nrf2 signaling pathway
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2022 ◽  
Vol 8 ◽  
I-Chen Li ◽  
Fang-Chia Chang ◽  
Ching-Chuan Kuo ◽  
Hsin-Tung Chu ◽  
Tsung-Ju Li ◽  

Sleep disturbances have been the hallmark of the recent coronavirus disease 2019 pandemic. Studies have shown that once sleep is disrupted, it can lead to psychological and physical health issues which can, in turn, disrupt circadian rhythm and induce further sleep disruption. As consumers are trying to establish healthy routines, nutritional and preclinical safety investigation of fermented hispidin-enriched Sanghuangporus sanghuang mycelia (GKSS) as a novel food material for spontaneous sleep in Sprague-Dawley rats is conducted for the first time. Results showed that the nutritional analysis of GKSS including moisture, ash, crude lipid, crude protein, carbohydrate, and energy were found to be 2.4 ± 0.3%, 8.0 ± 2.5%, 1.7 ± 0.3%, 22.9 ± 1.2%, 65.1 ± 3.1%, and 367.1 ± 10.2 kcal/100 g respectively. In the 28-day repeated-dose oral toxicity study, only Sprague-Dawley male rats receiving 5 g/kg showed a slight decrease in feed consumption at week 3, but no associated clinical signs of toxicity or significant weight loss were observed. Although a significant reduction of the platelet count was found in mid- and high-dose GKSS treated male groups, such changes were noted to be within the normal range and were not correlated with relative spleen weight changes. Hence, the no observed adverse effect level (NOAEL) of GKSS was identified to be higher than 5 g/kg in rats. After the safety of GKSS is confirmed, the sleep-promoting effect of GKSS ethanolic extract enriched with hispidin was further assessed. Despite 75 mg/kg of GKSS ethanolic extract does not affect wakefulness, rapid eye movement (REM) sleep and non-REM (NREM) sleep, GKSS ethanolic extract at 150 mg/kg significantly decreased wakefulness and enhanced NREM and REM sleep. Interestingly, such effects seem to be mediated through anti-inflammatory activities via NF-E2-related factor-2 (Nrf2) signaling pathway. Taken together, these findings provide the preliminary evidence to studies support the claims suggesting that GKSS contained useful phytochemical hispidin could be considered as and is safe to use as a functional food agent or nutraceutical for relieving sleep problems mediated by Nrf2 pathway, which the results are useful for future clinical pilot study.

2022 ◽  
Vol 12 ◽  
Hanchu Xiong ◽  
Zihan Chen ◽  
Baihua Lin ◽  
Bojian Xie ◽  
Xiaozhen Liu ◽  

NRF2 is an important regulatory transcription factor involved in tumor immunity and tumorigenesis. In this study, we firstly identified that FKBP4/NR3C1 axis was a novel negative regulator of NRF2 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at protein level of NRF2 since it could not suppress the expression of NRF2 at mRNA level. Bioinformatics analysis and in vitro experiments further demonstrated that FKBP4 regulated NRF2 via regulating nuclear translocation of NR3C1. We then reported that naringenin, a flavonoid, widely distributed in citrus and tomato, could suppress autophagy and proliferation of BC cells through FKBP4/NR3C1/NRF2 signaling pathway in vitro and in vivo. Naringenin was also found to promote dendritic cell (DC) differentiation and maturation through FKBP4/NR3C1/NRF2 axis. Therefore, our study found that naringenin could induce inhibition of autophagy and cell proliferation in BC cells and enhance DC differentiation and maturation, at least in part, though regulation of FKBP4/NR3C1/NRF2 signaling pathway. Identification of FKBP4/NR3C1/NRF2 axis would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.

2022 ◽  
Vol 2022 ◽  
pp. 1-15
Youjing Yang ◽  
Qianmin Li ◽  
Shuhui Wei ◽  
Kaimiao Chu ◽  
Lian Xue ◽  

Lung inflammatory injury is a global public health concern. It is characterized by infiltration of diverse inflammatory cells and thickening of pulmonary septum along with oxidative stress to airway epithelial cells. STAT6 is a nuclear transcription factor that plays a crucial role in orchestrating the immune response, but its function in tissue inflammatory injury has not been comprehensively studied. Here, we demonstrated that STAT6 activation can protect against particle-induced lung inflammatory injury by resisting oxidative stress. Specifically, genetic ablation of STAT6 was observed to worsen particle-induced lung injury mainly by disrupting the lungs’ antioxidant capacity, as reflected by the downregulation of the Nrf2 signaling pathway, an increase in malondialdehyde levels, and a decrease in glutathione levels. Vitamin D receptor (VDR) has been previously proved to positively regulate Nrf2 signals. In this study, silencing VDR expression in human bronchial epithelial BEAS-2B cells consistently suppressed autophagy-mediated activation of the Nrf2 signaling pathway, thereby aggravating particle-induced cell damage. Mechanically, STAT6 activation promoted the nuclear translocation of VDR, which increased the transcription of autophagy-related genes and induced Nrf2 signals, and silencing VDR abolished these effects. Our research provides important insights into the role of STAT6 in oxidative damage and reveals its potential underlying mechanism. This information not only deepens the appreciation of STAT6 but also opens new avenues for the discovery of therapies for inflammatory respiratory system disorders.

2022 ◽  
Vol 2022 ◽  
pp. 1-20
Yue Ren ◽  
Yanan Liu ◽  
Kaiyang Liu ◽  
Xiaoqian Huo ◽  
Chaoqun Liu ◽  

The pathogenesis of diabetic retinopathy (DR) is complicated, and there is no effective drug. Oxidative stress-induced human retinal microvascular endothelial cells (HRMECs) injury is one of the pathogenic factors for DR. Molecular switches are considered high-risk targets in disease progression. Identification of molecular switch is crucial to interpret the pathogenesis of disease and screen effective ingredients. In this study, a systematic process was executed to discover therapeutic candidates for DR based on HRMECs injury. First of all, the molecular mechanism of HRMECs oxidative stress injury was revealed by transcriptomics and network pharmacology. We found that oxidative stress was one of the pivotal pathogenic factors, which interfered with vascular system development, inflammation, cell adhesion, and cytoskeleton damaged HRMECs through crosstalk. Then, network topology analysis was used to recognize molecular switches. The results indicated that the Keap1-Nrf2-ARE signaling pathway was the molecular switch in HRMECs oxidative stress injury. On this basis, the HEK293-ARE overexpression cell line was applied to obtain 18 active traditional Chinese medicine (TCM) ingredients. Furthermore, andrographolide, one of the 18 candidates, was applied in the HRMECs oxidative stress model to evaluate the accuracy of the systematic process. The efficacy evaluation results showed that andrographolide could regulate oxidative stress, vascular system development, inflammation, adhesion, and skeleton tissue to inhibit HRMECs injury cooperatively. And its mechanism was related to the Nrf2 signaling pathway. Overall, our data suggest that the Nrf2 signaling pathway is the molecular switch in the HRMECs oxidative stress injury. 18 potential Nrf2 agonists are likely to be promising DR candidates.

2022 ◽  
Vol 2022 ◽  
pp. 1-19
Baining Cui ◽  
Yan Wang ◽  
Jiahui Jin ◽  
Zhen Yang ◽  
Ruoxi Guo ◽  

UVB exposure is one of the primary factors responsible for the development of photoaging, and the aim of this study was to investigate the mechanism involved in the photoprotective properties of resveratrol (RES) in UVB-induced photoaging. Photoaging models of Hacat cells and ICR mice were established by UVB irradiation. The effect of RES on cell viability was then assessed using the MTT assay. The effect of RES on reactive oxygen species (ROS) production was detected through a fluorescent probe assay. The effect of RES on oxidized glutathione (GSSH) content, and superoxide dismutase (SOD) activity in photoaging Hacat cells, were measured separately, using kits. An enzyme-linked immunosorbent assay (ELISA) was used to measure the effect of RES on IL-6 secretion. The effect of VEGF-B on RES photoprotection was examined through the RT-qPCR method, after silencing VEGF-B through siRNA transfection. For animal experiments, the relative water content of the skin of ICR mice was determined using the Corneometer CM825 skin moisture tester. Starting from the third week of the study, the back skin of photoaging ICR mice was photographed weekly using the TIVI700 camera, and the depth of skin wrinkles in photoaging ICR mice was also analyzed. The thickness of the epidermis in photoaging ICR mice was assessed by the hematoxylin-eosin (HE) staining method. The content of collagen fibers in the skin dermis of photoaging ICR mice was measured by the Masson trichrome staining method. The content of collagen III in the dermis of the skin in photoaging ICR mice was measured through immunohistochemistry (IHC) techniques. The effect of RES on the mRNA expression levels of MMP-1, MMP-9, HO-1, GPX-4, IL-6, TNF-α, VEGF-B, caspase9, and caspase3 in photoaging Hacat cells, and that of MMP-3, Nrf2, HO-1, NQO1, SOD1, GPX-4, caspase9, caspase3, and IL-6 in the skin of photoaging ICR mice, was measured by RT-qPCR. The effects of RES on caspase3, Nrf2 (intranuclear), COX-2, P-ERK1/2, ERK1/2, P-P38MAPK, and P38MAPK in photoaging Hacat cells, and on MMP-9, caspase3, COX-2, P-JNK, P-ERK1/2, and P-P38MAPK protein expression in the skin of photoaging ICR mice, were assayed by the WB method. The results of this study, therefore, show that RES has a protective effect against UVB-induced photoaging in both Hacat cells and ICR mice. Its mechanism of action may include reducing the expression of MMPs and the secretion of collagen and inflammatory factors by inhibiting the ROS-mediated MAPK and COX-2 signaling pathways, balancing oxidative stress in the skin of Hacat cells and ICR mice by promoting the Nrf2 signaling pathway, inducing antiapoptotic effects by inhibiting caspase activation, and exerting antioxidant and antiapoptotic effects by targeting the VEGF-B, demonstrating its photoprotective effects against UVB irradiation-induced photoaging.

2022 ◽  
Vol 15 ◽  
Wen-Jing Cheng ◽  
Peng Li ◽  
Wen-Ya Huang ◽  
Yang Huang ◽  
Wen-Jie Chen ◽  

Oxidative stress is closely related to the occurrence of depression. Acupuncture has been proved to be an effective method for treating depression. In order to explore the mechanism of the antidepressant effect of acupuncture, this study performed acupuncture prevention on chronic unpredictable mild stress (CUMS) depression model rats, and observed the effect of acupuncture on hippocampal oxidative stress and Nrf2 signaling pathway. Male SD rats were randomly divided into control group, CUMS group, acupuncture group, and fluoxetine group (n = 10/group). Fluoxetine, a common antidepressant, was used as a positive control drug in this study. In the fluoxetine group, rats were given fluoxetine (2.1 mg/kg) intragastrically once a day for 28 days. The acupoints of Shangxing (GV23) and Fengfu (GV16) were applied in acupuncture group, once every other day for 14 times in total. Behavioral tests and biological detections were used to evaluate the effects of the interventions and the changes of factors related to oxidative stress, Nrf2 pathway, and neuronal apoptosis. The results showed that both acupuncture and fluoxetine could increase sugar preference rate in SPT and decrease immobility time in FST in depression model rats. It also significantly decreased oxidative stress products such as ROS and H2O2, and elevated the protein and mRNA expressions of Nrf2 and HO-1. From Nissl’s staining, there were more abundant nerve cells in two intervention groups compared with CUMS group. Plus, acupuncture down-regulated the expression levels of Bax and caspase-3 and up-regulated the expression of Bcl-2. Our findings indicate that acupuncture improved depression-like behaviors of CUMS rats. And CUMS-induced depression-like behaviors in rats were related to oxidative stress and neuronal apoptosis in hippocampus. Acupuncture showed antidepressant effects in reducing oxidative stress products via regulating the Nrf2/HO-1 signaling pathway so that prevented neuronal apoptosis.

Mohammad Hassan Emami ◽  
Nasrin Sereshki ◽  
Zahra Malakoutikhah ◽  
Sayed Ali Ehsan Dehkordi ◽  
Alireza Fahim ◽  

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