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OBJECTIVE: To explore the role of nuclear transcription factor E2-related factor 2(NRF2)-mediated reductive stress in arsenite induced malignant transformation in human keratinocytes. METHODS: HaCaT cells and fluorescent labeled mitochondrial glutathione HaCaT cells(Mito-Grx1-roGFP2 HaCaT) were cultured to 35 passages in medium containing 0.0 and 1.0 µmol/L NaAsO_2 to establish a model of malignant transformation of cells. Cellular and mitochondrial reduced glutathione/oxidized glutathione(GSH/GSSG) and reduced coenzyme II/oxidized coenzyme II(NADPH/NADP~+) ratios were measured in HaCaT cells. Cell doubling time, cell migration ability, soft agar clone formation ability and GSH/GSSG at different times in the 0 passage, the early stage(1st, 7th and 14th passages) and later stage(21st, 28th and 35th passages) were measured in Mito-Grx1-roGFP2 HaCaT cells. NaAsO_2 induced malignant transformation cells were transfected with NRF2 siRNA, and detected the expression level of NRF2 and the redox-related indexes and malignant transformation indexes. RESULTS: Compared with the control group, the GSH/GSSG ratio in 1.0 µmol/L NaAsO_2 treated HaCaT cells significantly decreased in the 1st and 7th generations, but significantly increased after the 21st generation, and the NADPH/NADP~+ ratio significantly increased in the 1st, 14th, 21st, 28th and 35th generations; The levels of GSH/GSSG in mitochondria significantly increased from 1st to 35th generation, and the levels of NADPH/NADP~+ in mitochondria significantly increased at 1st, 7th, 21st, 28th and 35th generation. After continuous treatment of Mito-Grx1-roGFP2 HaCaT cells with 0.0 or 1.0 µmol/L NaAsO_2 to 35 passages, the doubling time of cells treated with 1.0 µmol/L NaAsO_2 was significantly shortened, the cell migration rate was increased greatly, and more clones with larger volumes than the control cells formed. The GSH/GSSG ratio in mitochondria of Mito-Grx1-roGFP2 HaCaT cells showed a significant decrease in the 1st generation and increased from the 7th generation onwards(all P<0.05). After transfection of NaAsO_2 treated cells with NRF2 siRNA, the levels of hydrogen peroxide and superoxide increased compared with the siRNA controls. The levels of cell and mitochondrial NADPH/NADP~+ and GSH/GSSG decreased and the level of mitochondrial GSH/GSSG in Mito-Grx1-roGFP2 HaCaT cells decreased. Cell doubling time increased, cell migration rate and soft agar clone formation ability decreased(all P<0.05). The malignant phenotype was reversed. CONCLUSION: In the early stage(1st, 7th and 14th passages) of NaAsO_2 treated HaCaT cells, oxidative stress occurred with continuous high NRF2 expression. Later(21st, 28th and 35th passages), NRF2 induced reductive stress, leading to malignant transformation.
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Transformación Celular Neoplásica , Queratinocitos , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Oxidación-Reducción , Línea Celular , Arsénico/toxicidad , Arsénico/efectos adversos , Glutatión/metabolismoRESUMEN
To investigate how contextual or environmental factors may influence the athletic performance of female soccer players during competitions, this study aimed to assess the impact of match-related variables (playing surface; opponent levels; opponent result trends; match status, and match outcomes) on the athletic performance of professional female soccer athletes. Seventeen athletes (25.5 ± 4.3 years of age) from the same team competing in the Italian second division were divided into two groups according to their roles and athletic characteristics: Group A (central defenders and forwards) and Group B (right/left full-backs and midfielders). Total distance (TD) and sprint distance (SD); high-speed running (HSR), acceleration (ACC), and deceleration numbers (DEC); average and maximal heart rate (HR_avg; HR_max); and match-related factors were collected during the 22 regular season matches. A T-test and ANOVA were used to calculate the differences between groups in GPS and HR variables and the effects of match-related factors, respectively. Results showed higher running performance in the B group compared to the A group during matches. Increased ACC number was seen in matches played on artificial turf; winning was associated with decreased HR_max and increased DEC number. Athletes covered higher TD reaching lower HR_max when playing against lower-ranking opponents while matches lost/drawn resulted in higher HSR. High HRs (max and avg) were found when playing against a team with a positive performance trend. In summary, match-related factors and opponents' characteristics can affect athletic performance in female soccer athletes. These factors should be considered during in-seasonal training to personalize match preparation and optimize athlete performance.
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BACKGROUND: Ferroptosis is an important type of cell death contributing to myocardial dysfunction induced by whole body ischemia reperfusion following cardiac arrest (CA) and resuscitation. Sulforaphane (SFN), known as the activator of the nuclear factor E2-related factor 2 (Nrf2), has been proven to effectively alleviate regional myocardial ischemia reperfusion injury. The present study was designed to investigate whether SFN could improve post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis and its potential regulatory mechanism. METHODS AND RESULTS: An in vivo pig model of CA and resuscitation was established. Hypoxia/reoxygenation (H/R)-stimulated AC16 cardiomyocytes was constructed as an in vitro model to simulate the process of CA and resuscitation. In vitro experiment, SFN reduced ferroptosis-related ferrous iron, lipid reactive oxygen species, and malondialdehyde, increased glutathione, and further promoted cell survival after H/R stimulation in AC16 cardiomyocytes. Mechanistically, the activation of Nrf2 with the SFN decreased interferon regulatory factor 1 (IRF1) expression, then reduced its binding to the promoter of glutathione peroxidase 4 (GPX4), and finally recovered the latter's transcription after H/R stimulation in AC16 cardiomyocytes. In vivo experiment, SFN reversed abnormal expression of IRF1 and GPX4, inhibited cardiac ferroptosis, and improved myocardial dysfunction after CA and resuscitation in pigs. CONCLUSIONS: SFN could effectively improve myocardial dysfunction after CA and resuscitation, in which the mechanism was potentially related to the inhibition of cardiomyocytes ferroptosis through the regulation of Nrf2/IRF1/GPX4 pathway.
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Background: Although ophthalmic ambulatory surgeries are less costly and may enhance the more efficient utilization of hospital resources, inpatient surgeries were preferable alternatives for patients with complicated eye diseases or poor general health. However, the incidence, causes, and related factors of ophthalmic inpatient surgery cancellation remained largely unknown. Methods: The electronic medical records of ophthalmic inpatient surgeries between January 2012 and December 2022 was retrospectively reviewed. Cancellation-related factors were explored using multivariate logistic regression analysis and the reasons of cancellation were also evaluated. Results: In total, 820 cancelled surgeries and 42,073 performed surgeries were included, with a cancellation rate of 1.9%. Any other ocular comorbidities were risk factors for cancellation (odds ratio (OR) 1.872, 95% confidence intervals (CI) 1.504-2.331; p < 0.001), while older age (OR 0.990, 95% CI 0.986-0.995; p < 0.001), local residence (OR 0.809, 95% CI 0.692-0.947; p = 0.008), any systemic comorbidities (OR 0.740, 95% CI 0.616-0.889; p = 0.001), and previous history of surgeries (OR 0.403, 95% CI 0.341-0.476; p < 0.001) were negatively associated with surgery cancellation. The top two categorical cancellation reasons were medical factors (508, 62.0%) and patient-related factors (285, 34.8%). "Patient/family refused surgery" (127, 15.5%), "acute conjunctivitis or uveitis relapse" (103, 12.6%), and "ocular condition improved and procedure no longer indicated" (71, 8.7%) were the three most common single cancellation reasons. Conclusion: Any other ocular comorbidities, younger age, no systemic comorbidities, non-local residence, and no past surgical history were related factors for ophthalmic inpatient surgery cancellation. The majority of cancellations were due to patient-related or medical factors. Great importance should be attached to the cancellation of the more complicated inpatient surgeries and further efforts are warranted to explore how to reduce cancellation.
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Non-alcoholic fatty liver disease (NAFLD) is becoming a significant global public health threat. Seabuckthorn (Hippophae rhamnoides L.) has been used in traditional Chinese medicine (TCM). The hypolipidemic effects of Seabuckthorn polysaccharides (SP) against high-fat diets (HFD)-induced NAFLD were systematically explored and compared with that of Bifidobacterium lactis V9 (B. Lactis V9). Results showed that HFD-induced alanine transaminase (ALT) and aspartate aminotransferase (AST) levels decreased by 2.8-fold and 4.5-fold, respectively, after SP supplementation. Moreover, the alleviating effect on hepatic lipid accumulation is better than that of B. Lactis V9. The ACC and FASN mRNA levels were significantly reduced by 1.8 fold (P < 0.05) and 2.3 folds (P < 0.05), respectively, while the CPT1α and PPARα mRNA levels was significantly increased by 2.3 fold (P < 0.05) and 1.6 fold (P < 0.05), respectively, after SP administration. SP activated phosphorylated-AMPK and inhibited PPARγ protein expression, improved serum oxidative stress and inflammation (P < 0.05). SP supplementation leads to increased hepatic expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and Superoxide dismutase-2 (SOD-2). Furthermore, SP treatment improved HFD-induced intestinal dysbiosis. Lentisphaerae, Firmicutes, Tenericutes and Peptococcus sp., RC9_gut_group sp., and Parabacteroides sp. of the gut microbiota were significantly associated with hepatic steatosis and indicators related to oxidative stress and inflammation. Therefore, SP can mitigate hepatic lipid accumulation by regulating Nrf-2/HO-1 signaling pathways and gut microbiota. This study offers new evidence supporting the use of SP as a prebiotic treatment for NAFLD.
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Oxidative stress in adipose tissue may alter the secretion pattern of adipocytokines and potentially promote atherosclerosis. However, the therapeutic role of hydrogen in adipose tissue under oxidative stress remains unclear. In this study, subcutaneous adipose tissue (SCAT) was collected from the mid-thoracic wounds of 12 patients who underwent open-heart surgery with a mid-thoracic incision. The adipose tissue was then immersed in a culture medium dissolved with hydrogen, which was generated using a hydrogen-generating device. The weight of the adipose tissue was measured before and after hydrogenation, and the tissue was immunostained for nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase (SOD), which are markers of oxidative stress. The immunostaining results showed that HO-1 and Nrf2 expression levels were significantly decreased in the hydrogenated group, whereas SOD expression levels increased, but did not attain statistical significance. Image analysis of adipose tissue revealed that a reduction in adipocyte size. Furthermore, hydrogenated adipose tissue showed a trend toward increased gene expression levels of adiponectin and decreased gene expression levels of chemerin, an adipocytokine involved in adipogenesis. These results demonstrated the therapeutic potential of hydrogen gas for oxidative stress in adipose tissue and for reducing adipocyte size.
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Tejido Adiposo , Hidrógeno , Estrés Oxidativo , Estrés Oxidativo/efectos de los fármacos , Humanos , Hidrógeno/farmacología , Hidrógeno/metabolismo , Masculino , Femenino , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacos , Persona de Mediana Edad , Superóxido Dismutasa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Anciano , Adiponectina/metabolismo , Adiponectina/genética , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Grasa Subcutánea/metabolismo , Grasa Subcutánea/efectos de los fármacos , Factor 2 Relacionado con NF-E2RESUMEN
The aim of this study was to investigate the anti-ferroptotic effect of resveratrol (RSV) on retinal Müller cells (RMCs) in the early stages of diabetic retinopathy (DR) via the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/prostaglandin-endoperoxide synthase 2 (PTGS2). The retina was obtained from normal and diabetic Sprague-Dawley rats or wild-type and Nrf2 knockout (KO) diabetic mice, with or without RSV (10 mg/kg/d) treatment for 12 weeks. RMCs transfected with or without SiNrf2 were cultured with high glucose and RSV (20 mM). The retinal neurofunctional changes were measured by electroretinogram (ERG). The retinal inner nuclear layer cell mitochondrial morphological changes were detected by transmission electron microscopy. The cell viabilities were measured by cell counting kit-8 (CCK-8) assay. The levels of Fe2+, malonic dialdehyde (MDA), and glutathione (GSH) were measured by colorimetric method. The expression of Nrf2, GPx4, and PTGS2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunocytochemistry. In vivo, RSV inhibited retinal neurofunctional changes and mitochondrial morphological changes; decreased Fe2+, MDA, and PTGS2; and increased GSH, Nrf2, and GPx4 in retina of DM rats. In vitro, RSV decreased MDA and PTGS2 and increased cell viability, GSH, Nrf2, and GPx4. In vivo and vitro, the role of Nrf2-regulated signaling pathway in anti-ferroptosis by RSV was further confirmed using Nrf2 KO mice and pre-transfected SiNrf2 in RMCs. These findings indicated that RSV is a potential therapeutic option for DR and that Nrf2/GPx4/PTGS2 plays a role in the anti-ferroptosis mechanism of RSV on RMCs.
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AIM: To determine whether etomidate (ET) has a protective effect on retinal ganglion cells (RGCs) injured with hydrogen peroxide (H2O2) and to explore the potential mechanism underlying the antioxidative stress effect of ET. METHODS: Cultured RGCs were identified by double immunofluorescent labeling of microtubule-associated protein 2 and Thy1.1. An injury model of H2O2-induced RGCs oxidative stress was established in vitro. Cells were pretreated with different concentrations of ET (1, 5, and 10 µmol/L) for 4h, followed by further exposure to H2O2 at 1000 µmol/L. Cell counting kit 8 and Annexin V/propidium iodide assays were applied to detect the viabilities and apoptosis rates of the RGCs at 12, 24, and 48h after H2O2 stimulation. The levels of nitric oxide, malondialdehyde, and glutathione in culture media were measured at these time points. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were performed to observe the effects of ET on the messenger RNA and protein expression of inducible nitric oxide synthase (iNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), glutathione peroxidase 1 and the level of conjugated acrolein in RGCs at 12, 24, and 48h after H2O2 stimulation and in the retina at 12h after optic nerve transection (ONT). RESULTS: The applications of 5 and 10 µmol/L of ET significantly increased the viability of RGCs. Results from qRT-PCR indicated a decrease in the expression of iNOS and an increase in the expressions of Nrf2 and HO-1 in ET-pretreated RGCs at 12, 24 and 48h after H2O2 stimulation, as well as in ET-treated retinas at 12h after ONT. Western blot analysis revealed a decrease in the expression of iNOS and levels of conjugated acrolein, along with an increase in the expressions of Nrf2 and HO-1 in ET-pretreated RGCs in vitro and ET-treated retinas in vivo. CONCLUSION: ET is a neuroprotective agent in primary cultured RGCs injured by H2O2. The effect of ET is dose-dependent with the greatest effect being at 10 µmol/L. ET plays an antioxidant role by inhibiting iNOS, up-regulating Nrf2/HO-1, decreasing the production of acrolein, and increasing the scavenge of acrolein.
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Objective To investigate the effects of pterostilbene on human colon cancer LoVo cells and study the regulatory mechanism of nuclear factor E2-related factor 2 (Nrf2) in the process of pterostilbene acting on LoVo cells. Methods LoVo cells were treated with different concentrations (5,10,20,40,60,80,100 µmol/L) of pterostilbene.Cell viability,migration,invasion,and apoptosis were examined by CCK-8,scratch,Transwell,and TUNEL assays,respectively.The mitochondrial membrane potential was measured by the mitochondrial membrane potential assay kit with JC-1.The reactive oxygen species level was measured by 2',7'-dichlorofluorescein diacetate.The protein levels of Nrf2,phosphorylated Nrf2,heme oxygenase 1,and apoptotic proteins (Bcl2 and Bax) were determined by Western blotting.In addition,cell viability,Nrf2 expression,and apoptosis rate were determined after co-application of the Nrf2-specific agonist sulforaphane. Results Compared with the control group,40,60,80,100 µmol/L pterostilbene reduced the viability of LoVo cells (P=0.014,P<0.001,P<0.001,P<0.001).Pterostilbene at 5,10,20 µmol/L did not show effects on cell viability but inhibited cell migration (P=0.008,P<0.001,P<0.001) and invasion (all P<0.001).Pterostilbene at 40,60,80 µmol/L increased apoptosis (P=0.014,P<0.001,P<0.001),promoted mitochondrial membrane potential depolarization (P=0.026,P<0.001,P<0.001) and reactive oxygen species accumulation (all P<0.001),and down-regulated the expression of phosphorylated Nrf2 (P=0.030,P<0.001,P<0.001),heme oxygenase 1 (P=0.015,P<0.001,P<0.001),and Bcl2 (P=0.039,P<0.001,P<0.001) in LoVo cells.Pterostilbene at 60,80 µmol/L down-regulated Nrf2 expression (P=0.001,P<0.001) and up-regulated Bax expression (both P<0.001).The application of sulforaphane reversed the effects of pterostilbene on cell viability (P<0.001),apoptosis (P<0.001),and Nrf2 expression (P=0.022). Conclusion Pterostilbene is a compound that can effectively inhibit colon cancer cells by inhibiting the Nrf2 pathway.
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Apoptosis , Neoplasias del Colon , Factor 2 Relacionado con NF-E2 , Estilbenos , Humanos , Estilbenos/farmacología , Apoptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Arsenic, a neurotoxic metalloid, poses significant health risks. However, ellagic acid, renowned for its antioxidant properties, has shown potential in neuroprotection. This study aimed to investigate the neuroprotective effects of ellagic acid against arsenic-induced neuronal ferroptosis and cognitive impairment and elucidate the underlying mechanisms. Using an arsenic-exposed Wistar rat model and an arsenic-induced HT22 cells model, we assessed cognitive ability, measured serum and brain arsenic levels, and evaluated pathological damage through histological analysis and transmission electron microscopy. Additionally, we examined oxidative stress and iron ion levels using GSH, MDA, ROS and tissue iron biochemical kits, and analyzed the expression of ferroptosis-related markers using western blot and qRT-PCR. Our results revealed that arsenic exposure increased both serum and brain arsenic levels, resulting in hippocampal pathological damage and subsequent decline in learning and memory abilities. Arsenic-induced neuronal ferroptosis was mediated by the inhibition of the xCT/GSH/GPX4/Nrf2 signaling axis and disruption of iron metabolism. Notably, ellagic acid intervention effectively reduced serum and brain arsenic levels, ameliorated neuronal damage, and improved oxidative stress, ferroptosis, and cognitive impairment. These beneficial effects were associated with the activation of the Nrf2/Keap1 signaling pathway, upregulation of GPX4 expression, and enhanced iron ion excretion. In conclusion, ellagic acid demonstrates promising neuroprotective effects against arsenic-induced neurotoxicity by mitigating neuronal ferroptosis and cognitive impairment.
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Arsénico , Disfunción Cognitiva , Ácido Elágico , Ferroptosis , Factor 2 Relacionado con NF-E2 , Neuronas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ratas Wistar , Transducción de Señal , Animales , Ácido Elágico/farmacología , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Arsénico/toxicidad , Transducción de Señal/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores/farmacologíaRESUMEN
Aim: This study aimed to investigate the in vitro antitumor activity of new series of 2-thiohydanotin derivatives (7 and 9) against two cancer cell lines.Materials & methods: A new series of 2-thioxoimidazolidine derivatives (3-9) were synthesized and investigated for its structure through spectral analysis and also tested against (HepG-2) and (HCT-116) cell line.Results: Among the synthesized compounds, compound 7 halted liver cancer cells at the G0/G1 phase and triggered apoptosis of liver cancer. Contrarily, compound 9 caused colon cancer cells to be arrested at the S phase and trigger apoptosis. Also, they had a good inhibitory effect on (Nrf2).Conclusion: Both compounds had attractive lead molecules for the creation of colon and liver cancer medications.
[Box: see text].
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Antineoplásicos , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Tionas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Tionas/química , Tionas/farmacología , Tionas/síntesis química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Células Hep G2 , Imidazolidinas/química , Imidazolidinas/farmacología , Imidazolidinas/síntesis química , Células HCT116 , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Línea Celular Tumoral , Relación Dosis-Respuesta a DrogaRESUMEN
Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.
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Ferroptosis , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Estrés Oxidativo , Daño por Reperfusión , Tionas , Tiofenos , Animales , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Tionas/farmacología , Tionas/uso terapéutico , Células PC12 , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Ratas , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Modelos Animales de Enfermedad , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , PirazinasRESUMEN
The newly identified estrogen receptor, G protein-coupled receptor 30 (GPR30), is prevalent in the brain and has been shown to provide significant neuroprotection. Recent studies have linked ferroptosis, a newly characterized form of programmed cell death, closely with cerebral ischemia-reperfusion injury (CIRI), highlighting it as a major contributing factor. Consequently, our research aimed to explore the potential of GPR30 targeting in controlling neuronal ferroptosis and lessening CIRI impacts. Results indicated that GPR30 activation not only improved neurological outcomes and decreased infarct size in a mouse model but also lessened iron accumulation and malondialdehyde formation post-middle cerebral artery occlusion (MCAO). This protective effect extended to increased levels of Nrf2 and GPX4 proteins. Similar protective results were replicated in PC12 cells subjected to Oxygen Glucose Deprivation and Reoxygenation (OGD/R) using the GPR30-specific agonist G1. Importantly, inhibition of Nrf2 with ML385 curtailed the neuroprotective effects of GPR30 activation, suggesting that GPR30 mitigates CIRI primarily through inhibition of neuronal ferroptosis via upregulation of Nrf2 and GPX4.
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Ferroptosis , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Daño por Reperfusión , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Transducción de Señal/efectos de los fármacos , Ratones , Células PC12 , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Masculino , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Modelos Animales de EnfermedadRESUMEN
PURPOSE: In this in vitro study, we investigated the effects of polychlorinated biphenyls (PCBs) on human thyrocytes, with a focus on the involvement of AhR, a key player in xenobiotic response, and the anti-oxidant Nrf-2/HO-1 pathway. METHODS: Primary cultured thyrocytes were exposed to the dioxin-like congeners PCB118 and PCB126 at 2.5 and 5 µM concentrations. mRNA expression was assessed by real-time PCR, and protein expression by Western Blot and ELISA, while protein quantification was assessed by densitometric analysis. RESULTS: In cultured thyrocytes, PCB118 and PCB126 induced a significant (P < 0.01) increase of mRNA and protein levels of the pro-inflammatory cytokines IL-1beta and IL-6, while reducing those of thyroglobulin (TG) and NIS (p < 0.05), indicating down-regulation of these thyroid-specific genes in PCB-induced inflammation. ROS production also increased (p < 0.001). mRNA levels of AhR and the downstream molecules cytochrome P4501A, Nrf-2/HO-1 increased (p < 0.001), as well as related protein levels (p < 0.01), suggesting the activation of AhR and Nrf-2 pathways in response to PCBs exposure. AhR silencing decreased AhR-related gene expression and restored NIS and TG expression, while reducing inflammatory cytokines and oxidative stress markers (p < 0.05). CONCLUSIONS: Dioxin-like PCBs (PCB118 and PCB126) may promote inflammation and oxidative stress in thyrocytes, impairing the expression of genes that are key players of thyroid function. These effects can be partially attributed to the activation of the AhR and Nrf-2 pathways. These data may contribute to explain the mechanisms underlying thyroid toxicity of PCBs, highlighting the potential role of these pollutants as a trigger of autoimmune thyroid inflammation and damage.
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BACKGROUND: Sodium Benzoate (SB) is used in daily products such as drinks, juices, sauces, oils, ketchup, toothpaste, mouthwashes, cosmetics, dentifrices, and pharmaceutical products. However, SB has been implicated in gonadotoxicity even at a dosage within the safe limit. Zinc (Zn), on the other hand, has been shown to improve various fertility indices. Hence, this study was designed to explore the possible ameliorative effect of Zn on SB-induced testicular toxicity. METHODS: Animals were randomly divided into control, SB, Zn, and SB+Zn. All treatment lasted for 28 days. RESULTS: SB treatment caused a derangement in reproductive hormone levels, sperm function, and kinematics and a down-regulation of the Androgen receptor (ANDR). Also, a decrease in testicular levels of SOD, CAT, GSH, Nrf2, and HO- 1 activity and an increase in IL-1ß, TNF-α, Nf-κB, and Caspase 3 were observed. These SB-induced distortions were ameliorated in SB-treated rats exposed to Zn. CONCLUSION: Our study suggests that zinc abates SB-induced testicular toxicity by modulating Nrf2/HO-1/ Nf-κB signaling and ANDR upregulation.
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BACKGROUND: Hypothermia during laparoscopic surgery in patients with multiple trauma is a significant concern owing to its potential complications. Machine learning models offer a promising approach to predict the occurrence of intraoperative hypothermia. AIM: To investigate the value of machine learning model to predict hypothermia during laparoscopic surgery in patients with multiple trauma. METHODS: This retrospective study enrolled 220 patients who were admitted with multiple injuries between June 2018 and December 2023. Of these, 154 patients were allocated to a training set and the remaining 66 were allocated to a validation set in a 7:3 ratio. In the training set, 53 cases experienced intraoperative hypothermia and 101 did not. Logistic regression analysis was used to construct a predictive model of intraoperative hypothermia in patients with polytrauma undergoing laparoscopic surgery. The area under the curve (AUC), sensitivity, and specificity were calculated. RESULTS: Comparison of the hypothermia and non-hypothermia groups found significant differences in sex, age, baseline temperature, intraoperative temperature, duration of anesthesia, duration of surgery, intraoperative fluid infusion, crystalloid infusion, colloid infusion, and pneumoperitoneum volume (P < 0.05). Differences between other characteristics were not significant (P > 0.05). The results of the logistic regression analysis showed that age, baseline temperature, intraoperative temperature, duration of anesthesia, and duration of surgery were independent influencing factors for intraoperative hypothermia during laparoscopic surgery (P < 0.05). Calibration curve analysis showed good consistency between the predicted occurrence of intraoperative hypothermia and the actual occurrence (P > 0.05). The predictive model had AUCs of 0.850 and 0.829 for the training and validation sets, respectively. CONCLUSION: Machine learning effectively predicted intraoperative hypothermia in polytrauma patients undergoing laparoscopic surgery, which improved surgical safety and patient recovery.
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Background: Tamoxifen (TAM) is a widely used drug in patients with gynecomastia and breast cancer. TAM exerts its anticancer effects via its antiestrogenic activities. Unfortunately, TAM has been reported to exert gonadotoxic effects on male testes. Therefore, this study was designed to explore the possible associated mechanisms involved in TAM-induced testicular dysfunction and the possible ameliorative effects of omega-3 fatty acids (O3FA). Methodology: Animals were randomly divided into control, O3FA, TAM, and TAM + O3FA. All treatment lasted for 28 days. Results: TAM exposure impaired sperm qualities (count, motility, and normal morphology) and decreased testicular 3ß-HSD and 17ß-HSD. It was accompanied by a decline in serum testosterone and an increase in estradiol, luteinizing and follicle-stimulating hormones. These observed alterations were associated with an increase in testicular injury markers, oxido-inflammatory response, and mitochondria-mediated apoptosis. These observed alterations were ameliorated by O3FA treatments. Conclusions: O3FA ameliorated TAM-induced testicular dysfunction in male Wistar rats by modulating XO/UA and Nrf2/NF-kb signaling and cytochrome c-mediated apoptosis in TAM-treated rats.
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BACKGROUND: Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid-related factor 2 (Nrf2) and Kruppel-like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti-inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin-sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long-term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti-inflammatory effect, may attenuate the development and progression of AS. AIMS: Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. CONCLUSION: In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis.
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Aterosclerosis , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Factores de Transcripción de Tipo Kruppel , Metformina , Factor 2 Relacionado con NF-E2 , Metformina/uso terapéutico , Metformina/farmacología , Humanos , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Factores de Transcripción de Tipo Kruppel/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Animales , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
In this editorial, we review the work of Razali et al published in World J Gastroenterology, with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase (PI3K) pathway and buparlisib on colitis-associated cancer. The role of PI3K in promoting cancer progression has been widely recognized, as it is involved in regulating the survival, differentiation, and proliferation of cancer cells. The complement Clq/TNF-related protein 6 (CTRP6) is a newer tumor-associated factor. Recent studies have revealed the pro-tumor effect of CTRP6 in gastric cancer, hepatocellular carcinoma, colorectal cancer, and other gastrointestinal tumors through the PI3K pathway. This article attempts to reveal the mechanism through which the CTRP6 affects the development of digestive system tumors through the PI3K pathway by summarizing recent research.
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Fosfatidilinositol 3-Quinasa , Transducción de Señal , Humanos , Fosfatidilinositol 3-Quinasa/metabolismo , Neoplasias del Sistema Digestivo/patología , Neoplasias del Sistema Digestivo/metabolismoRESUMEN
High-fat diet-induced metabolic syndrome (MetS) is closely associated with cardiac dysfunction. Recent research studies have indicated a potential association between MetS and ferroptosis. Furthermore, metformin can alleviate MetS-induced cardiac ferroptosis. Metformin is a classic biguanide anti-diabetic drug that has protective effects on cardiovascular diseases, which extend beyond its indirect glycemic control. This study aimed to assess whether MetS mediates cardiac ferroptosis, thereby causing oxidative stress and mitochondrial dysfunction. The results revealed that metformin can mitigate cardiac reactive oxygen species and mitochondrial damage, thereby preserving cardiac function. Mechanistic analysis revealed that metformin upregulates the expression of cardiac Nrf2. Moreover, Nrf2 downregulation compromises the cardio-protective effects of metformin. In summary, this study indicated that MetS promotes cardiac ferroptosis, and metformin plays a preventive and therapeutic role, partially through modulation of Nrf2 expression.