Activation Of Nrf2 Signaling Pathway Research Articles

The Neuroprotective Mechanisms of PPAR-γ: Inhibition of Microglia-Mediated Neuroinflammation and Oxidative Stress in a Neonatal Mouse Model of Hypoxic-Ischemic White Matter Injury.

Neuroinflammation and oxidative stress, mediated by microglial activation, hinder the development of oligodendrocytes (OLs) and delay myelination in preterm infants, leading to white matter injury (WMI) and long-term neurodevelopmental sequelae. Peroxisome proliferator-activated receptor gamma (PPAR-γ) has been reported to inhibit inflammation and oxidative stress via modulating microglial polarization in various central nervous system diseases. However, the relationship between PPAR-γ and microglial polarization in neonatal WMI is not well understood. Therefore, this study aimed to elucidate the role and mechanisms of PPAR-γ in preterm infants affected by WMI. In this study, an invivo hypoxia-ischemia (HI) induced brain WMI neonatal mouse model was established. The mice were administered intraperitoneally with either RSGI or GW9662 to activate or inhibit PPAR-γ, respectively. Additionally, an invitro oxygen-glucose deprivation (OGD) cell model was established and pretreated with pcDNA 3.1-PPAR-γ or si-PPAR-γ to overexpress or silence PPAR-γ, respectively. The neuroprotective effects of PPAR-γ were investigated invivo. Firstly, open field test, novel object recognization test, and beam-walking test were employed to assess the effects of PPAR-γ on neurobehavioral recovery. Furthermore, assessment of OLs loss and OL-maturation disorder, the number of myelinated axons, myelin thickness, synaptic deficit, activation of microglia and astrocyte, and blood-brain barrier (BBB) were used to evaluate the effects of PPAR-γ on pathological repair. The mechanisms of PPAR-γ were explored both invivo and invitro. Assessment of microglia polarization, inflammatory mediators, reactive oxygen species (ROS), MDA, and antioxidant enzymes was used to evaluate the anti-inflammatory and antioxidative effects of PPAR-γ activation. An assessment of HMGB1/NF-κB and NRF2/KEAP1 signaling pathway was conducted to clarify the mechanisms by which PPAR-γ influences HI-induced WMI in neonatal mice. Activation of PPAR-γ using RSGI significantly mitigated BBB disruption, promoted M2 polarization of microglia, inhibited activation of microglia and astrocytes, promoted OLs development, and enhanced myelination in HI-induced WMI. Conversely, inhibition of PPAR-γ using GW9662 further exacerbated the pathologic hallmark of WMI. Neurobehavioral tests revealed that neurological deficits were ameliorated by RSGI, while further aggravated by GW91662. In addition, activation of PPAR-γ significantly alleviated neuroinflammation and oxidative stress by suppressing HMGB1/NF-κB signaling pathway and activating NRF2 signaling pathway both invivo and invitro. Conversely, inhibition of PPAR-γ further exacerbated HI or OGD-induced neuroinflammation, oxidative stress via modulation of the same signaling pathway. Our findings suggest that PPAR-γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF-κB and NRF2/KEAP1 signaling pathway, thereby contributing to neuroprotection and amelioration of HI-induced WMI in neonatal mice.

Extracellular Vesicles Derived from Adipose-Derived Mesenchymal Stem Cells Alleviate Apoptosis and Oxidative Stress of Retinal Pigment Epithelial Cells Through Activation of Nrf2 Signaling Pathway.

Purpose: To examine the potential protective effects of adipose-derived mesenchymal stem cell-derived extracellular vesicles (ASC-EVs) on ARPE-19 cells exposed to hydrogen peroxide (H2O2) stress and to evaluate their ability to delay retinal degeneration in Royal College of Surgeons (RCS) rats. Methods: ARPE-19 cells were pre-treated with ASC-EVs for 24 h, followed by exposure to 200 μM H2O2 for an additional 24 h. RCS rats received an intravitreal injection of phosphate-buffered saline in one eye and ASC-EVs in the other eye. Results: ASC-EV pretreatment significantly protected against H2O2 in the Cell Counting Kit-8 assay and was also effective in the lactate dehydrogenase-release assay. It notably reduced early apoptosis (Annexin V-fluorescein isothiocyanate/propidium iodide assay) and late apoptosis (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay), while significantly decreasing intracellular reactive oxygen species, glutathione levels, and superoxide dismutase activity. NFE2L2, HMOX1, and NQO1 mRNA levels, along with Nrf2, HO-1, and NQO1 protein levels, were significantly elevated with ASC-EV pretreatment. Compared with ARPE-19-derived EVs, 11 miRNAs were upregulated and 34 were downregulated in ASC-EVs. In RCS rats, intravitreal injections of ASC-EVs led to significant preservation of the outer nuclear layer and photoreceptor segments, along with increased nuclear Nrf2 expression and elevated HO-1 and NQO1 levels in the inner retina. Eyes that received intravitreal injections of ASC-EVs demonstrated significantly preserved electroretinography a- and b-wave amplitudes at 1 week post-injection, though this effect faded by 2 weeks. Conclusions: ASC-EVs mitigated apoptosis and oxidative stress in ARPE-19 cells subjected to H2O2 exposure and temporarily slowed retinal degeneration in RCS rats via Nrf2 pathway activation by miRNAs.

Tanshinone IIA inhibits H2O2-induced ferroptosis in melanocytes through activating Nrf2 signaling pathway.

Melanocyte ferroptosis has been proven to contribute to the development of vitiligo. Tanshinone IIA (TSA), a Chinese herbal extract, has been shown to inhibit vitiligo progression. Whether TSA regulates ferroptosis in melanocytes remains unclear. Hydrogen peroxide (H2O2) was used to induce melanocytes to stimulate vitiligo cell model in vitro. Cell proliferation was examined by 5-ethynyl-2'-deoxyuridine assay. The levels of malondialdehyde (MDA), reactive oxygen species (ROS), glutathione peroxidase (GSH) and iron (Fe2+) were detected by corresponding commercial kit. The protein levels of ferroptosis-related markers and Nrf2 pathway-related markers were examined using western blot and immunofluorescence staining. Cell viability and cytotoxicity were analyzed using cell counting kit 8 assay and lactate dehydrogenase (LDH) detection. Mitochondrial morphology was examined using a transmission electron microscope. After H2O2 treatment, melanocyte proliferation was reduced, while oxidative stress and ferroptosis were enhanced. TSA treatment could inhibit ferroptosis in H2O2-induced melanocytes. Besides, TSA could activate Nrf2 pathway and promote Nrf2 nuclear translocation, and Nrf2 specific inhibitor (ML385) also reversed the inhibitory effect of TSA on H2O2-induced melanocyte ferroptosis. Our data showed that TSA alleviated H2O2-induced melanocyte ferroptosis via activating Nrf2 pathway.

Supplementation with L-theanine promotes intestinal antioxidant ability via Nrf2 signaling pathway in weaning piglets and H2O2-induced IPEC-J2 cells

This study aimed to investigate the effect of L-theanine in regulating the intestinal antioxidant of weaned piglets and its underlying mechanism. We found that L-theanine increased the activities of antioxidant enzymes and the level of GSH, while decreased the MDA content of weaned piglet jejunum mucosa and H2O2-induced IPEC-J2 cells. In addition, the mRNA expression of SOD1, SOD2, GPx1, CAT, HO-1 and NQO1 was also significantly increased in jejunum mucosa and H2O2-induced IPEC-J2 cells by L-theanine treatment. Furthermore, L-theanine promoted the nuclear Nrf2 expression and decreased the keap1 expression. However, blocking of Nrf2 signaling by ML385 (the Nrf2 inhibitor) repressed the promoting effects of L-theanine on the activities of antioxidative enzymes and the expression of antioxidant related genes, while increased the MDA content and keap1 expression in IPEC-J2 cells. These data provided the first evidence that L-theanine improved intestinal antioxidant ability of weaned piglets by activating Nrf2 signaling pathway.

Exploring the Underlying Mechanisms of Preventive Treatment Related to Dietary Factors for Gastric Diseases.

Gastric diseases have emerged as one of the main chronic diseases in humans, leading to considerable health, social, and economic burdens. As a result, using food or "food and medicinal homologous substances" has become an effective strategy to prevent gastric diseases. Diet may play a crucial role in the prevention and mitigation of gastric diseases, particularly long-term and regular intake of specific dietary components that have a protective effect on the stomach. These key components, extracted from food, include polysaccharides, alkaloids, terpenoids, polyphenols, peptides, probiotics, etc. The related mechanisms involve regulating gastric acid secretion, protecting gastric mucosa, increasing the release of gastric defense factors, decreasing the level of inflammatory factors, inhibiting Helicobacter pylori infection, producing antioxidant effects or reducing oxidative damage, preventing gastric oxidative stress by inhibiting lipid peroxides, activating Nrf2 signaling pathway, and inhibiting NF-κB, TLR4, and NOS/NO signaling pathways.

Probiotic spore-derived multifunctional nanoparticles for enhanced ulcerative colitis treatment by activating metabolic pathways and repairing epithelial barrier

Ulcerative colitis is an agnogenic and refractory intestinal disease. Probiotic therapy has gained prevalence in medical research. Particularly, the probiotic spore coat has shown effectiveness in delivering oral drugs or probiotics for colitis treatment. Nevertheless, challenges persist in understanding the exact mechanism of the spore coat for optimal anti-inflammatory efficacy. Consequently, we develop a type of multifunctional spore coat nanoparticles (CN) derived from probiotic spore coat to comprehensively investigate its mechanisms of action in alleviating inflammation. Surprisingly, our research findings demonstrate that CN exhibits remarkable resistance to the harsh gastric acid environment and possesses the ability to selectively target inflammatory colonic sites characterized by an accumulation of positive charges. Additionally, CN effectively maintains the normal expression levels of zonula-1, occludin, and claudin-1 while simultaneously enhancing the small intestinal mucin 2 to ensure the integrity of intestinal barriers. Furthermore, the metabolomics analysis identifies 88 potential biomarkers that are enriched in three metabolic pathways, including tyrosine metabolism, tryptophan metabolism, and biosynthesis of valine, leucine, and isoleucine. These pathways are associated with Nrf2 signaling pathway activation, NF-κB and Nrf2 signaling pathways regulation, and metabolic disorders regulation. Collectively, our work provides a multifunctional nanomaterial CN and elucidates its anti-inflammatory mechanisms for ulcerative colitis treatment.

SIRT1-driven mechanism: sevoflurane's interference with mESC neural differentiation via PRRX1/DRD2 cascade.

Investigating the sevoflurane-induced perturbation in the differentiation of mouse embryonic stem cells (mESCs) into neural stem cells (mNSCs), our study delineates a novel SIRT1/PRRX1/DRD2/PKM2/NRF2 axis as a key player in this intricate process. Sevoflurane treatment hindered mESC differentiation, evidenced by altered expression patterns of pluripotency and neural lineage markers. Mechanistically, sevoflurane downregulated Sirt1, setting in motion a signaling cascade. Sevoflurane may inhibit PKM2 dimerization and NRF2 signaling pathway activation by inhibiting the expression of SIRT1 and its downstream genes Prrx1 and DRD2, ultimately inhibiting mESCs differentiation into mNSCs. These findings contribute to our understanding of the molecular basis of sevoflurane-induced neural toxicity, presenting a potential avenue for therapeutic intervention in sevoflurane-induced perturbation in the differentiation of mESCs into mNSCs by modulating the SIRT1/PRRX1/DRD2/PKM2/NRF2 axis.

Leonurine as a dietary compound: Its role in ferroptosis inhibition through Nrf2 signaling pathway activation

This research explores the potential of leonurine, a component found in motherwort, to inhibit intestinal inflammatory response in patients of inflammatory bowel disease (IBD) through dietary means with a particular emphasis on how it influences the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Using colon epithelial cell lines, HT29 and Caco-2, we set up models to study the impact of inflammation, oxidative stress, and apoptosis induced by lipopolysaccharide (LPS). In addition, we employed Nrf2 knockout cell lines to understand its function in a better way. The introduction of leonurine is aimed to evaluate its ability to reduce cell damage and inflammatory reactions by activating the Nrf2–heme oxygenase-1 (HO-1) pathway. Results indicated that LPS exposure led to inflammation, oxidative stress, apoptosis, and potential ferroptosis. It was observed that Nrf2 acted as a suppressor in this scenario; its absence increased cell susceptibility to these challenges. Treatment with leonurine notably decreased inflammation, oxidative stress, and apoptosis; however, these protective effects were significantly reduced in cells lacking Nrf2. This confirms that leonurine can inhibit oxidative stress, inflammatory response, apoptosis, and potential ferroptosis mechanism of colon epithelial cells by activating Nrf2. This study not only enhances our understanding of how leonurine regulates IBD but also highlights the importance of Nrf2 by shedding light on IBD development and potential nutritional approaches for its management.

Oxidised rice bran oil induced oxidative stress and apoptosis in IPEC-J2 cells via the Nrf2 signalling pathway.

Rice bran oil is a type of rice oil made by leaching or pressing during rice processing and has a high absorption rate after consumption. When oxidative rancidity occurs, it may cause oxidative stress (OS) and affect intestinal function. Meanwhile, the toxic effects of oxidised rice bran oil have been less well studied in pigs. Therefore, the IPEC-J2 cells model was chosen to explore the regulatory mechanisms of oxidised rice bran oil on OSand apoptosis. Oxidised rice bran oil extract treatment(OR) significantly decreased the viability of IPEC-J2 cells. The results showed that OR significantly elevated apoptosis and reactive oxygen species levelsand promoted the expression of pro-apoptotic gene Caspase-3 messenger RNA levels. The activation of Nrf2 signalling pathway by OR decreased the cellular antioxidant capacity. This was further evidenced by the expression of kelch-like ECH-associated protein 1, heme oxygenase 1, NADH: quinone oxidoreductase 1, superoxide dismutase2and heat shock 70 kDa protein genes and proteins were all downregulated. In conclusion, our results suggested that oxidised rice bran oil induced damage in IPEC-J2 cells through the Nrf2 signalling pathway.

Optimization of Enzyme-Assisted Extraction of Rosemary Essential Oil Using Response Surface Methodology and Its Antioxidant Activity by Activating Nrf2 Signaling Pathway.

Rosemary essential oil (REO) is widely recognized as a food flavoring and traditional herb and possesses potential antioxidant activity. However, its low yield rate and unclarified antioxidant mechanism warrant further investigation. In this study, an enzyme pretreatment-assisted extraction method with Box-Behnken design (BBD) and response surface methodology (RSM) models was employed to optimize the main factors of REO, and its antioxidant molecular mechanism under oxidative stress was elucidated in hydrogen peroxide-induced human lung carcinoma (A549) cells. The optimized yield (4.10%) of REO was recorded with the following optimum conditions: enzyme amount 1.60%, enzyme digestion pH 5.0, enzyme digestion temperature 46.50 °C, and enzyme digestion time 1.7 h. Meanwhile, 1.8-cineole (53.48%) and β-pinene (20.23%) exhibited radical scavenging activity higher than that of BHA and BHT. At the cellular level, REO (12.5-50 µg/mL) increased the levels of cell viability, CAT, SOD, and GSH significantly while reducing the contents of ROS, MDA, and GSSG, when compared to H2O2 exposure. Mechanically, REO relieved oxidative stress via activating the Nrf2 signaling pathway and enhancing the protein expression of Nrf2, NQO-1, and HO-1, which was further verified by molecular docking between the main component 1.8-cineole and the Kelch domain of KEAP1. Therefore, REO could be considered as a potent natural antioxidant with a potential strategy in the food and pharmaceutical industries.

Honokiol Mitigates Metabolic-Associated Fatty Liver Disease by Regulating Nrf2 and RIPK3 Signaling Pathways.

Metabolic-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease worldwide. However, there is currently no recognized effective drugs for treating it. In this study, we investigated the efficacy of Honokiol (HNK) in vitro for mitigating MAFLD. Then, 0.4 mM palmitic acid (PA) and LO2 cells were used to establish the MAFLD model. The protective effect of HNK on MAFLD was confirmed by Oil Red O staining and cell counting kit (CCK-8) assay in LO2 cell line. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were carried out to analyze the regulatory role of HNK on Nrf2 and RIPK3 signaling pathways. The effect of HNK and its downstream signaling pathways on oxidative stress were verified by the detection of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). The concentration of IL-1β, IL-6L, and TNF-α was assessed by enzyme-linked immunosorbent assay (ELISA). The middle concentration of HNK (50 μmol/L) was selected as the best option for inhibiting lipidosis and oxidative stress in MAFLD models. Honokiol mitigates MAFLD via activation of nuclear factor E2-related factor 2 (Nrf2) signaling pathways in vitro. Honokiol suppressed MAFLD via activating the Nrf2 signaling pathway to play an antioxidant and anti-inflammatory role. Also, HNK regulates Nrf2 and RIPK3 signaling pathways to mitigate MAFLD. Our results showed that HNK may suppress the oxidative stress and inflammation in MAFLD via activation of Nrf2 signaling pathway.

Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that threatens human health worldwide. The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containing α-glucan (FLA), in a concanavalin A (ConA)-induced AIH mouse model and to determine the underlying liver-protective mechanism. The results showed that compared with the model group, the level of proinflammatory cytokines in serum of FLA pretreated mice was significantly decreased, and the degree of inflammatory cell infiltration in liver, thymus and spleen was significantly reduced. Quantitative polymerase chain reaction, immunohistochemistry, and Western blotting showed that FLA pre-treatment inhibited the ConA-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2. Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway. Thus, FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of inflammatory cytokines in the serum and prevent the necrosis of hepatocytes. Up-regulation of NRF2 signaling pathway, down-regulation of TRAF6/NF-κB signaling pathway, and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.

Gomisin N rescues cognitive impairment of Alzheimer's disease by targeting GSK3β and activating Nrf2 signaling pathway

Oxidative stress is one of the earlier events causing neuronal dysfunction in Alzheimer's disease (AD). Gomisin N (GN), a lignin isolated from Schisandra chinensis, has anti-oxidative stress effects. There are currently no studies on the neuroprotective potential of GN in AD. In this study, two AD models were treated with GN for 8 weeks. The cognitive functions, amyloid deposition, and neuronal death were assessed. Additionally, the expressions of critical proteins in the GSK3β/Nrf2 signaling pathway were determined in vivo and in vitro. We showed that GN significantly upregulated the expressions of Nrf2, p-GSK3βSer9/GSK3β, NQO1 and HO-1 proteins in SHSY-5Y/APPswe cells after H2O2 injury, whereas the PI3K inhibitor LY294002 reversed the increase in the expressions of Nrf2, p-GSK3βSer9/GSK3β, NQO1 and HO-1 proteins induced by GN administration. In a further study, GN could significantly improve the learning and memory dysfunctions of the rat and mouse AD models, reduce the area of Aβ plaques in the hippocampus and cortex, and increase the number and function of neurons. Here, we first demonstrate the neuroprotective effects of GN on AD in vivo and in vitro. A possible mechanism by which GN prevents AD is proposed: GN significantly increased the expressions of Nrf2, p-GSK3Ser9/GSK3β and NQO1 proteins in the brain of AD animal models and promoted Nrf2 nuclear translocation, then activated Nrf2 downstream genes to combat oxidative stress in AD pathogenesis. GN might be a promising therapeutic agent for AD.

Salvianolic acid A inhibits ferroptosis and protects against intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein–protein interactions (PPIs). Find the specific mechanism of SAA acting on ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 μM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that AKT (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3β/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the AKT inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting ferroptosis was activating the Akt/GSK-3β/Nrf2 signaling pathway.

Nuclear Factor Erythroid 2-Related Factor 2 as a Potential Therapeutic Target in Neonatal Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a prominent cause of neonatal mortality and neurodevelopmental disorders; however, effective therapeutic interventions remain limited. During neonatal hypoxic-ischemic injury events, increased reactive oxygen species (ROS) production and decreased antioxidant levels lead to the induction of oxidative stress, which plays a pivotal role in the pathological process of neonatal HIE. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key endogenous antioxidant transcription factor that protects against oxidative stress by promoting the transcription of various antioxidant genes. It has been demonstrated that Nrf2 signaling pathway activation by different compounds may protect against neonatal HIE. This review outlines the role of oxidative stress in neonatal HIE and summarizes the impact of antioxidants on neonatal HIE via activation of the Nrf2 signaling pathway. In conclusion, Nrf2 signaling pathway potentially exerts antioxidant, anti-inflammatory, antiapoptotic and antiferroptotic effects, thereby emerging as a focal point for future neonatal HIE treatment strategies.

FGF21 relieves calcium oxalate-induced cell injury, apoptosis, oxidative damage and ferroptosis of renal tubular epithelial cells through activating Nrf2 signaling pathway.

Nephrolithiasis is a common urological disease accompanied by high morbidity worldwide. Evidences indicate that high-level CaOx crystals in the body can lead to renal tubular epithelial cell (RTEC) injury and RTEC injury is a critical precipitating factor for the formation of kidney stones. FGF21 has recently been revealed as the considerable marker in various kidney dysfunction and exerts the nephroprotective effects in various kidney diseases. This current study was formulated to fully elucidate the biological role of FGF21 in nephrolithiasis and probe into the intrinsic mechanisms underlying the protective effects of FGF21 against RTEC injury. In this work, HK-2 cells were incubated with 100mg/ml COM for 24h to establish in vitro RTEC injury model. COM-treated HK-2 cells were transfected with Oe-FGF21 to perform gain-of-function experiments. For rescue experiments, HK-2 cells were pretreated with 10μM Nrf2 inhibitor ML385 for 24h to thoroughly discuss the role of Nrf2 signaling in FGF21-mediating nephroprotective effects. It was verified that overexpression of FGF21 relieved COM-induced proliferation inhibition, cell injury, apoptosis, oxidative damage and ferroptosis of RTECs. ML385 treatment partially abolished the protective effects of FGF21 against COM injury in RTECs. In conclusion, up-regulation of FGF21 can relieve COM-induced proliferation inhibition, cell injury, apoptosis, oxidative damage and ferroptosis of RTECs through activating Nrf2 signaling pathway.

Commentary on: Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury.

Commentary on: Activation of Nrf2 signalling pathway by tectoridin protects against ferroptosis in particulate matter-induced lung injury.

Paeoniflorin attenuates particulate matter-induced acute lung injury by inhibiting oxidative stress and NLRP3 inflammasome-mediated pyroptosis through activation of the Nrf2 signaling pathway

Particulate matter (PM), the main component of air pollutants, emerges as a research hotspot, especially in the area of respiratory diseases. Paeoniflorin (PAE), known as anti-inflammatory and immunomodulatory effects, has been reported to alleviate acute lung injury (ALI). However, the effect of PAE on PM-induced ALI and the underlying mechanisms are still unclear yet. In this study, we established the PM-induced ALI model using C57BL/6J mice and BEAS-2B cells to explore the function of PAE. In vivo, mice were intraperitoneally injected with PAE (100 mg/kg) or saline 1 h before instilled with 4 mg/kg PM intratracheally and were euthanized on the third day. For lung tissues, HE staining and TUNEL staining were used to evaluate the degree of lung injury, ELISA assay was used to assess inflammatory mediators and oxidative stress level, Immunofluorescence staining and western blotting were applied to explore the role of pyroptosis and Nrf2 signaling pathway. In vitro, BEAS-2B cells were pretreated with 100 μM PAE before exposure to 200 μg/ml PM and were collected after 24h for the subsequent experiments. TUNEL staining, ROS staining, and western blotting were conducted to explore the underlying mechanisms of PAE on PM-induced ALI. According to the results, PAE can attenuate the degree of PM-induced ALI in mice and reduce PM-induced cytotoxicity in BEAS-2B cells. PAE can relieve PM-induced excessive oxidative stress and NLRP3 inflammasome-mediated pyroptosis. Additionally, PAE can also activate Nrf2 signaling pathway and inhibition of Nrf2 signaling pathway can impair the protective effect of PAE by aggravating oxidative stress and pyroptosis. Our findings demonstrate that PAE can attenuate PM-induced ALI by inhibiting oxidative stress and NLRP3 inflammasome-mediated pyroptosis, which is mediated by Nrf2 signaling pathway.

Unsaponifiable matter from walnut oil ameliorate memory deficits and mitochondrial dysfunction in aging mice via activating Nrf2 signaling pathway

Unsaponifiable matter from walnut oil ameliorate memory deficits and mitochondrial dysfunction in aging mice via activating Nrf2 signaling pathway

DACH1 Attenuates Airway Inflammation in COPD by Activating NRF2 Signaling.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways, it is characterized by impaired lung function induced by cigarette smoke (CS). Reduced DACH1 expression has a detrimental role in numerous disorders. However, its role in COPD remains understudied. This study aims to elucidate the role and underlying mechanism of DACH1 in airway inflammation of COPD. DACH1 expression was measured in lung tissues of patients with COPD. Airway epithelium-specific DACH1 knockdown mice and AAV-transfected DACH1 overexpressed mice were used to investigate its role and potential for therapeutic targeting in experimental COPD caused by CS. Furthermore, we discovered a potential mechanism of DACH1 in inflammation induced by cigarette smoke extract simulation (CSE) in vitro. Compared to non-smokers and smokers without COPD, COPD patients had reduced DACH1 expression, especially in the airway epithelium. Airway epithelium-specific DACH1 knockdown aggravated mice airway inflammation and lung function decline caused by CS, whereas DACH1 overexpression protected mice from airway inflammation and lung function decline. DACH1 knockdown and overexpression promoted and inhibited IL-6 and IL-8 secretion in 16 HBE cells after CSE simulation, respectively. Nuclear factor erythroid 2-related factor 2 (NRF2) was discovered to be a novel downstream target of DACH1, which binds directly to its promoter. By activating NRF2 signaling, DACH1 induction reduced inflammation. DACH1 levels are lower in smokers and nonsmoking COPD patients when compared to nonsmokers. DACH1 has protective effects against inflammation induced by CS by activating NRF2 signaling pathway. Targeting DACH1 is a potentially viable therapeutic approach for COPD treatment.