RESUMO
Arsenic, a naturally occurring toxic element, manifests in various chemical forms and is widespread in the environment. Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases. The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress, characterized by an unsettling imbalance between oxidants and antioxidants, accompanied by the rampant generation of reactive oxygen species and free radicals. In response to this oxidative turmoil, cells deploy their defense mechanisms, prominently featuring the redox-sensitive transcription factor known as nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 stands as a primary guardian against the oxidative harm wrought by arsenic. When oxidative stress activates NRF2, it orchestrates a symphony of downstream antioxidant genes, leading to the activation of pivotal antioxidant enzymes like glutathione-S-transferase, heme oxygenase-1, and NAD(P)H: quinone oxidoreductase 1. This comprehensive review embarks on the intricate and diverse ways by which various arsenicals influence the NRF2 antioxidant pathway and its downstream targets, shedding light on their roles in defending against arsenic exposure toxic effects. It offers valuable insights into targeting NRF2 as a strategy for safeguarding against or treating the harmful and carcinogenic consequences of arsenic exposure.
Assuntos
Arsênio , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Fator 2 Relacionado a NF-E2/metabolismo , Arsênio/toxicidade , Humanos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.
Assuntos
Astrócitos , Ácido Glutâmico , Ribonucleoproteínas Nucleares Heterogêneas , Homeostase , Fator 2 Relacionado a NF-E2 , Proteína de Ligação a Regiões Ricas em Polipirimidinas , RNA Interferente Pequeno , Animais , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Camundongos , Transdução de Sinais , Membrana Celular/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Humanos , Mitocôndrias/metabolismoRESUMO
ETHNOPHARMACOLOGICAL PREVALENCE: Hyperglycemia in diabetes increases the generation of advanced glycation end products (AGEs) through non-enzymatic reactions. The interaction between AGEs and their receptors (RAGE) leads to oxidative and inflammatory stress, which plays a pivotal role in developing diabetic nephropathy. Syzygium cumini (SC) L. (DC.) homeopathic preparations viz. 200C, 30C, and mother tincture [MT] are used to treat diabetes. This study aimed to elucidate the regulatory effects of SC preparations (200C, 30C, and MT) on the nuclear factor erythroid 2-related factor 2 (Nrf2) - nuclear factor-κB (NF-κB) pathways and mitochondrial dysfunction in mitigating diabetic nephropathy (DN). MATERIALS AND METHODS: Streptozotocin-induced diabetic rats were treated with SC preparations (200C, 30C, MT; 1:20 dilution in distilled water; 600 µL/kg body weight) and metformin (45 mg/kg body weight) twice daily for 40 days. DN was evaluated through biochemical parameters and histological examination. Renal tissue lysates were analyzed for glycation markers. Protein and gene levels of Nrf2, NF-κB, and mitochondrial dysfunctional signaling were determined via western blotting and RT-qPCR. An immunohistochemical analysis of the kidneys was performed. In vitro, human serum albumin (HSA - 10 mg/ml) was glycated with methylglyoxal (MGO - 55 mM) in the presence of SC preparations (200C, 30C, MT) for eight days. Glycated samples (400 µg/mL) were incubated with renal cells (HEK-293) for 24 h. Further reactive oxygen species production, Nrf2 nuclear translocation, and protein or gene expression of Nrf2 and apoptosis markers were analyzed by western blotting, RT-qPCR, and flow cytometry. Molecular docking of gallic and ellagic acid with the HSA-MGO complex was performed. RESULT: In vivo experiments using streptozotocin-induced diabetic rats treated with SC preparations exhibited improved biochemical parameters, preserved kidney function, and reduced glycation adduct formation in a dose-dependent manner. Furthermore, SC preparations downregulated inflammatory mediators such as RAGE, NF-κB, vascular endothelial growth factor (VEGF), and Tumor necrosis factor α (TNF-α) while upregulating the Nrf2-dependent antioxidant and detoxification pathways. They downregulated B-cell lymphoma 2 (Bcl-2) associated X-protein (BAX), C/EBP homologous protein (CHOP), Dynamin-related protein 1 (DRP1), and upregulated BCL 2 gene expression. Notably, SC preparations facilitated nuclear translocation of Nrf2, leading to the upregulation of antioxidant enzymes and the downregulation of oxidative stress markers. Molecular docking studies revealed favorable interactions between gallic (-5.26 kcal/mol) and ellagic acid (-4.71 kcal/mol) with the HSA-MGO complex. CONCLUSION: SC preparations mitigate renal cell apoptosis and mitochondrial dysfunction through Nrf2-dependent mechanisms.
Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Fator 2 Relacionado a NF-E2 , Syzygium , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Syzygium/química , Humanos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células HEK293 , Estresse Oxidativo/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Produtos Finais de Glicação Avançada/metabolismo , Estreptozocina , Ratos Wistar , Antioxidantes/farmacologia , Ratos Sprague-DawleyRESUMO
PURPOSE: To examine whether isoflurane preconditioning (IsoP) has a protective effect against renal ischemia/reperfusion injury (I/RI) in diabetic conditions and to further clarify the underlying mechanisms. METHODS: Control and streptozotocin-induced diabetic rats were randomly assigned to five groups, as follows: normal sham, normal I/R, diabetic sham, diabetic I/R, and diabetic I/R + isoflurane. Renal I/RI was induced by clamping renal pedicle for 45 min followed by reperfusion for 24 h. IsoP was achieved by exposing the rats to 2% isoflurane for 30 min before vascular occlusion. Kidneys and blood were collected after reperfusion for further analysis. Renal histology, blood urea nitrogen, serum creatinine, oxidative stress, inflammatory cytokines, and renal cell apoptosis were assessed. Furthermore, the expression of brahma related gene 1 (Brg1), nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear factor-κB (NF-κB) were determined. RESULTS: Compared with control, diabetic rats undergoing I/R presented more severe renal injury, oxidative stress, inflammatory reaction, and apoptosis with the impairment of Brg1/Nrf2/HO-1 signaling. All these alterations were significantly attenuated by pretreatment with isoflurane. CONCLUSIONS: These findings suggest that isoflurane could alleviate renal I/RI in diabetes, possibly through improving Brg1/Nrf2/HO-1 signaling.
Assuntos
Apoptose , Diabetes Mellitus Experimental , Precondicionamento Isquêmico , Isoflurano , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Distribuição Aleatória , Traumatismo por Reperfusão , Transdução de Sinais , Fatores de Transcrição , Animais , Isoflurano/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Diabetes Mellitus Experimental/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Precondicionamento Isquêmico/métodos , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , DNA Helicases/metabolismo , Rim/efeitos dos fármacos , Rim/irrigação sanguínea , Rim/patologia , Proteínas Nucleares/metabolismo , Heme Oxigenase-1/metabolismo , Anestésicos Inalatórios/farmacologia , Ratos , Ratos Sprague-Dawley , NF-kappa B/metabolismoRESUMO
BACKGROUND: The transcription factor NRF2 plays a significant role in regulating genes that protect cells from oxidative damage. O-GlcNAc modification, a type of posttranslational modification, is crucial for cellular response to stress. Although the involvement of both NRF2 and O-GlcNAc in maintaining cellular redox balance and promoting cancer malignancy has been demonstrated, the potential mechanisms remain elusive. METHODS: The immunoblotting, luciferase reporter, ROS assay, co-immunoprecipitation, and immunofluorescence was used to detect the effects of global cellular O-GlcNAcylation on NRF2. Mass spectrometry was utilised to map the O-GlcNAcylation sites on NRF2, which was validated by site-specific mutagenesis and O-GlcNAc enzymatic labelling. Human lung cancer samples were employed to verify the association between O-GlcNAc and NRF2. Subsequently, the impact of NRF2 O-GlcNAcylation in lung cancer malignancy and cisplatin resistance were evaluated in vitro and in vivo. RESULTS: NRF2 is O-GlcNAcylated at Ser103 residue, which hinders its binding to KEAP1 and thus enhances its stability, nuclear localisation, and transcription activity. Oxidative stress and cisplatin can elevate the phosphorylation of OGT at Thr444 through the activation of AMPK kinase, leading to enhanced binding of OGT to NRF2 and subsequent elevation of NRF2 O-GlcNAcylation. Both in cellular and xenograft mouse models, O-GlcNAcylation of NRF2 at Ser103 promotes the malignancy of lung cancer. In human lung cancer tissue samples, there was a significant increase in global O-GlcNAcylation, and elevated levels of NRF2 and its O-GlcNAcylation compared to paired adjacent normal tissues. Chemotherapy promotes NRF2 O-GlcNAcylation, which in turn decreases cellular ROS levels and drives lung cancer cell survival. CONCLUSION: Our findings indicate that OGT O-GlcNAcylates NRF2 at Ser103, and this modification plays a role in cellular antioxidant, lung cancer malignancy, and cisplatin resistance.
Assuntos
Cisplatino , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Fator 2 Relacionado a NF-E2 , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Camundongos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos NusRESUMO
OBJECTIVE: Ferroptosis of neurons is a significant cause of brain injury following intracerebral hemorrhage (ICH). As an iron-containing compound in hemoglobin, heme contributes to nerve injury post-ICH. Melatonin has been shown to mitigate the effects of ICH, yet its specific functions remain largely elusive. In this study, we aimed to explore the roles and mechanisms of melatonin in heme-induced ferroptosis subsequent to ICH. MATERIALS AND METHODS: C57BL/6 mice were intracranially injected with heme and then treated with melatonin. Behavior tests [modified neurological severity score (mNSS), forelimb placing, and corner turn tests], H&E staining, Nissl staining, and Prussian blue staining were used to evaluate mouse brain tissue injury. In vitro, HT-22 cells were stimulated with heme and cell viability was determined by crystal violet staining. The iron contents were determined in heme-treated brains and cells, and the levels of 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA) were assessed by ELISA. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate the mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Immunoblotting was used to analyze the protein expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Finally, small interfering RNA (siRNA) was used to knock down Nrf2 in HT-22 cells. RESULTS: Melatonin treatment alleviated heme-induced injuries to neural function, as indicated by improved behavior in the mice. Moreover, melatonin decreased cell death and iron concentrations, increased MDA and 4-HNE levels, and reversed the decreases in GPX4, SLC7A11, Nrf2, and HO-1 induced by heme in vitro and in vivo. These results indicated that melatonin could improve the ferroptosis induced by heme. In addition, we found that Nrf2 knockdown attenuated the therapeutic effect of melatonin on neuronal ferroptosis induced by heme. CONCLUSIONS: In general, melatonin alleviates heme-induced ferroptosis by activating the Nrf2/HO-1 pathway, which implies that melatonin is a promising treatment for ferroptosis in ICH.
Assuntos
Ferroptose , Heme Oxigenase-1 , Heme , Melatonina , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Neurônios , Animais , Ferroptose/efeitos dos fármacos , Melatonina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Heme Oxigenase-1/metabolismo , Heme/metabolismo , Masculino , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas de MembranaRESUMO
Oxidative stress is crucial in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). Intestinal epithelial cells (IECs) are an important component of the intestinal barrier. In previous studies, we have demonstrated that suppressing microRNA-222-3p (miR-222-3p) can protect against oxidative stress in IECs, which ameliorates colonic injuries in UC mice and prevents the conversion of UC to CAC. In this case, we hope to explore whether moxibustion can alleviate UC and CAC by inhibiting miR-222-3p based on mouse models of UC and CAC. After herb-partitioned moxibustion (HPM) intervention, the disease activity index (DAI) and colon macroscopic damage index (CMDI) were significantly reduced in UC mice, and the number and volume of intestinal tumors were decreased considerably in CAC mice. Meanwhile, we found that HPM suppressed miR-222-3p expression and upregulated the mRNA and protein expression of Brahma-related gene 1 (BRG1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), while inhibiting Kelch-like ECH-associated protein 1 (Keap1) expression in IECs of UC and CAC mice. With changes in reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and inflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)-α), we verified that HPM protects against oxidative stress and inflammation in IECs of UC and CAC mice. The effect of HPM was inhibited in miR-222-3p overexpression mice, further demonstrating that the protective effect of HPM on UC and CAC mice was through inhibiting miR-222-3p. In summary, HPM regulates the BRG1/Nrf2/HO-1 pathway by inhibiting miR-222-3p to attenuate oxidative stress in IECs in UC and CAC.
Assuntos
Colite Ulcerativa , Modelos Animais de Doenças , Heme Oxigenase-1 , MicroRNAs , Moxibustão , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Transdução de Sinais , Fatores de Transcrição , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Colite Ulcerativa/terapia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/genética , Camundongos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , DNA Helicases/metabolismo , DNA Helicases/genética , Neoplasias Associadas a Colite/etiologia , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/metabolismo , Neoplasias Associadas a Colite/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , HumanosRESUMO
The immune response gene 1 (IRG1) and its metabolite itaconate are implicated in modulating inflammation and oxidative stress, with potential relevance to sepsis-induced myocardial dysfunction (SIMD). This study investigates their roles in SIMD using both in vivo and in vitro models. Mice were subjected to lipopolysaccharide (LPS)-induced sepsis, and cardiac function was assessed in IRG1 knockout (IRG1-/-) and wild-type mice. Exogenous 4-octyl itaconate (4-OI) supplementation was also examined for its protective effects. In vitro, bone marrow-derived macrophages and RAW264.7 cells were treated with 4-OI following Nuclear factor, erythroid 2 like 2 (NRF2)-small interfering RNA administration to elucidate the underlying mechanisms. Our results indicate that IRG1 deficiency exacerbates myocardial injury during sepsis, while 4-OI administration preserves cardiac function and reduces inflammation. Mechanistic insights reveal that 4-OI activates the NRF2/HO-1 pathway, promoting macrophage polarization and attenuating inflammation. These findings underscore the protective role of the IRG1/itaconate axis in SIMD and suggest a therapeutic potential for 4-OI in modulating macrophage responses.
Assuntos
Inflamação , Macrófagos , Camundongos Knockout , Fator 2 Relacionado a NF-E2 , Animais , Camundongos , Macrófagos/efeitos dos fármacos , Inflamação/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Succinatos/farmacologia , Células RAW 264.7 , Monócitos/metabolismo , Antígenos Ly/genética , Antígenos Ly/metabolismo , Sepse/genética , Masculino , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , HidroliasesRESUMO
BACKGROUND: Numerous diseases-related acute lung injury (ALI) contributed to high mortality. Currently, the therapeutic effect of ALI was still poor. The detailed mechanism of ALI remained elusive and this study aimed to elucidate the mechanism of ALI. METHOD: This study was performed to expose the molecular mechanisms of AMPK/Nrf2 pathway regulating oxidative stress in LPS-induced AMI mice. The mouse ALI model was established via intraperitoneal injection of LPS, then the lung tissue and blood samples were obtained, followed by injection with Dimethyl fumarate (DMF). Finally, Western blot, HE staining, injury score, lung wet/dry ratio, reactive oxygen species (ROS) and ELISA were used to elucidate the mechanism of AMPK/Nrf2 pathway in LPS -induced acute lung injury by mediating oxidative stress. RESULTS: The lung tissue injury score was evaluated, showing higher scores in the model group compared to the AMPK activator and control groups. DCFH-DA indicated that LPS increased ROS production, while AMPK activator DMF reduced it, with the model group exhibiting higher ROS levels than the control and AMPK activator groups. The lung wet/dry ratio was also higher in the model group. Western blot analysis revealed LPS reduced AMPK and Nrf2 protein levels, but DMF reversed this effect. ELISA results showed elevated IL-6 and IL-1ß levels in the model group compared to the AMPK activator and control groups. CONCLUSION: CONCLUSION: Activating the AMPK/Nrf2 pathway can improve LPS-induced acute lung injury by down-regulation of the oxidative stress and corresponding inflammatory factor level.
Assuntos
Proteínas Quinases Ativadas por AMP , Lesão Pulmonar Aguda , Modelos Animais de Doenças , Inflamação , Lipopolissacarídeos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Transdução de Sinais , Animais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Hyperuricemic nephropathy (HN) is renal injury caused by hyperuricemia (HUA). While sleeve gastrectomy (SG) has shown promise in improving renal injury in patients with obesity-related HN, the mechanisms are not fully understood. This study induced an obesity-combined HN model in male ob/ob mice and measured serum uric acid (SUA), creatinine, and other biochemical indicators 6 weeks post-surgery. Renal histological changes were evaluated through staining techniques, and the study also assessed renal adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation levels and urate transporter ABCG2 expression. In vitro experiments involved Nrf2 knockdown in AMPK-activated HK-2 cells and ChIP to confirm Nrf2 binding to the ABCG2 promoter. Results showed that SG reduced SUA levels, serum creatinine, and blood urea nitrogen, increased p-AMPK, p-Nrf2 protein, and ABCG2 expression, and alleviated renal fibrosis and inflammation. In vitro, Nrf2 knockdown down-regulated ABCG2 expression, and ChIP confirmed Nrf2's role in ABCG2 transcription. The study suggests that SG may improve renal injury in HN mice by modulating the AMPK/Nrf2 pathway and upregulating ABCG2 transcription.
Assuntos
Proteínas Quinases Ativadas por AMP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Gastrectomia , Hiperuricemia , Fator 2 Relacionado a NF-E2 , Obesidade , Animais , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Hiperuricemia/metabolismo , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Obesidade/metabolismo , Obesidade/complicações , Obesidade/cirurgia , Gastrectomia/métodos , Transdução de Sinais , Nefropatias/metabolismo , Nefropatias/etiologia , Nefropatias/patologia , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Humanos , Camundongos Endogâmicos C57BLRESUMO
Fucoxanthin (Fx) has garnered significant interest due to its exceptional biological properties. However, its efficacy in enhancing food quality and human health is contingent upon the solubility of the compound in water and its physicochemical stability. Therefore, nanocarriers must be developed to enhance the stability and biocompatibility of Fx. In this study, oxidized paramylon and Fx self-assembled nanoparticles (Fx-OEP) were prepared via the anti-solvent method, with a loading rate of 82.47 % for Fx. The Fx-OEP exhibited robust storage and photostability. In vitro simulated digestion assays demonstrated that Fx-OEP effectively protected Fx from premature gastric release, while achieving a release efficiency of 72.17 % in the intestinal phase. Fx-OEP has the capacity to scavenge a range of reactive oxygen species (ROS) induced by cellular oxidative stress. Treatment with Fx-OEP resulted in a significant reduction in ROS accumulation in insulin-resistant HepG2 cells, which was attributed to the activation of the nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. This, in turn, activated insulin receptor substrate 1/glucose transporter type 4 (IRS1/GLUT4), promoting cellular glucose absorption and utilization. These findings indicate the potential of self-assembled nanoparticles based on oxidized paramylon as a new type of nanocarrier for delivering hydrophobic substances.
Assuntos
Resistência à Insulina , Nanopartículas , Xantofilas , Humanos , Xantofilas/farmacologia , Xantofilas/química , Nanopartículas/química , Células Hep G2 , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Portadores de Fármacos/química , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Liberação Controlada de Fármacos , Glucanos/química , Glucanos/farmacologiaRESUMO
The likelihood of survival for cancer patients has greatly improved due to chemotherapy medicines. However, these antitumor agents might also have unfavorable effects on the cardiovascular system, which could result in sudden or gradual cardiac failure. The production of free radicals that result in oxidative stress appears to be the key mechanism by which chemotherapy-induced cardiotoxicity (CIC) happens. Reports suggest that the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) signaling pathway has been considered an alternative path for counteracting cardiotoxicity by suppressing oxidative stress, inflammation, and apoptosis. This review concludes recent knowledge about CIC with a special focus on the anti-oxidative regulation properties of the Sirt1/Nrf2 pathway.
Assuntos
Antineoplásicos , Cardiotoxicidade , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Sirtuína 1 , Humanos , Sirtuína 1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Cardiotoxicidade/etiologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Background: Dental pulp inflammation, often initiated by Gram-negative microorganisms and lipopolysaccharides (LPS), can lead to pulpitis and, subsequently, dental pulp necrosis, compromising tooth structure and increasing susceptibility to fracture. Asiatic acid, derived from Centella asiatica, has demonstrated pharmacological properties, including anti-inflammatory and antioxidant effects, making it a potential candidate for mitigating LPS-induced pulp inflammation. This in vivo study aims to investigate the impact of Asiatic acid on the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in Rattus norvegicus with LPS-induced pulp inflammation. Methods: This quasi-laboratory experimental in vivo study employed a post-test-only control group design to investigate the effects of Asiatic acid on LPS-induced pulp inflammation in Wistar rats. Thirty rats were randomly divided into six groups subjected to various interventions. LPS was administered to all groups for 6 h except the standard control group (CG, n = 5). The negative control group (NCG, n = 5) received only glass ionomer cement. The positive control group (PCG, n = 5) received Eugenol with glass ionomer cement. Intervention groups 1, 2, and 3 (IG1, IG2, IG3; n = 5 each) received Asiatic acid at concentrations of 0.5%, 1%, and 2%, respectively, with glass ionomer cement. Dental pulp inflammation was confirmed through immunological (tumor necrosis factor alpha (TNF-α) levels), histopathological (inflammatory parameters), and physiological (pain assessment using the rat grimace scale) analyses. Additionally, Nrf2 levels were examined using enzyme-linked immunosorbent assay (ELISA). Results: Asiatic acid administration significantly influenced Nrf2 levels in rats with LPS-induced pulp inflammation. Nrf2 levels were significantly higher in groups treated with 0.5% (IG1) (8.810 ± 1.092 ng/mL; p = 0.047), 1.0% (IG2) (9.132 ± 1.285 ng/mL; p = 0.020), and 2.0% (IG3) (11.972 ± 1.888 ng/mL; p = 0.000) Asiatic acid compared to NCG (7.146 ± 0.706). Notably, Nrf2 levels were also significantly higher in the 2.0% Asiatic acid group (IG3) compared to the PCG treated with Eugenol (8.846 ± 0.888 ng/mL; p = 0.001), as well as IG1 (p = 0.001) and IG2 (p = 0.002). However, no significant difference was observed between administering 0.5% Asiatic acid (IG1), 1.0% Asiatic acid (IG2), and Eugenol (PCG). Conclusion: This research showed that Asiatic acid significantly impacted the Nrf2 levels in rats with LPS-induced pulp inflammation. This suggests that it has the potential to be used as a therapeutic agent for reducing dental pulp inflammation. These findings support the need to further explore Asiatic acid as a promising intervention for maintaining dental pulp health.
Assuntos
Lipopolissacarídeos , Fator 2 Relacionado a NF-E2 , Triterpenos Pentacíclicos , Pulpite , Ratos Wistar , Animais , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/uso terapêutico , Lipopolissacarídeos/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Pulpite/tratamento farmacológico , Pulpite/patologia , Pulpite/metabolismo , Pulpite/induzido quimicamente , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/metabolismo , Polpa Dentária/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/induzido quimicamenteRESUMO
Prolonged strenuous exercise induces oxidative stress, leading to oxidative damage, skeletal muscle fatigue, and reduced exercise performance. The body compensates for oxidative stress through antioxidant actions, while related enzymes alone may not overcome excessive oxidative stress during prolonged strenuous exercise. Phycocyanin is an important antioxidant supplement derived from blue-green algae, which may be helpful in this type of situation. This study determined the effects of phycocyanin on exercise performance from prolonged strenuous exercise. Forty Sprague Dawley male rats were divided into 5 groups (n = 8 /group); Control group (C), Exercise group (E), and Exercise with supplement groups receiving low dose (Phycocyanin = 100 mg/kg BW; ELP) and high dose (Phycocyanin = 200 mg/kg BW; EHP) or vitamin C (Vitamin C = 200 mg/kg BW; VC). Phycocyanin was found to decrease oxidative damage markers, muscle fatigue, and muscle atrophy through the activated AKT/mTOR pathway. This was also found to have greater increases in antioxidants via Nrf2 signaling and increases ATP synthesis, GLUT4 transporters, and insulin signaling due to increased IRS-1/AKT signaling. In conclusion, phycocyanin was found to reduce oxidative damage and muscle atrophy, including an increase in insulin signaling in skeletal muscles leading to increased exercise performance in rats.
Assuntos
Músculo Esquelético , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ficocianina , Condicionamento Físico Animal , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Estresse Oxidativo/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ratos , Ficocianina/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Fadiga Muscular/efeitos dos fármacos , Antioxidantes/metabolismo , Antioxidantes/farmacologiaRESUMO
AIM: In previous studies, the researchers observed an increase in insulin secretion in STZ-treated diabetic rats following treatment with the hydroalcoholic extract of Securigera securidaca (HESS) seeds. This study focuses on the relationship between the antioxidant properties of HESS with changes in diabetic pancreatic tissue and the gene expression of factors that impact insulin secretion. METHODS: In this controlled experimental study, three varying doses of HESS were administered to three groups of diabetic rats induced by STZ. Oxidative stress indicators like total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde were assessed in both pancreatic and liver tissues. Pancreatic histology was studied post-haematoxylin staining. Insulin and FGF21 levels in the blood were measured using the ELISA method. The expression of Nrf2 and FGF21 genes in the pancreas and liver, along with MafA and PDX-1 genes in the pancreas, was quantified using real-time PCR. RESULTS: The administration of HESS in varying doses led to a dose-dependent rise in blood insulin levels and a decrease in blood glucose levels and oxidative stress. By reducing oxidative stress, HESS treatment lowered the heightened levels of NRF2 and FGF21 in the liver and pancreas of diabetic rats, improving pancreatic tissue health. As oxidative stress decreased, the expression of MafA and PDX1 genes in the pancreas approached levels seen in healthy rats. CONCLUSION: HESS elicits an increase in insulin secretion through the mitigation of oxidative stress and tissue damage, as well as the modulation of gene expression related to the insulin transcription factors PDX-1 and MafA.
Assuntos
Diabetes Mellitus Experimental , Secreção de Insulina , Insulina , Extratos Vegetais , Sementes , Regulação para Cima , Animais , Extratos Vegetais/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Sementes/química , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , Masculino , Securidaca , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Antioxidantes/farmacologia , Fígado/metabolismo , Transativadores , Proteínas de HomeodomínioRESUMO
The pathogenesis of acute lung injury is complex. Studies have demonstrated the role of neutrophil extracellular traps (NETs) in the process of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, the underlying mechanism remains unclear. In this study, the regulation of Nrf2 in the formation of NETs, which was pathogenic in LPS-induced ALI, was identified by analyzing the levels of Cit-H3, lung function, lung tissue pathology, lung wet/dry ratio, the inflammatory cells, cytokines and proteins in the bronchoalveolar lavage fluid (BALF) and in addition, the activity of lung myeloperoxidase (MPO) was also measured. Results showed that the levels of Cit-H3 measured by western blot in Nrf2-knockout (KO) mice were higher compared with the WT mice after LPS stimulation. To further investigate the NETs formation was pathogenic during LPS-induced ALI, the Nrf2-KO mice were treated with DNase I. Results showed that DNase I improved lung function and lung tissue pathology and significantly reduced lung wet/dry ratio and proteins in the BALF. Besides, DNase I also attenuated the infiltration of inflammatory cells and the cytokines (TNF-α, IL-1ß) production in the BALF and the activity of lung MPO. Therefore, these results together indicate that Nrf2 may intervene in the release of NETs during LPS-induced ALI in mice.
Assuntos
Lesão Pulmonar Aguda , Líquido da Lavagem Broncoalveolar , Armadilhas Extracelulares , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2 , Animais , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Armadilhas Extracelulares/metabolismo , Líquido da Lavagem Broncoalveolar/química , Masculino , Peroxidase/metabolismo , Neutrófilos/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Desoxirribonuclease I/metabolismo , Citocinas/metabolismo , Western BlottingRESUMO
Rationale: Ferroptosis-driven loss of dopaminergic neurons plays a pivotal role in the pathogenesis of Parkinson's disease (PD). In PD patients, Hspb1 is commonly observed at abnormally high levels in the substantia nigra. The precise consequences of Hspb1 overexpression in PD, however, have yet to be fully elucidated. Methods: We used human iPSC-derived dopaminergic neurons and Coniferaldehyde (CFA)-an Nrf2 agonist known for its ability to cross the blood-brain barrier-to investigate the role of Hspb1 in PD. We examined the correlation between Hspb1 overexpression and Nrf2 activation and explored the transcriptional regulation of Hspb1 by Nrf2. Gene deletion techniques were employed to determine the necessity of Nrf2 and Hspb1 for CFA's neuroprotective effects. Results: Our research demonstrated that Nrf2 can upregulate the transcription of Hspb1 by directly binding to its promoter. Deletion of either Nrf2 or Hspb1 gene abolished the neuroprotective effects of CFA. The Nrf2-Hspb1 pathway, newly identified as a defense mechanism against ferroptosis, was shown to be essential for preventing neurodegeneration progression. Additionally, we discovered that prolonged overexpression of Hspb1 leads to neuronal death and that Hspb1 released from ruptured cells can trigger secondary cell death in neighboring cells, exacerbating neuroinflammatory responses. Conclusions: These findings highlight a biphasic role of Hspb1 in PD, where it initially provides neuroprotection through the Nrf2-Hspb1 pathway but ultimately contributes to neurodegeneration and inflammation when overexpressed. Understanding this dual role is crucial for developing therapeutic strategies targeting Hspb1 and Nrf2 in PD.
Assuntos
Neurônios Dopaminérgicos , Ferroptose , Chaperonas Moleculares , Fator 2 Relacionado a NF-E2 , Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Ferroptose/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Animais , Camundongos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP27/genética , Morte CelularRESUMO
Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment.
Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glucose , Fator 2 Relacionado a NF-E2 , Via de Pentose Fosfato , Proteína-Arginina N-Metiltransferases , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Via de Pentose Fosfato/genética , Glucose/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Linhagem Celular Tumoral , Animais , Glucosefosfato Desidrogenase/metabolismo , Glucosefosfato Desidrogenase/genética , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Histonas/metabolismo , Regiões Promotoras Genéticas/genética , Camundongos Nus , Transcrição Gênica , Proliferação de Células/genéticaRESUMO
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
Assuntos
Hipotálamo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Síndrome do Ovário Policístico , Piroptose , Ratos Wistar , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Feminino , Animais , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Piroptose/efeitos dos fármacos , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Resistência à Insulina , Fator 2 Relacionado a NF-E2/metabolismo , Modelos Animais de Doenças , Letrozol/farmacologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Adiponectina/metabolismo , Adiponectina/sangue , Testosterona/sangue , Leptina/sangue , Leptina/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
AIMS: We aimed to resolve the uncertainty as to whether betulin exerted neuroprotection on early brain injury (EBI) caused by subarachnoid hemorrhage (SAH), and to investigate the related molecular mechanisms. METHODS: Bioinformatic analysis was performed to pre-study the differently expressed genes (DEGs) and the possible signaling pathways. Rat and cellular model of SAH were introduced in this study, and betulin, an activator of DJ-1 protein, was administered to reveal the effect. Gross assessment regarding mortality, neurofunctions, SAH grade, brain water content (BWC) along with multiple cellular and molecular studies in vivo or/and in vitro such as immunofluorescence (IF) staining, western blot (WB), reactive oxygen species (ROS) assay, and flow cytometry (FCM) were all conducted after SAH induction to verify the protective effect and the relevant mechanisms of DJ-1 in diverse levels. In addition, MK2206 (selective inhibitor of Akt) and iRNADj-1 (interfering RNA to Dj-1) were utilized to confirm the mechanisms of the effect. RESULTS: The data from our study showed that DJ-1 protein was moderately expressed in neurons, microglia, and astrocytes; its level in brain tissue elevated and peaked at 24-72 h after SAH induction. Betulin could efficaciously induce the expression of DJ-1 which in turn activated Akt and Bcl-2, and anti-oxidative enzymes SOD2 and HO-1, functioning to reduce the activation of cleaved caspase-3 (c-Casp-3) and reactive oxygen species (ROS). The induced DJ-1 could upregulate the expression of Nrf2. However, Akt seemed no direct effect on elevating the expression of Nrf2. DJ-1 alone could as well activate Akt-independent antiapoptotic pathway via suppressing the activation of caspase-8 (Casp-8). CONCLUSIONS: Betulin which was a potent agonist of DJ-1 had the ability to induce its expression in brain tissue. DJ-1 had neuroprotective effect on EBI through comprehensive mechanisms, including facilitating intrinsic and extrinsic antiapoptotic pathway, and reducing oxidative injury by upregulating the expression of redox proteins. Betulin as an inexpensive drug showed the potential for SAH treatment.