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Cadmium (Cd) is a global pollutant, and its accumulation in the liver causes oxidative stress, inflammation, insulin resistance (IR), and metabolic complications. This study investigated whether curcumin treatment could alleviate hepatic IR in Wistar rats exposed to sub-chronic cadmium and explored the underlying molecular pathways. Male Wistar rats were divided into a control group (standard normocaloric diet + cadmium-free water) and a cadmium group (standard normocaloric diet + drinking water with 32.5 ppm CdCl2) for 30 days. Oral glucose tolerance, insulin response, and IR were assessed using mathematical models. Liver tissue was analyzed for markers of oxidative stress, inflammation, and key regulatory pathways, including NF-κB, Nrf2, MAPKs (JNK and p38), and the IRS1-Akt pathway. We established an effective curcumin dose of 250 mg/kg for 5 days orally. Results demonstrated that after 30 days of exposure, cadmium accumulated in the liver, inducing an oxidative and inflammatory state. This was characterized by increased expression of NF-κB, JNK, and p38, along with diminished Nrf2 expression, hepatic IR, hyperglycemia, and hyperinsulinemia. Curcumin treatment effectively alleviated these metabolic disorders by restoring the balance between NF-κB and Nrf2 in the liver, modulating the MAPK pathway, and, consequently, improving oxidative and inflammatory balance. In conclusion, this study suggests that cadmium induces hepatic IR through an imbalance between NF-κB and Nrf2 signaling pathways. Curcumin treatment appears to improve these pathways, thereby ameliorating hepatic IR.

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INTRODUCTION: One of the markers of aging is oxidative stress, a condition characterized by an increase in free radicals concomitant with a reduction in antioxidant defenses. Within this, resveratrol is a compound that has been shown to act as a potent antioxidant. However, few studies highlight the cellular signaling pathways that are activated or inhibited during aging and that are responsible for this biological effect. AIM: To verify the antioxidant profile of resveratrol (5 µM) in leukocytes from donors in different age groups. METHODS: The project was approved by the Ethics Committee. Individuals were divided into three groups: 20-39, 40-59, and 60-80 years old. After separating the leukocytes, assays were performed to evaluate the AMPK (AMP-activated protein kinase) and Nrf2 (erythroid nuclear factor 2-related factor 2) pathways. In addition, luciferase assay and enzyme-linked immunosorbent assay were performed to evaluate transcription factor activation and Nrf2 expression, respectively. The analysis between age and treatment was performed using Pearson correlation (*P < 0.05). RESULTS: There was a reduction in the antioxidant effect of resveratrol during the aging process. In leukocytes from donors over 60 years of age, the AMPK pathway was silenced. Nrf2 was active at all ages. There was an increase in the activation of the transcription factor and phosphorylated protein in all age groups. CONCLUSIONS: Nrf2 is an important biochemical mechanism responsible for the antioxidant effect of resveratrol. This effect diminishes with aging but is still observed. Geriatr Gerontol Int 2024; ••: ••-••.

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Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor that activates antioxidant genes and increases detoxifying enzymes. Studies have shown that dietary compounds can activate the Nrf2 expression and improve the antioxidant response in patients with exacerbated oxidative stress, such as chronic kidney disease (CKD). We aimed to evaluate the efficacy of nutritional interventions on Nrf2 expression and phase II antioxidant enzymes in clinical trials in CKD. We searched PubMed, Lilacs, Embase, Scopus, and Cochrane Library databases of published clinical trials and the Cochrane tool was used for the quality assessment of the studies included. We reported this review according to the PRISMA and it was registered in PROSPERO (42023389619). Thirty-nine studies were included in this review; nine evaluated the Nrf2 expression and three showed an increase in its expression. Twenty-three studies found an increase in the antioxidant enzyme levels, including superoxide dismutase, catalase, and glutathione peroxidase. Moreover, a high risk of bias was found in most of the studies and high heterogeneity in the designs, type, and duration of supplementation administered. These results suggest that dietary supplementations have a promising effect on the antioxidant enzyme response, however, it is recommended that further studies should be carried out.

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Neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are characterized by persistent changes in communication and social interaction, as well as restricted and stereotyped patterns of behavior. The complex etiology of these disorders possibly combines the effects of multiple genes and environmental factors. Hence, exposure to insecticides such as imidacloprid (IMI) has been used to replicate the changes observed in these disorders. Lutein is known for its anti-inflammatory and antioxidant properties and is associated with neuroprotective effects. Therefore, the aim of this study was to evaluate the protective effect of lutein-loaded nanoparticles, along with their mechanisms of action, on Drosophila melanogaster offspring exposed to IMI-induced damage. To simulate the neurodevelopmental disorder model, flies were exposed to a diet containing IMI for 7 days. Posteriorly, their offspring were exposed to a diet containing lutein-loaded nanoparticles for a period of 24 h, and male and female flies were subjected to behavioral and biochemical evaluations. Treatment with lutein-loaded nanoparticles reversed the parameters of hyperactivity, aggressiveness, social interaction, repetitive movements, and anxiety in the offspring of flies exposed to IMI. It also protected markers of oxidative stress and cell viability, in addition to preventing the reduction of Nrf2 and Shank3 immunoreactivity. These results demonstrate that the damage induced by exposure to IMI was restored through treatment with lutein-loaded nanoparticles, elucidating lutein's mechanisms of action as a therapeutic agent, which, after further studies, can become a co-adjuvant in the treatment of neurodevelopmental disorders, such as ASD and ADHD.

Assuntos

Comportamento Animal , Drosophila melanogaster , Luteína , Nanopartículas , Nitrocompostos , Animais , Drosophila melanogaster/efeitos dos fármacos , Luteína/farmacologia , Luteína/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Masculino , Feminino , Nitrocompostos/toxicidade , Neonicotinoides/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Inseticidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Transtornos do Neurodesenvolvimento/prevenção & controle , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo

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Glioblastoma (GBM) is an aggressive form of cancer affecting the Central Nervous System (CNS) of thousands of people every year. Redox alterations have been shown to play a key role in the development and progression of these tumors as Reactive Oxygen Species (ROS) formation is involved in the modulation of several signaling pathways, transcription factors, and cytokine formation. The second-generation oral alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic drug used to treat of GBM, though patients often develop primary and secondary resistance, reducing its efficacy. Antioxidants represent promising and potential coadjutant agents as they can reduce excessive ROS formation derived from chemo- and radiotherapy, while decreasing pharmacological resistance. S-allyl-cysteine (SAC) has been shown to inhibit the proliferation of several types of cancer cells, though its precise antiproliferative mechanisms remain poorly investigated. To date, SAC effects have been poorly explored in GBM cells. Here, we investigated the effects of SAC in vitro, either alone or in combination with TMZ, on several toxic and modulatory endpoints-including oxidative stress markers and transcriptional regulation-in two glioblastoma cell lines from rats, RG2 and C6, to elucidate some of the biochemical and cellular mechanisms underlying its antiproliferative properties. SAC (1-750 µM) decreased cell viability in both cell lines in a concentration-dependent manner, although C6 cells were more resistant to SAC at several of the tested concentrations. TMZ also produced a concentration-dependent effect, decreasing cell viability of both cell lines. In combination, SAC (1 µM or 100 µM) and TMZ (500 µM) enhanced the effects of each other. SAC also augmented the lipoperoxidative effect of TMZ and reduced cell antioxidant resistance in both cell lines by decreasing the TMZ-induced increase in the GSH/GSSG ratio. In RG2 and C6 cells, SAC per se had no effect on Nrf2/ARE binding activity, while in RG2 cells TMZ and the combination of SAC + TMZ decreased this activity. Our results demonstrate that SAC, alone or in combination with TMZ, exerts antitumor effects mediated by regulatory mechanisms of redox activity responses. SAC is also a safe drug for testing in other models as it produces non-toxic effects in primary astrocytes. Combined, these effects suggest that SAC affords antioxidant properties and potential antitumor efficacy against GBM.

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Understanding the complex biological processes of cells in culture, particularly those related to metabolism, can be biased by culture conditions, since the choice of energy substrate impacts all of the main metabolic pathways. When glucose is replaced by galactose, cells decrease their glycolytic flux, working as an in vitro model of limited nutrient availability. However, the effect of these changes on related physiological processes such as redox control is not well documented, particularly in endothelial cells, where mitochondrial oxidation is considered to be low. We evaluated the differences in mitochondrial dynamics and function in endothelial cells exposed to galactose or glucose culture medium. We observed that cells maintained in galactose-containing medium show a higher mitochondrial oxidative capacity, a more fused mitochondrial network, and higher intercellular coupling. These factors are documented to impact the cellular response to oxidative stress. Therefore, we analyzed the levels of two main redox regulators and found that bovine aortic endothelial cells (BAEC) in galactose media had higher levels of FOXO3 and lower levels of Nrf2 than those in glucose-containing media. Thus, cultures of endothelial cells in a galactose-containing medium may provide a more suitable target for the study of in vitro mitochondrial-related processes than those in glucose-containing media; the medium deeply influences redox signaling in these cells.

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BACKGROUND: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. METHODS: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. RESULTS: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. CONCLUSIONS: Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.

Assuntos

Modelos Animais de Doenças , Hidrogênio , Neuroglia , Oxigênio , Neovascularização Retiniana , Retinopatia da Prematuridade , Animais , Hidrogênio/farmacologia , Neovascularização Retiniana/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Camundongos , Retinopatia da Prematuridade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Retina/efeitos dos fármacos , Animais Recém-Nascidos , Regeneração/efeitos dos fármacos , Imuno-Histoquímica , Vasos Retinianos/efeitos dos fármacos

RESUMO

One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson's disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.

Assuntos

Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Glutationa Transferase/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico

RESUMO

OBJECTIVE: This study aims to analyze the relationship between the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) and Epilepsy (EP), as well as its mechanism of action. METHODS: Thirty Wistar rats were divided into a control group (without treatment), a model group (EP modeling), and an inhibition group (EP modeling + intervention by Keap1/Nrf2 signaling pathway inhibitor ATRA) and subject to Morris water maze experiment. Then, the expression of Oxidative Stress (OS) markers, ferroptosis-associated proteins and Keap1/Nrf2 pathway in rat hippocampus was measured. In addition, rat hippocampal neuronal cell HT22 was purchased and treated accordingly based on the results of grouping, and cell proliferation and apoptosis in the three groups were determined. RESULTS: Compared with rats in the model group, those in the inhibition group showed shorter escape latency and an increased number of platform crossings (p < 0.05). Significant OS and neuron ferroptosis, increased apoptosis rate, elevated Keap1 expression, and decreased Nrf2 expression were observed in the model group compared to the control group (p < 0.05). The inhibition group exhibited notably improved OS and ferroptosis, as well as enhanced neuronal viability (p < 0.05). CONCLUSION: Inhibition of the Keap1/Nrf2 pathway can reverse the OS and neuron viability in EP rats.

Assuntos

Epilepsia , Ferroptose , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Neurônios , Estresse Oxidativo , Ratos Wistar , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/fisiologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Ferroptose/fisiologia , Ferroptose/efeitos dos fármacos , Neurônios/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Masculino , Hipocampo/metabolismo , Apoptose/fisiologia , Ratos , Progressão da Doença , Modelos Animais de Doenças

RESUMO

Homocysteine (Hcy) is an independent cardiovascular disease (CVD) risk factor, whose mechanisms are poorly understood. We aimed to explore mild hyperhomocysteinemia (HHcy) effects on oxidative status, inflammatory, and cholinesterase parameters in aged male Wistar rats (365 days old). Rats received subcutaneous Hcy (0.03 µmol/g body weight) twice daily for 30 days, followed by euthanasia, blood collection and heart dissection 12 h after the last injection. Results revealed increased dichlorofluorescein (DCF) levels in the heart and serum, alongside decreased antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase), reduced glutathione (GSH) content, and diminished acetylcholinesterase (AChE) activity in the heart. Serum butyrylcholinesterase (BuChE) levels also decreased. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) protein content decreased in both cytosolic and nuclear fractions, while cytosolic nuclear factor kappa B (NFκB) p65 increased in the heart. Additionally, interleukins IL-1ß, IL-6 and IL-10 showed elevated expression levels in the heart. These findings could suggest a connection between aging and HHcy in CVD. Reduced Nrf2 protein content and impaired antioxidant defenses, combined with inflammatory factors and altered cholinesterases activity, may contribute to understanding the impact of Hcy on cardiovascular dynamics. This study sheds light on the complex interplay between HHcy, oxidative stress, inflammation, and cholinesterases in CVD, providing valuable insights for future research.

Assuntos

Hiper-Homocisteinemia , Inflamação , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ratos Wistar , Animais , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Hiper-Homocisteinemia/metabolismo , Ratos , Inflamação/metabolismo , Envelhecimento/metabolismo , Sistema Cardiovascular/metabolismo , Colinesterases/metabolismo , Colinesterases/sangue , Acetilcolinesterase/metabolismo , Miocárdio/metabolismo , Butirilcolinesterase/metabolismo

RESUMO

Gastric diseases represent a significant global public health challenge, characterized by molecular dysregulation in redox homeostasis and heightened oxidative stress. Although prior preclinical studies have demonstrated the cytoprotective antioxidant effects of alginate oligosaccharides (AOSs) through the Nrf2 pathway, whether such mechanisms apply to gastric diseases remains unclear. In this study, we used the GES-1 gastric cell line exposed to hydrogen peroxide (H2O2) as a damage model to investigate the impact of AOS on cell viability and its associated mechanisms. Our results revealed that pre-incubation with AOS for either 4 h or 24 h significantly improved the viability of GES-1 cells exposed to H2O2. In addition, AOS reduced the intracellular ROS levels, activating the Nrf2 signaling pathway, with increased Nrf2 protein and mRNA expression and a significant upregulation of the target genes HO-1 and NQO1. The activation of Nrf2 was correlated with decreased Keap1 protein expression and an increased level of the autophagy protein p62/SQSTM1, suggesting the activation of Nrf2 through a noncanonical pathway. This study suggests that AOS is a potential treatment for protecting gastric epithelial cells from oxidative stress by activating the p62/SQSTM1-Keap1-Nrf2 axis and laying the foundation for future investigations about its specific therapeutic mechanisms.

RESUMO

HIV-associated neurocognitive disorders (HAND) affect 15-55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.

Assuntos

Canabinoides , Infecções por HIV , HIV-1 , Humanos , Feminino , NF-kappa B/metabolismo , Proteômica , Espectrometria de Massas em Tandem , Macrófagos/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Estresse Oxidativo , Exocitose , Lisossomos/metabolismo

RESUMO

Maternal obesity (MO) is a significant cause of increased cardiometabolic risk in offspring, who present endothelial dysfunction at birth. Alterations in physiologic and cellular redox status are strongly associated with altered gene regulation in arterial endothelium. However, specific mechanisms by which the pro-oxidant fetal environment in MO could modulate the vascular gene expression and function during the offspring's postnatal life are elusive. We tested if oxidative stress could reprogram the antioxidant-coding gene's response to a pro-oxidant challenge through an epigenetic transcriptional memory (ETM) mechanism. A pro-oxidant double-hit protocol was applied to human umbilical artery endothelial cells (HUAECs) and EA.hy 926 endothelial cell lines. The ETM acquisition in the HMOX1 gene was analyzed by RT-qPCR. HMOX1 mRNA decay was evaluated by Actinomycin-D treatment and RT-qPCR. To assess the chromatin accessibility and the enrichment of NRF2, RNAP2, and phosphorylation at serin-5 of RNAP2, at HMOX1 gene regulatory regions, were used DNase HS-qPCR and ChIP-qPCR assays, respectively. The CpG methylation pattern at the HMOX1 core promoter was analyzed by DNA bisulfite conversion and Sanger sequencing. Data were analyzed using two-way ANOVA, and p < 0.05 was statistically significant. Using a pro-oxidant double-hit protocol, we found that the Heme Oxygenase gene (HMOX1) presents an ETM response associated with changes in the chromatin structure at the promoter and gene regulatory regions. The ETM response was characterized by a paused-RNA Polymerase 2 and NRF2 enrichment at the transcription start site and Enhancer 2 of the HMOX1 gene, respectively. Changes in DNA methylation pattern at the HMOX1 promoter were not a hallmark of this oxidative stress-induced ETM. These data suggest that a pro-oxidant milieu could trigger an ETM at the vascular level, indicating a potential epigenetic mechanism involved in the increased cardiovascular risk in the offspring of women with obesity.

RESUMO

Probiotic supplementation has been identified as a potential target to reduce inflammatory mediators associated with obesity. Therefore, this study assessed the effect of probiotic Lacticaseibacillus rhamnosus LB1.5 on anxiety-like behavior, gene expression in the prefrontal cortex, and neuroinflammation in the cerebral cortex and hippocampus of male mice fed a high-fat diet. Mice aged 21 days were divided into four groups: control (CONT), control plus probiotic (CONT + PROB), high-fat diet (HFD), and high-fat diet plus probiotic (HFD + PROB), and fed for 13 weeks. The probiotic Lact. rhamnosus 1.5 (3.1 × 108 CFU/mL, derived from raw buffalo milk) was administered by gavage three times a week. Probiotic supplementation provided an anxiolytic effect in CONT and HFD. The IL-6 showed lower levels after probiotic supplementation in the HFD. Regarding immunoreactivity for GFAP in the cerebral cortex, we demonstrated that animals HFD-fed had a reduction in cells number compared to CONT. In the hippocampus, we found an interaction between diet and supplementation, as well as an effect of probiotic supplementation. A higher number of Th positive cells was observed in the cerebral cortex in mice fed HFD. Lact. rhamnosus LB1.5 supplementation decreased serum IL-6 levels in HFD-fed mice and promoted a reduction in anxiety-like behavior.

Assuntos

Lacticaseibacillus rhamnosus , Probióticos , Camundongos , Masculino , Animais , Dieta Hiperlipídica/efeitos adversos , Doenças Neuroinflamatórias , Interleucina-6 , Neuroproteção , Ansiedade/prevenção & controle , Camundongos Endogâmicos C57BL

RESUMO

Hydroxytyrosol (HT) or dimethyl fumarate (DMF), activators of nuclear factor erythroid 2-related factor 2 (Nrf2), may reduce obesity in high-fat diet (HFD)-fed animals; nevertheless, the role of these activators on skin tissue repair of HFD-fed animals was not reported. This study investigated whether HT or DMF could improve skin wound healing of HFD-fed obese animals. Mice were fed with an HFD, treated with HT or DMF, and full-thickness skin wounds were created. Macrophages isolated from control and obese animals were treated in vitro with HT. DMF, but not HT, reduced the body weight of HFD-fed mice. Collagen deposition and wound closure were improved by HT or DMF in HFD-fed animals. HT or DMF increased anti-inflammatory macrophage phenotype and protein Nrf2 levels in wounds of HFD-fed mice. Lipid peroxidation and protein tumor necrosis factor-α levels were reduced by HT or DMF in wounds of HFD-fed animals. In in vitro, HT stimulated Nrf2 activation in mouse macrophages isolated from obese animals. In conclusion, HT or DMF improves skin wound healing of HFD-fed mice by reducing oxidative damage and inflammatory response. HT or DMF may be used as a therapeutic strategy to improve the skin healing process in individuals with obesity.

Assuntos

Dieta Hiperlipídica , Fumarato de Dimetilo , Álcool Feniletílico/análogos & derivados , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL

RESUMO

Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin-proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration.

Assuntos

Doenças Neurodegenerativas , Complexo de Endopeptidases do Proteassoma , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Citoplasma/metabolismo , Doenças Neurodegenerativas/metabolismo

RESUMO

BACKGROUND & AIMS: Turmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. METHODS: This longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500 mg of Curcuma longa extract, with 98.42 % total curcuminoids) or placebo (three capsules of 500 mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: Twenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. CONCLUSION: Curcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT04413266.

Assuntos

Curcumina , Diálise Peritoneal , Insuficiência Renal Crônica , Uremia , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Leucócitos Mononucleares/metabolismo , Método Simples-Cego , Inflamação , Estresse Oxidativo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Diarileptanoides/farmacologia , Diarileptanoides/uso terapêutico , Suplementos Nutricionais , Uremia/tratamento farmacológico

RESUMO

BACKGROUND: Patients with chronic kidney disease (CKD) have reduced expression of erythroid nuclear factor-related factor 2 (NRF2) and increased nuclear factor κB (NF-κB). "Food as medicine" has been proposed as an adjuvant therapeutic alternative in modulating these factors. No studies have investigated the effects of sulforaphane (SFN) in cruciferous vegetables on the expression of these genes in patients with CKD. OBJECTIVE: The study aimed to evaluate the effects of SFN on the expression of NRF2 and NF-κB in patients on hemodialysis (HD). DESIGN AND METHODS: A randomized, double-blind, crossover study was performed on 30 patients on regular HD. Fourteen patients were randomly allocated to the intervention group (1 sachet/day of 2.5 g containing 1% SFN extract with 0.5% myrosinase) and 16 patients to the placebo group (1 sachet/day of 2.5 g containing corn starch colored with chlorophyll) for 2 months. After a washout period of 2 months, the groups were switched. NRF2 and NF-κB mRNA expression was evaluated by real-time quantitative polymerase chain reaction, and tumor necrosis factor alpha and interleukin-6 levels were quantified by enzyme-linked immunosorbent assay. Malondialdehyde was evaluated as a marker of lipid peroxidation. RESULTS: Twenty-five patients (17 women, 55 [interquartile range = 19] years and 55 [interquartile range = 74] months on HD) completed the study. There was no significant difference concerning the expression of mRNA NRF2 (P = .915) and mRNA NF-κB (P = .806) after supplementation with SFN. There was no difference in pro-inflammatory and oxidative stress biomarkers. CONCLUSION: 150 µmol of SFN for 2 months had no antioxidant and anti-inflammatory effect in patients with CKD undergoing HD.

Assuntos

Isotiocianatos , NF-kappa B , Insuficiência Renal Crônica , Sulfóxidos , Humanos , Feminino , NF-kappa B/genética , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estudos Cross-Over , Estresse Oxidativo , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/etiologia , RNA Mensageiro/metabolismo , RNA Mensageiro/farmacologia , Suplementos Nutricionais

RESUMO

Metabolic syndrome (MS) is a disorder that increasingly affects the world population, mainly because of changes in lifestyle and dietary habits. In this regard, both physical exercise and caffeine are low-cost and easily accessible therapies that separately have shown positive effects against metabolic disorders. Therefore, we hypothesized that physical exercise combined with caffeine could have a synergistic effect in the treatment of MS, risk factors, and cognitive deficits. Animals were divided into 8 groups and received fructose (15% w/v) or vehicle for 10 weeks. Swimming training and caffeine (6 mg/kg) started 4 weeks after fructose administration. Trained animals presented decreased body weight and visceral fat mass and increased soleus weight compared with untrained fructose-treated animals. Caffeine supplementation also prevented the gain of visceral fat mass induced by fructose. Furthermore, both treatments reversed fructose-induced decrease in glucose clearance over time and fructose-induced increase in 4-hydroxynonenal and nuclear factor-κB immunoreactivity. Physical training also improved the lipidic profile in fructose-treated animals (high-density lipoprotein, low-density lipoprotein, and triglycerides), improved short-term, long-term, and localization memory, and reversed the fructose-induced deficit in short-term memory. Physical training also increased nuclear factor erythroid 2-related factor 2 immunoreactivity per se. Considering that physical training and caffeine reversed some of the damages induced by fructose it is plausible to consider these treatments as alternative, nonpharmacological, and low-cost therapies to help reduce MS-associated risk factors; however, combined treatments did not show additive effects as hypothesized.

Assuntos

Síndrome Metabólica , Ratos , Animais , Síndrome Metabólica/prevenção & controle , Cafeína/farmacologia , NF-kappa B , Natação , Ratos Wistar , Suplementos Nutricionais , Cognição , Frutose/efeitos adversos

RESUMO

Abstract Objective This study aims to analyze the relationship between the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) and Epilepsy (EP), as well as its mechanism of action. Methods Thirty Wistar rats were divided into a control group (without treatment), a model group (EP modeling), and an inhibition group (EP modeling + intervention by Keap1/Nrf2 signaling pathway inhibitor ATRA) and subject to Morris water maze experiment. Then, the expression of Oxidative Stress (OS) markers, ferroptosis-associated proteins and Keap1/Nrf2 pathway in rat hippocampus was measured. In addition, rat hippocampal neuronal cell HT22 was purchased and treated accordingly based on the results of grouping, and cell proliferation and apoptosis in the three groups were determined. Results Compared with rats in the model group, those in the inhibition group showed shorter escape latency and an increased number of platform crossings (p < 0.05). Significant OS and neuron ferroptosis, increased apoptosis rate, elevated Keap1 expression, and decreased Nrf2 expression were observed in the model group compared to the control group (p < 0.05). The inhibition group exhibited notably improved OS and ferroptosis, as well as enhanced neuronal viability (p < 0.05). Conclusion Inhibition of the Keap1/Nrf2 pathway can reverse the OS and neuron viability in EP rats.