RESUMEN

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.

RESUMEN

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.

Asunto(s)

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-E2

RESUMEN

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.

RESUMEN

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.

RESUMEN

Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12-24 h, with approximate levels of 1200 µg/mL, 0.14 µg/mL, and 0.2-0.3 µg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 µg/mg) is 10-fold higher than that in normal prostate tissues (0.14 µg/mg). The analysis also reveals that C6-STA has t1/2 of 12.8 h and Tmax of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.

Asunto(s)

Peroxirredoxinas , Prebióticos , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Animales , Ratones , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Peroxirredoxinas/metabolismo , Humanos , Línea Celular Tumoral , Oligosacáridos/farmacología , Oligosacáridos/química , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo

RESUMEN

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.

RESUMEN

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.

Asunto(s)

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 Enfermedad

RESUMEN

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.

RESUMEN

Cerebral ischemic/reperfusion (I/R) injury has high disability and morbidity. Hypoxia-inducible factor-1α (HIF-1α) may enhance the transcriptional activity of transferrin ferroportin 1 (FPN1) in regulating ferroptosis after cerebral ischemia injury (CII). In this study, cerebral I/R injury rat models were established and treated with pcDNA3.1-HIF-1α, pcDNA3.1-NC lentiviral plasmid, or ML385 (a specific Nrf2 inhibitor). Additionally, oxygen-glucose deprivation/reoxygenation (OGD/R) exposed PC12 cells were used as an in vitro model of cerebral ischemia and treated with pcDNA3.1-HIF-1α, si-FPN1, or ML385. The results elicited that cerebral I/R injury rats exhibited increased Longa scores, TUNEL and NeuN co-positive cells, Fe2+ concentration, ROS and HIF-1α levels, and MDA content, while reduced cell density and number, GSH content, and GPX4 protein level. Morphologically abnormal and disordered hippocampal neurons were also observed in CII rats. HIF-1α inhibited brain neuron ferroptosis and ameliorated I/R injury. HIF-1α alleviated OGD-induced PC12 cell ferroptosis. OGD/R decreased FPN1 protein level in PC12 cells, and HIF-1α enhanced FPN1 transcriptional activity. FPN1 knockdown reversed HIF-1α-mediated alleviation of OGD/R-induced ferroptosis. HIF-1α activated the Nrf2/HO-1 pathway by enhancing FPN1 expression and alleviating OGD/R-induced ferroptosis. Conjointly, HIF-1α enhanced the transcriptional activity of FPN1, activated the Nrf2/HO-1 pathway, and inhibited ferroptosis of brain neurons, thereby improving I/R injury in CII rats.

RESUMEN

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.

RESUMEN

Gestational diabetes mellitus (GDM) disrupts glucolipid metabolism, endangering maternal and fetal health. Despite limited research on its pathogenesis and treatments, we conducted a study using serum samples from GDM-diagnosed pregnant women. We performed metabolic sequencing to identify key small molecule metabolites and explored their molecular interactions with FGF21. We also investigated FGF21's impact on GDM using blood samples from affected women. Our analysis revealed a novel finding: elevated levels of L-Cystine in GDM patients. Furthermore, we observed a positive correlation between L-Cystine and FGF21 levels, and found that L-Cystine induces NRF2 expression via FGF21 for a period of 96 h. Under high glucose (HG) conditions, FGF21 upregulates NRF2 and downstream genes NQO1 and EPHX1 via AKT phosphorylation induced by activation of IRS1, enhancing endothelial function. Additionally, we confirmed that levels of FGF21, L-Cystine, and endothelial function at the third trimester were effectively enhanced through appropriate exercise and diet during pregnancy in GDM patients (GDM + ED). These findings suggest FGF21 as a potential therapeutic agent for GDM, particularly in protecting endothelial cells. Moreover, elevated L-Cystine via appropriate exercise and diet might be a potential strategy to enhance FGF21's efficacy.

Asunto(s)

Cistina , Diabetes Gestacional , Factores de Crecimiento de Fibroblastos , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Humanos , Diabetes Gestacional/metabolismo , Femenino , Embarazo , Factores de Crecimiento de Fibroblastos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Adulto , Transducción de Señal/efectos de los fármacos , Cistina/metabolismo

RESUMEN

In recent years, the interest in cell transplantation therapy using human dental pulp cells (DPCs) has been increasing. However, significant differences exist in the individual cellular characteristics of human DPC clones and in their therapeutic efficacy in rodent models of spinal cord injury (SCI); moreover, the cellular properties associated with their therapeutic efficacy for SCI remain unclear. Here, using DPC clones from seven different donors, we found that most of the clones were highly resistant to H2O2 cytotoxicity if, after transplantation, they significantly improved the locomotor function of rats with complete SCI. Therefore, we examined the effects of the basic fibroblast growth factor 2 (FGF2) and bardoxolone methyl (RTA402), which is a nuclear factor erythroid 2-related factor 2 (Nrf2) chemical activator, on the total antioxidant capacity (TAC) and the resistance to H2O2 cytotoxicity. FGF2 treatment enhanced the resistance of a subset of clones to H2O2 cytotoxicity. Regardless of FGF2 priming, RTA402 markedly enhanced the resistance of many DPC clones to H2O2 cytotoxicity, concomitant with the upregulation of heme oxygenase-1 (HO-1) and NAD(P)H-quinone dehydrogenase 1 (NQO1). With the exception of a subset of clones, the TAC was not increased by either FGF2 priming or RTA402 treatment alone, whereas it was significantly upregulated by both treatments in each clone, or among all seven DPC clones together. Thus, the TAC and resistance to H2O2 cytotoxicity were, to some extent, independently regulated and were strongly enhanced by both FGF2 priming and RTA402 treatment. Moreover, even a DPC clone that originally exhibited no therapeutic effect on SCI improved the locomotor function of mice with SCI after transplantation under both treatment regimens. Thus, combined with FGF2, RTA402 may increase the number of transplanted DPCs that migrate into and secrete neurotrophic factors at the lesion epicenter, where reactive oxygen species are produced at a high level.

Asunto(s)

Antioxidantes , Pulpa Dental , Factor 2 de Crecimiento de Fibroblastos , Factor 2 Relacionado con NF-E2 , Traumatismos de la Médula Espinal , Pulpa Dental/metabolismo , Pulpa Dental/citología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Humanos , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Ratas , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Peróxido de Hidrógeno , Masculino , Ratas Sprague-Dawley , Hemo-Oxigenasa 1/metabolismo , Ratones

RESUMEN

Aloe-emodin, a natural hydroxyanthraquinone, exerts both adverse and protective effects. This study aimed at investigating these potential effects of aloe-emodin in humans upon the use of food supplements and herbal medicines using a physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach. For this, PBK models in rats and humans were established for aloe-emodin including its active metabolite rhein and used to convert in vitro data on hepatotoxicity, nephrotoxicity, reactive oxidative species (ROS) generation, and Nrf2 induction to corresponding in vivo dose-response curves, from which points of departure (PODs) were derived by BMD analysis. The derived PODs were subsequently compared to the estimated daily intakes (EDIs) resulting from the use of food supplements or herbal medicines. It is concluded that the dose levels of aloe-emodin from food supplements or herbal medicines are unlikely to induce toxicity, ROS generation, or Nrf2 activation in liver and kidney.

Asunto(s)

Antraquinonas , Riñón , Hígado , Animales , Humanos , Ratas , Riñón/metabolismo , Riñón/efectos de los fármacos , Antraquinonas/química , Antraquinonas/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Cinética , Masculino , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Suplementos Dietéticos/análisis , Aloe/química , Aloe/metabolismo , Ratas Sprague-Dawley , Femenino

RESUMEN

Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)-nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR-NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.

Asunto(s)

Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Queratinocitos , Factor 2 Relacionado con NF-E2 , Inhibidores de Fosfodiesterasa 4 , Receptores de Hidrocarburo de Aril , Transducción de Señal , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa 4/farmacología , Interleucina-33/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Línea Celular

RESUMEN

BACKGROUND: Diallyl trisulfide (DATS) has a direct antioxidant capacity and emerges as a promising neuroprotective agent. This study was designed to investigate the role of DATS in traumatic brain injury (TBI). METHODS: TBI mouse models were established using the controlled cortical impact, followed by DATS administration. The effects of DATS on neurological deficit, brain damage, inflammation and phosphoglycerate kinase 1 (PGK1) expression were detected using mNSS test, histological analysis, TUNEL assay, enzyme-linked immunosorbent assay and immunofluorescence. PC12 cells were subjected to H2O2-induced oxidative injury after pre-treatment with DATS, followed by cell counting kit-8 assay, flow cytometry and ROS production detection. Apoptosis-related proteins and the PGK1/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway were examined using Western blot. RESULTS: DATS ameliorated the cerebral cortex damage, neurological dysfunction and apoptosis, as well as decreased PGK1 expression and expressions of pro-inflammatory cytokines (IL-6, IL-1ß, TNF-α) in mice after TBI. DATS also enhanced viability, blocked apoptosis and inhibited ROS production in H2O2-induced PC12 cells. DATS downregulated Cleaved-Caspase3, Bax and PGK1 levels, and upregulated Bcl-2 and Nrf2 levels in TBI mouse models and the injured cells. CONCLUSION: DATS regulates PGK1/Nrf2 expression and inflammation to alleviate neurological damage in mice after TBI.

Asunto(s)

Compuestos Alílicos , Apoptosis , Lesiones Traumáticas del Encéfalo , Factor 2 Relacionado con NF-E2 , Fosfoglicerato Quinasa , Sulfuros , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Sulfuros/farmacología , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Fosfoglicerato Quinasa/metabolismo , Compuestos Alílicos/farmacología , Células PC12 , Masculino , Apoptosis/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Ratas , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Antioxidantes/farmacología

RESUMEN

Maternal prenatal hypoxia is an important contributor to intrauterine growth restriction (IUGR), which impedes fetal lung maturation and leads to the development of chronic lung diseases. Although evidence suggests the involvement of pyroptosis in IUGR, the molecular mechanism of pyroptosis is still unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been found to potentially interact with gasdermin D (GSDMD), the key protein responsible for pyroptosis, indicating its crucial role in inhibiting pyroptosis. Therefore, we hypothesized that Nrf2 deficiency is a key molecular responsible for lung pyroptosis in maternal hypoxia-induced IUGR offspring mice. Pregnant WT and Nrf2-/- mice were exposed to hypoxia (10.5 % O2) to mimic IUGR model. We assessed body weight, lung histopathology, pulmonary angiogenesis, oxidative stress levels, as well as mRNA and protein expressions related to inflammation in the 2-week-old offspring. Additionally, we conducted a dual-luciferase reporter assay to confirm the targeting relationship between Nrf2 and GSDMD. Our findings revealed that offspring with maternal hypoxia-induced IUGR exhibited reduced birth weight, catch-up growth delay, and pulmonary dysplasia. Furthermore, we observed impaired nuclear translocation of Nrf2 and increased GSDMD-mediated pyroptosis in these offspring with IUGR. Moreover, the dual-luciferase reporter assay demonstrated that Nrf2 could directly inhibit GSDMD transcription; deficiency of Nrf2 exacerbated pyroptosis and pulmonary dysplasia in offspring with maternal hypoxia-induced IUGR. Collectively, our findings suggest that Nrf2 deficiency induces GSDMD-mediated pyroptosis and pulmonary dysplasia in offspring with maternal hypoxia-induced IUGR; thus highlighting the potential therapeutic approach of targeting Nrf2 for treating prenatal hypoxia-induced pulmonary dysplasia in offspring.

Asunto(s)

Retardo del Crecimiento Fetal , Hipoxia , Pulmón , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2 , Piroptosis , Animales , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Embarazo , Femenino , Hipoxia/complicaciones , Pulmón/patología , Pulmón/metabolismo , Ratones , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Efectos Tardíos de la Exposición Prenatal , Masculino , Estrés Oxidativo , Gasderminas

RESUMEN

Head and neck squamous cell carcinoma (HNSCC) affects squamous cells in the head and neck region and is currently ranked as the sixth most common cancer worldwide. NF-E2-related factor 2 (NRF2) plays a crucial role in cellular protection and defence mechanisms and NRF2 over-expression has been linked to various cancers; however, its role in the response of HNSCC cells remains elusive. We investigated the effects of ML385, a selective NRF2 inhibitor, on HNSCC to understand the underlying molecular mechanisms, and to assess the potential of ML385 as a therapeutic agent. We treated HNSCC cell lines with ML385 and observed a significant reduction in the expression of NRF2 and its downstream target, heme oxygenase-1 (HO-1), using Western blotting. We evaluated its effects on various cellular processes, including cell proliferation, cloning, migration, and wound healing, in HNSCC cell lines. ML385 treatment substantially reduced NRF2 expression, promoting a decrease in the investigated cellular activities. Additionally, we examined changes in the expression of cell-cycle-related proteins and found that ML385 induced cell cycle arrest at the G1/S phase in HNSCC cell lines. Our findings suggest that ML385 can regulate cell cycle progression, inhibit HNSCC growth, and have potential as a therapeutic agent for HNSCC.

Asunto(s)

Movimiento Celular , Proliferación Celular , Neoplasias de Cabeza y Cuello , Factor 2 Relacionado con NF-E2 , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Movimiento Celular/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , Acetamidas , Benzodioxoles

RESUMEN

Obesity is commonly linked with white adipose tissue (WAT) dysfunction, setting off inflammation and oxidative stress, both key contributors to the cardiometabolic complications associated with obesity. To improve metabolic and cardiovascular health, countering these inflammatory and oxidative signaling processes is crucial. Offering potential in this context, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by nitro-fatty acids (NO2-FA) promote diverse anti-inflammatory signaling and counteract oxidative stress. Additionally, we previously highlighted that nitro-oleic acid (NO2-OA) preferentially accumulates in WAT and provides protection against already established high fat diet (HFD)-mediated impaired glucose tolerance. The precise mechanism accounting for these protective effects remained largely unexplored until now. Herein, we reveal that protective effects of improved glucose tolerance by NO2-OA is absent when Nrf2 is specifically ablated in adipocytes (ANKO mice). NO2-OA treatment did not alter body weight between ANKO and littermate controls (Nrf2fl/fl) mice on both the HFD and low-fat diet (LFD). As expected, at day 76 (before NO2-OA treatment) and notably at day 125 (daily treatment of 15 mg/kg NO2-OA for 48 days), both HFD-fed Nrf2fl/fl and ANKO mice exhibited increased fat mass and reduced lean mass compared to LFD controls. However, throughout the NO2-OA treatment, no distinction was observed between Nrf2fl/fl and ANKO in the HFD-fed mice as well as in the Nrf2fl/fl mice fed a LFD. Glucose tolerance tests revealed impaired glucose tolerance in HFD-fed Nrf2fl/fl and ANKO compared to LFD-fed Nrf2fl/fl mice. Notably, NO2-OA treatment improved glucose tolerance in HFD-fed Nrf2fl/fl but did not yield the same improvement in ANKO mice at days 15, 30, and 55 of treatment. Unraveling the pathways linked to NO2-OA's protective effects in obesity-mediated impairment in glucose tolerance is pivotal within the realm of precision medicine, crucially propelling future applications and refining novel drug-based strategies.

Asunto(s)

Adipocitos , Dieta Alta en Grasa , Factor 2 Relacionado con NF-E2 , Obesidad , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Ratones , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Intolerancia a la Glucosa/metabolismo , Ácidos Oléicos/farmacología , Ratones Noqueados

RESUMEN

Obesity aggravates ferroptosis, and vitamin D (VD) may inhibit ferroptosis. We hypothesized that weight reduction and/or calcitriol administration have benefits against the sepsis-induced liver redox imbalance and ferroptosis in obese mice. Mice were fed a high-fat diet for 11 weeks, then half of the mice continued to consume the diet, while the other half were transferred to a low-energy diet for 5 weeks. After feeding the respective diets for 16 weeks, sepsis was induced by cecal ligation and puncture (CLP). Septic mice were divided into four experimental groups: OS group, obese mice injected with saline; OD group, obese mice with calcitriol; WS group, weight-reduction mice with saline; and WD group, weight-reduction mice with calcitriol. Mice in the respective groups were euthanized at 12 or 24 h after CLP. Results showed that the OS group had the highest inflammatory mediators and lipid peroxide levels in the liver. Calcitriol treatment reduced iron content, enhanced the reduced glutathione/oxidized glutathione ratio, upregulated nuclear factor erythroid 2-related factor 2, ferroptosis-suppressing protein 1, and solute carrier family 7 member 11 expression levels. Also, mitochondrion-associated nicotinamide adenine dinucleotide phosphate oxidase 1, peroxisome proliferator-activated receptor-γ coactivator 1, hypoxia-inducible factor-1α, and heme oxidase-1 expression levels increased in the late phase of sepsis. These results were not noted in the WS group. These findings suggest that calcitriol treatment elicits a more-balanced glutathione redox status, alleviates liver ferroptosis, and enhances mitochondrial biogenesis-associated gene expressions. Weight reduction alone had minimal influences on liver ferroptosis and mitochondrial biogenesis in obese mice with sepsis.

Asunto(s)

Calcitriol , Dieta Alta en Grasa , Ferroptosis , Hígado , Ratones Endogámicos C57BL , Obesidad , Oxidación-Reducción , Sepsis , Animales , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Oxidación-Reducción/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Masculino , Ratones , Calcitriol/farmacología , Calcitriol/administración & dosificación , Ratones Obesos

RESUMEN

Ferroptosis induction is particularly promising for cancer therapy when the apoptosis pathway is compromised. Current strategies in nanomedicine for inducing ferroptosis primarily focus on promoting the accumulation of reactive oxygen species (ROS). However, the presence of intracellular antioxidants, such as nuclear factor erythroid 2-related factor 2 (Nrf2), can limit the effectiveness of such therapy by activating detoxification systems and eliminating ROS. To overcome this challenge, we developed a synergistic ferroptosis-inducing agent by modifying manganese (Mn2+)-1,8-dihydroxy-3-hydroxymethyl-anthraquinone (aloe-emodin, AE) with polyvinyl pyrrolidone (PVP) to create nanoparticles (MAP NPs). In the tumor microenvironment, these NPs degraded and released AE and Mn(II), facilitating the generation of ROS and Mn(IV) through a Fenton-like reaction between hydrogen peroxide (H2O2) and Mn(II). Mn(IV) subsequently interacts with glutathione (GSH) to induce a cyclic catalytic effect, and the depletion of GSH diminished the activation of glutathione-dependent peroxidase 4 (GPX4). Furthermore, AE inhibits the activity of Nrf2 and depleted GSH, thereby synergistically enhancing antitumor efficacy. Here it is demonstrated that MAP NPs effectively generate a robust ROS storm within tumor cells, suggesting that high-performance ferroptosis therapy is effective. Additionally, the inclusion of Mn(II) in the MAP NPs enables real-time monitoring of therapeutic efficacy via magnetic resonance T1-weighted contrast imaging.