose , Neoplasias , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Morte Celular/fisiologia , Ferro/metabolismo , Peroxidação de Lipídeos , Neoplasias/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa/metabolismo
4.
Medicina (Kaunas) ; 59(1)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36676755

RESUMO

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.


Assuntos
Antioxidantes , Neoplasias da Bexiga Urinária , Humanos , Pessoa de Meia-Idade , Idoso , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Espécies Reativas de Oxigênio , Polimorfismo de Nucleotídeo Único/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Genótipo , Neoplasias da Bexiga Urinária/genética , Radicais Livres , Predisposição Genética para Doença , Estudos de Casos e Controles
5.
Vitam Horm ; 121: 109-141, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36707132

RESUMO

Reduced glutathione (GSH) is an essential non-enzymatic antioxidant in mammalian cells. GSH can act directly as an antioxidant to protect cells against free radicals and pro-oxidants, and as a cofactor for antioxidant and detoxification enzymes such as glutathione peroxidases, glutathione S-transferases, and glyoxalases. Glutathione peroxidases detoxify peroxides by a reaction that is coupled to GSH oxidation to glutathione disulfide (GSSG). GSSG is converted back to GSH by glutathione reductase and cofactor NADPH. GSH can regenerate vitamin E following detoxification reactions of vitamin E with lipid peroxyl radicals (LOO). GSH is a cofactor for GST during detoxification of electrophilic substances and xenobiotics. Dicarbonyl stress induced by methylglyoxal and glyoxal is alleviated by glyoxalase enzymes and GSH. GSH regulates redox signaling through reversible oxidation of critical protein cysteine residues by S-glutathionylation. GSH is involved in other cellular processes such as protein folding, protecting protein thiols from oxidation and crosslinking, degradation of proteins with disulfide bonds, cell cycle regulation and proliferation, ascorbate metabolism, apoptosis and ferroptosis.


Assuntos
Antioxidantes , Glutationa , Animais , Humanos , Antioxidantes/farmacologia , Dissulfeto de Glutationa/metabolismo , Glutationa/química , Glutationa/metabolismo , Vitamina E , Glutationa Peroxidase/metabolismo , Estresse Oxidativo , Mamíferos
6.
Chemosphere ; 316: 137779, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36632955

RESUMO

Exposure to mercury can interfere with the expression of proteins and enzymes, compromise important pathways, such as apoptosis and glucose metabolism, and even induce the expression of metallothioneins. In this study, analytical techniques were used to determine the concentration of total mercury (THg) in muscle and liver tissue, protein pellets, and spots [using graphite furnace atomic absorption spectrometry (GFAAS)], and molecular techniques were used to identify metalloproteins present in mercury-associated protein spots. Thirty individuals from three different fish species, Cichla sp. (n = 10), Brachyplatystoma filamentosum (n = 10), and Semaprochilodus sp. (n = 10) from the Brazilian Amazon were used. Oxidative stress indicators [such as glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), a marker of lipid peroxidation (LPO)] and the possible expression of metallothioneins in muscle and liver tissues were investigated. The two piscivorous species, Cichla sp. and B. filamentosum, presented the highest concentrations of mercury in their hepatic tissue, 1219 ± 15.00 and 1044 ± 13.6 µg kg-1, respectively, and in their muscle tissue, 101 ± 1.30 µg kg-1 and 87.4 ± 0.900 µg kg-1, respectively. The non-carnivorous species Semaprochilodus sp. had comparatively low concentrations of mercury in both its hepatic (852 ± 11.1 µg kg-1) and muscle (71.4 ± 0.930 µg kg-1) tissues. The presence of mercury was identified in 24 protein spots using GFAAS; concentrations ranged from 11.5 to 787 µg kg-1, and mass spectrometry identified 21 metal-binding proteins. The activities of GSH-Px, CAT, and SOD, related to oxidative stress, decreased proportionally as tissue Hg concentrations increased, while the levels of LPO markers increased, indicating the presence of stress. Our study results demonstrate possible mercury interference in oxidative stress markers (GSH-Px, CAT, SOD, and LPO), in addition to the identification of 21 metal-binding proteins as possible biomarkers of mercury exposure in fish.


Assuntos
Caraciformes , Ciclídeos , Mercúrio , Animais , Peixes/metabolismo , Mercúrio/análise , Caraciformes/metabolismo , Músculos/química , Ciclídeos/metabolismo , Superóxido Dismutase/metabolismo , Glutationa Peroxidase/metabolismo , Biomarcadores/metabolismo , Estresse Oxidativo , Fígado/metabolismo
7.
FASEB J ; 37(2): e22738, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36583727

RESUMO

Vitamin D receptor was previously reported to be protective in acute kidney injury (AKI) with the mechanism unclear, while the role of renal localized glutathione peroxidase 3 (GPX3) was not illustrated. The present study aims to investigate the role of GPX3 as well as its correlation with vitamin D-vitamin D receptor (VD-VDR) in ischemia-reperfusion (I/R)-induced renal oxidative stress injury. We showed that the expression of GPX3 and VDR were consistently decreased in renal tissues of I/R-related AKI patients and mice models. VDR agonist paricalcitol could reverse GPX3 expression and inhibit oxidative stress in I/R mice or hypoxia-reoxygenation (H/R) insulted HK-2 cells. VDR deficiency resulted in aggregated oxidative stress and severer renal injury accompanied by further decreased renal GPX3, while tubular-specific VDR overexpression remarkably reduced I/R-induced renal injury with recovered GPX3 in mice. Neither serum selenium nor selenoprotein P was affected by paricalcitol administration nor Vdr modification in vivo. In addition, inhibiting GPX3 abrogated the protective effects of VD-VDR in HK-2 cells, while GPX3 overexpression remarkably attenuated H/R-induced oxidative stress and apoptosis. Mechanistic probing revealed the GPX3 as a VDR transcriptional target. Our present work revealed that loss of renal GPX3 may be a hallmark that promotes renal oxidative stress injury and VD-VDR could protect against I/R-induced renal injury via inhibition of oxidative stress partly by trans-regulating GPX3. In addition, maintenance of renal GPX3 could be a therapeutic strategy for ischemic AKI.


Assuntos
Injúria Renal Aguda , Glutationa Peroxidase , Receptores de Calcitriol , Animais , Camundongos , Injúria Renal Aguda/metabolismo , Apoptose , Glutationa Peroxidase/metabolismo , Isquemia/metabolismo , Rim/metabolismo , Estresse Oxidativo , Receptores de Calcitriol/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
8.
Free Radic Biol Med ; 195: 158-177, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36586451

RESUMO

BACKGROUND AND OBJECTIVE: Imbalance of oxidative stress has been detected in a range of fibrotic diseases. Melatonin as an indoleamine hormone plays an important role in regulating the circadian rhythm of human, while in recent years, its antioxidant effect has also attracted increasing attention. This study aimed to perform a systematic review and meta-analysis to comprehensively evaluate the antioxidant effect of melatonin in animal models of fibrosis. METHODS: The PubMed, Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang database, China Science and Technology Journal Database (VIP), and SinoMed databases were searched from inception to March 1st, 2022 to retrieve eligible studies that evaluated the effect of melatonin supplementation on the levels of malondialdehyde (MDA), lipid peroxidation (LPO), nitric oxide (NO), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT) in animal models of fibrosis. RESULTS: A total of 64 studies were included in this meta-analysis. The results showed that melatonin supplementation significantly reduced the levels of oxidative indicators including MDA (P < 0.00001), LPO (P < 0.00001) and NO (P < 0.0001), and elevated the levels of antioxidant indicators including GSH (P < 0.00001), GPx (P < 0.00001) and SOD (P < 0.00001) in fibrotic diseases. CONCLUSIONS: Our research findings showed that melatonin supplementation could significantly reduce the levels of oxidative indicators including MDA, LPO and NO and elevate the levels of antioxidant indicators including GSH, GPx and SOD so as to correct oxidative stress in animal models of fibrosis. However, no significant changes were observed in CAT level. More clinical studies are needed to further confirm the beneficial role of melatonin in fibrotic diseases.


Assuntos
Antioxidantes , Melatonina , Animais , Humanos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Melatonina/farmacologia , Estresse Oxidativo , Catalase/metabolismo , Glutationa/metabolismo , Superóxido Dismutase/metabolismo , Fibrose , Óxido Nítrico/farmacologia , Modelos Animais , Glutationa Peroxidase/metabolismo , Malondialdeído/farmacologia
9.
Biosensors (Basel) ; 12(12)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36551145

RESUMO

Glutathione peroxidase 4 (GPX4) plays an important effect on ferroptosis. Down-regulating the expression of GPX4 mRNA can decrease the content of GPX4. In this work, a gold nanoflare (AuNF) probe loaded with anti-sense sequences targeting for GPX4 mRNA was designed to monitor and down-regulate intracellular GPX4 mRNA using fluorescence imaging in situ and using anti-sense technology. The results revealed that there was a marked difference for the expression of GPX4 mRNA in different cell lines, and the survival rate of cancer cells was not significantly effected when the relative mRNA and protein expression levels of GPX4 was down-regulated by AuNF probes. However, when co-treated with AuNF probes, the low expression of GPX4 strengthened erastin-induced ferroptosis, and this synergy showed a better effect on inhibiting the proliferation of cancer cells.


Assuntos
Ferroptose , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/farmacologia , Ferroptose/genética , Linhagem Celular , Piperazinas/farmacologia
10.
Molecules ; 27(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36558121

RESUMO

Cataracts are an ailment representing the leading cause of blindness in the world. The pathogenesis of cataracts is not clear, and there is no effective treatment. An increasing amount of evidence shows that oxidative stress and autophagy in lens epithelial cells play a key role in the occurrence and development of cataracts. Buddleja officinalis Maxim flavonoids (BMF) are natural antioxidants and regulators that present anti-inflammatory and anti-tumor effects, among others. In this study, we optimized the extraction method of BMFs and detected three of their main active monomers (luteolin, apigenin, and acacetin). In addition, a model of oxidative damage model using rabbit lens epithelial cells induced by hydrogen peroxide (H2O2). By detecting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and OH (OH), the expression of autophagosomes and autolysosomes were observed after MRFP-GFP-LC3 adenovirus was introduced into the cells. Western blotting was used to detect the expression of Beclin-1 and P62. Our research results showed that the optimal extraction parameters to obtain the highest yield of total flavonoids were a liquid-solid ratio of 1:31 g/mL, an ethanol volume fraction of 67%, an extraction time of 2.6 h, and an extraction temperature of 58 °C. Moreover, the content of luteolin was 690.85 ppb, that of apigenin was 114.91 ppb, and the content of acacetin was 5.617 ppb. After oxidative damage was induced by H2O2, the cell survival rate decreased significantly. BMFs could increase the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decrease the levels of malondialdehyde (MDA) and OH (OH). After the MRFP-GFP-LC3 virus was introduced into rabbit lens epithelial cells and detecting the expression of P62 and Beclin-1, we found that the intervention of BMF could promote the binding of autophagosomes to lysosomes. Compared with the model group, the level of P62 in the low-, middle-, and high-dose groups of BMF was significantly down-regulated, the level of Beclin-1 was significantly increased, and the difference was statistically significant (p < 0.05). In other words, the optimized extraction method was better than others, and the purified BMF contained three main active monomers (luteolin, apigenin, and acacetin). In addition, BMFs could ameliorate the H2O2-induced oxidative damage to rabbit lens cells by promoting autophagy and regulating the level of antioxidation.


Assuntos
Buddleja , Catarata , Animais , Coelhos , Peróxido de Hidrogênio/farmacologia , Flavonoides/farmacologia , Proteína Beclina-1/metabolismo , Apigenina/farmacologia , Luteolina/farmacologia , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Superóxido Dismutase/metabolismo , Autofagia , Malondialdeído/metabolismo , Glutationa Peroxidase/metabolismo
11.
Int J Mol Sci ; 23(23)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36499171

RESUMO

Oxidative stress is an essential factor in the development and progression of Alzheimer's disease (AD). An excessive amount of reactive oxygen species (ROS) induces the peroxidation of lipid membranes, reduces the activity of antioxidant enzymes and causes neurotoxicity. In this study, we investigated the antioxidant and cholinesterase inhibitory potential of a novel galantamine-curcumin hybrid, named 4b, administered orally in two doses (2.5 mg/kg and 5 mg/kg) in scopolamine (SC)-induced neurotoxicity in mice. To evaluate the effects of 4b, we used galantamine (GAL) (3 mg/kg) and curcumin (CCN) (25 mg/kg) as positive controls. Ex vivo experiments on mouse brains showed that the higher dose of 4b (5 mg/kg) increased reduced glutathione (GSH) levels by 46%, catalase (CAT) and superoxide dismutase (SOD) activity by 57%, and glutathione peroxidase (GPx) activity by 108%, compared with the SC-treated group. At the same time, 4b (5 mg/kg) significantly reduced the brain malondialdehyde (MDA) level by 31% and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities by 40% and 30%, respectively, relative to the SC-impaired group. The results showed that 4b acted as an antioxidant agent and brain protector, making it promising for further experimental research in the field of neurodegenerative diseases.


Assuntos
Curcumina , Síndromes Neurotóxicas , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Butirilcolinesterase , Escopolamina/farmacologia , Acetilcolinesterase/metabolismo , Curcumina/farmacologia , Peroxidação de Lipídeos , Galantamina/farmacologia , Superóxido Dismutase/metabolismo , Catalase/metabolismo , Estresse Oxidativo , Glutationa Peroxidase/metabolismo , Glutationa/metabolismo
12.
Biomed Res Int ; 2022: 2988334, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36337844

RESUMO

Liver damage occurs following renal ischemia-reperfusion (RIR) that can cause inflammation and inflammatory cytokines activated after kidney injury. In this study, thyme essential oil (TE) with antioxidant and anti-inflammatory properties was used to reduce liver damage induced by renal IR. 32 male rats were randomly divided into 4 equal groups: (1) control, (2) RIR, (3) RIR+TE, and (4) TE. Rats received TE as a pretreatment at a dose of 0.5 ml/kg for one week. Then, under anesthesia for 45 minutes for ischemia, the kidneys of the animals were closed with clamps, and reperfusion was performed for 24 hours. Animal serum was isolated to evaluate alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) parameters. The liver of rats was examined for the measurement of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), glutathione peroxidase (GPX), catalase (CAT), and expression of genes such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and caspase-3. ALP, AST, ALT, MDA, NO, IL-6, TNF-α, and caspase-3 increased significantly in the RIR group compared to the control group (p < 0.05). GSH, GPX, and CAT decreased significantly in the RIR group compared to the control group (p < 0.05). TE caused a decrease in ALP, AST, ALT, MDA, NO, IL-6, and TNF-α compared to the RIR group and caused an increase in the amount of GSH, GPX, and CAT in the RIR group (p < 0.05). This study showed that TE has antioxidant and anti-inflammatory properties that reduce liver damage induced by RIR.


Assuntos
Hepatopatias , Óleos Voláteis , Traumatismo por Reperfusão , Thymus (Planta) , Ratos , Animais , Masculino , Caspase 3/metabolismo , Antioxidantes/metabolismo , Óleos Voláteis/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Traumatismo por Reperfusão/metabolismo , Interleucina-6/metabolismo , Fígado/patologia , Glutationa Peroxidase/metabolismo , Hepatopatias/patologia , Isquemia/patologia , Anti-Inflamatórios/farmacologia , Reperfusão , Estresse Oxidativo
13.
F1000Res ; 11: 1072, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405557

RESUMO

Background: The mammalian retina contains an autonomous circadian clock that controls many physiological functions within this tissue. Our previous studies have indicated that disruption of this circadian clock by removing Bmal1 from the retina affects the visual function, retinal circuitry, and cone photoreceptor viability during aging. In the present study, we employed a mouse-derived cone photoreceptor‒like cell, 661W, to investigate which molecular mechanisms of the circadian clock may modulate cone photoreceptor viability during aging. Methods: Bmal1 knockout (BKO) cells were generated from 661W cells using the CRISPR/Cas9 gene editing tool. Deletion of Bmal1 from 661W was verified by western blot and monitoring Per2-luc bioluminescence circadian rhythms. To investigate the effect of Bmal1 removal on an oxidative stress challenge, cells were treated with hydrogen peroxide (H 2O 2,1 mM) for two hours and then cell viability was assessed. Cells were also cultured and harvested for gene expression analysis and antioxidant assay. Results: Our data indicated that 661W cells contain a functional circadian clock that mediates the response to an oxidative stress challenge in vitro and that such a response is no longer present in the BKO cell. We also hypothesized that the effect was due to the circadian regulation of the intracellular antioxidant defense mechanism. Our results indicated that in 661W cells, the antioxidant defense mechanism is under circadian control, whereas in BKO cells, there is an overall reduction in this antioxidant defense mechanism, and it is no longer under circadian control. Conclusions: Our work supported the notion that the presence of a functional circadian clock and its ability to modulate the response to an oxidative stress is the underlying mechanism that may protect cones during aging.


Assuntos
Relógios Circadianos , Camundongos , Animais , Relógios Circadianos/genética , Células Fotorreceptoras Retinianas Cones/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Glutationa Peroxidase/metabolismo , Antioxidantes/metabolismo , Estresse Oxidativo , Linhagem Celular , Mamíferos/metabolismo
14.
Front Immunol ; 13: 965954, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405693

RESUMO

High-fat diet is regarded as crucial inducers of oxidative stress, inflammation, and metabolic imbalance. In order to investigate the ameliorative potential of resveratrol against the progression of liver injury towards steatohepatitis, common carp (Cyprinus carpio) were distributed into six experimental groups and were fed with a normal-fat diet, a high-fat diet, and supplemented with resveratrol (0.8, 1.6, 2.4, and 3.2 g/kg diet) for 8 weeks. The high-fat diet decreased the antioxidant capacities, as well as causing the inflammatory response and lipid deposition of common carp. Resveratrol induced a marked elevation in the final body weight, weight gain rate, condition factor and significant decrease in the feed conversion ratio. Moreover, dietary resveratrol showed a significant decrease in the alanine aminotransferase, aspartate aminotransferase, triglyceride and low-density lipoprotein levels, which was accompanied by an increase in high-density lipoprotein concentration in serum. A significant elevation in total superoxide dismutase, catalase, glutathione peroxidase and a decreased malondialdehyde content were observed, along with a substantial elevation in antioxidant activities were found. Additionally, fish fed with resveratrol had an up-regulation of hepatic catalase, copper, zinc superoxide dismutase, glutathione peroxidase 1a, and glutathione peroxidase 1b gene expression via Nrf2 signaling pathway. Expectedly, our results also demonstrated that resveratrol regulates hepatic lipid metabolism in fish by inhibiting the expression of hepatic lipogenesis genes (acetyl-CoA carboxylase 1, fatty acid synthase, and sterol regulatory element binding protein 1), fatty acid uptake-related genes of lipoprotein lipase, and ß-oxidation-related genes via PPAR-γ signaling pathway. Furthermore, dietary resveratrol reduced inflammation, as evident by down-regulating the interleukin-1ß, interleukin-6, interleukin-8, and tumor necrosis factor-α expression levels and upregulating the interleukin-10 and transforming growth factor-ß2 expression levels via NF-κB signaling pathway. As a whole, our results demonstrated that resveratrol defensed the impacts against high-fat diet on the serum biochemical, hepatic antioxidants, inflammation, and lipid metabolism.


Assuntos
Carpas , Dieta Hiperlipídica , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/genética , Resveratrol/farmacologia , Carpas/metabolismo , Catalase/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glutationa Peroxidase/metabolismo , Estresse Oxidativo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Superóxido Dismutase/metabolismo
15.
Sci Rep ; 12(1): 19396, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371529

RESUMO

Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers.


Assuntos
Ferroptose , Neoplasias da Glândula Tireoide , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Morte Celular , Glutationa Peroxidase/metabolismo , Glutationa/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Serina-Treonina Quinases TOR
16.
Zhonghua Yi Xue Za Zhi ; 102(43): 3476-3481, 2022 Nov 22.
Artigo em Chinês | MEDLINE | ID: mdl-36396365

RESUMO

Objective: To examine the antioxidant effect of low dosage insulin glargine intervention at different time in rats with delayed resuscitation after burn, in order to acquire a better time of antioxidant intervention during delayed resuscitation following burn injury. Methods: With 10 rats in each group, 50 male SD rats were assigned to sham injury group, delayed resuscitation group, immediate post-burn insulin glargine treatment group (immediate treatment group), 2 hours post-burn insulin glargine treatment group(2 h treatment group), and 6 hours post-burn insulin treatment group(6 h treatment group) with random number table. Each treatment group received subcutaneous injections of insulin glargine (1.0 U·kg-1·d-1) immediately, two hours and six hours after the burn, while the delayed resuscitation group received the same amount of normal saline six hours after the burn. To imitate delayed fluid resuscitation, the delayed resuscitation group and each therapy group were intraperitoneally injected with normal saline (40 ml/kg) 6 hours after injury. No medicine and fluid resuscitation was administered to the sham injury group. Rats in the sham injury group had their abdominal aortic blood, hearts, and kidney tissues collected immediately after injury, while rats in the other groups had their blood and tissues collected 24 hours later. To analyze the timing of antioxidant intervention, the activities of CuZn-superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), xanthine oxidase (XOD) and myeloperoxidase (MPO) in blood glucose and myocardial and renal tissues were measured by spectrophotometry. Results: Compared with the sham group, blood glucose levels in the delayed resuscitation group increased [(10.72±0.80) vs (6.57±0.82)mmol/L,P<0.001], while in the myocardium and kidney, the activities of CuZn-SOD, CAT, GSH-Px and T-AOC decreased (all P<0.05) and the activities of XOD and MPO increased (all P<0.05). Compared with the delayed resuscitation group, blood glucose decreased in the immediate, 2 h, and 6 h treatment groups (all P<0.05). In the immediate and 2 h treatment group, the activities of CuZn-SOD, CAT, GSH-Px and T-AOC in the myocardium and kidney increased(all P<0.05). In the 6 h treatment group, only the activities of GSH-Px in myocardium, CAT and GSH-Px in kidney increased (all P<0.05). Compared with the delayed resuscitation group, in the immediate treatment group, the activities of MPO and XOD in myocardial tissue and XOD in renal tissue decreased (all P<0.05). The activities of MPO and XOD in myocardial and renal tissues of the 2 h treatment group both decreased (all P<0.05). In the 6 h treatment group, the activities of MPO in myocardial tissue and XOD in renal tissue both decreased (all P<0.05). Compared with the immediate treatment group, the activity of GSH-Px in myocardial tissue increased (P<0.05), and the activities of CuZn-SOD, CAT, GSH-Px and T-AOC in renal tissue increased in the 2 h treatment group (all P<0.05). The activities of CuZn-SOD, CAT, GSH-Px and T-AOC in myocardium of 6 h treatment group decreased (all P<0.05). Compared with the immediate treatment group, the activities of XOD and MPO in myocardial tissue and XOD in renal tissue of the 2 h treatment group had no significant difference (all P>0.05), but the activity of MPO in renal tissue decreased (P<0.05). The activities of XOD and MPO in myocardial tissue of the 6 h treatment group increased (all P<0.05). Compared with the 2 h treatment group, the activities of CuZn-SOD, CAT and GSH-Px and T-AOC in myocardium and kidney tissues in the 6 h treatment group decreased (all P<0.05), while the activities of XOD and MPO in myocardium and kidney tissues increased [myocardium: (374±8) vs (290±19) U/g, (0.021 8±0.003 9) vs (0.010 7±0.002 4) U/g, kidney: (157±6) vs (128±9) U/g, (0.026 8±0.004 3) vs (0.013 4±0.003 1) U/g, all P<0.05]. Conclusions: The timing of the intervention is related to the antioxidant effect of insulin glargine during delayed burn resuscitation. The intervention immediately and 2 hours after burn could have a better antioxidant effect compared to the intervention at 6 hours after burn.


Assuntos
Antioxidantes , Glicemia , Ratos , Animais , Masculino , Antioxidantes/farmacologia , Insulina Glargina/uso terapêutico , Solução Salina , Ratos Sprague-Dawley , Estresse Oxidativo , Glutationa Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1
17.
Nutrients ; 14(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364921

RESUMO

Placental extract has been used for skin care and delaying skin aging. Cow placenta is an abundant resource with a large mass, which has not been harnessed effectively. Cow placenta extract (CPE) has the functions of antioxidation, anti-inflammatory, promoting growth and development, and promoting hair growth. However, little is known about the effect of oral administration of cow placenta extract on skin conditions. Therefore, the present study aimed to investigate the antioxidant capacity of CPE in vitro and in vivo and its protective effect on d-galactose (D-gal) induced skin aging in mice. The results showed that CPE had strong free radical scavenging, reducing and metal chelating activities. CPE can increase the activity of catalase (CAT), glutathione peroxidase (GSH-Px), peroxidase (POD), superoxide dismutase (SOD), and the content of glutathione (GSH), decrease the content of malondialdehyde (MDA). Moreover, CPE can decrease the gene and protein expression of matrix metalloproteinase 1a (MMP-1a) and matrix metalloproteinase 3 (MMP-3) and increase the expression of transforming growth factor-ß (TGF-ß) and tissue inhibitor of metalloproteinase 1 (TIMP-1) of mouse skin. Histopathological analysis showed CPE reduced the collagen damage caused by D-gal, increased collagen synthesis and reduced its degradation to delay skin aging.


Assuntos
Antioxidantes , Envelhecimento da Pele , Animais , Bovinos , Feminino , Camundongos , Gravidez , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Galactose/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo , Placenta/metabolismo , Extratos Vegetais/farmacologia , Superóxido Dismutase/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo
18.
Bull Exp Biol Med ; 173(6): 775-778, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36322310

RESUMO

The study involved 138 women aged 45-60 years in perimenopause (n=55) and postmenopause (n=83) with insomnia (main groups) and without it (control). The levels of reduced (GSH) and oxidized (GSSG) glutathione and glutathione peroxidase activity were determined in erythrocytes; activities of glutathione S-transferase and glutathione reductase were measured in blood serum. The differences with the control groups were found only in perimenopause: higher glutathione reductase activity and reduced GSSG level and GSH/GSSG ratio in women with insomnia (p<0.05). The results of the comparative analysis between the main groups showed lower glutathione reductase activity, increased GSSG level, and a decrease the GSH/GSSG ratio in the postmenopausal period compared with the perimenopause (p<0.05). These results can be used in choosing the tactics for complex therapy of insomnia in menopausal women to correct free radical homeostasis and prevention of oxidative stress.


Assuntos
Antioxidantes , Distúrbios do Início e da Manutenção do Sono , Feminino , Humanos , Antioxidantes/metabolismo , Glutationa Redutase/metabolismo , Dissulfeto de Glutationa , Glutationa Peroxidase/metabolismo , Glutationa/metabolismo , Estresse Oxidativo , Glutationa Transferase/metabolismo , Menopausa
19.
Cell Stress Chaperones ; 27(6): 685-702, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36322346

RESUMO

The global trade in used vehicles and their components generates huge financial benefits but leads to detrimental environmental consequences including groundwater pollution and potential adverse health effects mediated by free-radical processes such as lipid peroxidation. We investigated oxidative stress responses in thirty-six, female mice orally exposed (via drinking) to graded concentrations (0%, 50%, and 100%) of groundwater from a well located within a major automobile junk market in SW-Nigeria containing extremely high levels of arsenic (0.332 ± 0.089 mg/l) and seventeen PAHs, which serves as domestic water supply. Blood samples from the mice were assayed for selected biochemical parameters at intervals of 7, 14, and 28 days. A significant dose- and duration-dependent increase in malondialdehyde (MDA) and Myeloperoxidase (MPO) confirmed oxidative stress onset due to exposure to the polluted well-water, while a significant decline in nitric oxide (NO-) levels may suggest impaired endothelial smooth-muscle relaxation which may lead to the development of metabolic diseases over time. Superoxide dismutase (SOD) and reduced glutathione (GSH) showed a contrasting trend with Glutathione peroxidase (GPx), while Glutathione-S-Transferase (GST) declined significantly by the 28th day. Two clusters were identified by principal component analysis-one involving MDA, SOD, and GSH suggesting that antioxidant responses driven mainly by SOD and GSH proved insufficient in scavenging the free radicals generated by lipid peroxidation. NO- and total protein clustered together possibly due to the significant declines in both over the study period. Histological examination of liver tissue of exposed mice corroborated the above findings and highlights the need for urgent remedial action.


Assuntos
Automóveis , Água Subterrânea , Estresse Oxidativo , Poluentes da Água , Animais , Feminino , Camundongos , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Água Subterrânea/química , Peroxidação de Lipídeos , Nigéria , Superóxido Dismutase/metabolismo , Poluentes da Água/toxicidade
20.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430753

RESUMO

The circadian system synchronizes daily with the day-night cycle of our environment. Disruption of this rhythm impacts the emergence and development of many diseases caused, for example, by the overproduction of free radicals, leading to oxidative damage of cellular components. The goal of this study was to determine the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione transferase (GST), glutathione reductase (R-GSSG), and the concentration of glutathione (GSH) in the circadian rhythm. The study group comprised 66 healthy volunteers (20-50 years; 33 women; 33 men). The blood was collected at 2, 8 a.m., and 2, 8 p.m. All samples marked the serum melatonin concentration to confirm the correct sleeping rhythm and wakefulness throughout the day. The activity of study enzymes and the concentration of GSH were measured by the spectrophotometric method. Confirmed the existence of circadian regulation of oxidative stress enzymes except for GST activity. The peak of activity of study enzymes and GSH concentration was observed at 2 a.m. The increased activity of enzymes and the increase in GSH concentration observed at night indicate that during sleep, processes allowing to maintain of the redox balance are intensified, thus limiting the formation of oxidative stress.


Assuntos
Ritmo Circadiano , Estresse Oxidativo , Feminino , Animais , Glutationa Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Glutationa/metabolismo
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