scholarly journals Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1610
Author(s):  
Reziyamu Wufuer ◽  
Zhuo Fan ◽  
Keli Liu ◽  
Yiguo Zhang
Keyword(s):  
Oxidative Stress ◽  
Regulatory Networks ◽  
Substantial Reduction ◽  
Normal Growth ◽  
Antioxidant Response ◽  
Related Factor ◽  
Nuclear Factor ◽  
Expression Levels ◽  
Hormetic Effect ◽  
Cytoprotective Response

In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)—rather than Nrf2—is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., Nrf1α−/−, Nrf2−/−ΔTA, and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tert-butylhydroquinone (tBHQ) serving as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α’s function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2−/−ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of Nrf1 expression resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, whether or not it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2’s functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2.

scholarly journals Differential yet integral contributions of Nrf1 and Nrf2 in the human antioxidant cytoprotective response against tert-butylhydroquinone as a pro-oxidative stressor

2021 ◽  
Author(s):  
Reziyamu Wufuer ◽  
Zhuo Fan ◽  
Keli Liu ◽  
Yiguo Zhang
Keyword(s):  
Oxidative Stress ◽  
Regulatory Networks ◽  
Substantial Reduction ◽  
Normal Growth ◽  
Antioxidant Response ◽  
Ros Scavenging ◽  
Hormetic Effect ◽  
Genes Encoding ◽  
Regulatory Effects ◽  
Cytoprotective Response

In the past 25 years, Nrf2 had been preferentially parsed as a master hub of regulating antioxidant, detoxification and cytoprotective genes, albeit as a matter of fact that Nrf1, rather than Nrf2, is indispensable for cell homeostasis and organ integrity during normal growth and development. Here, distinct genotypic cell lines (Nrf1α−/−, Nrf2−/−ΔTA and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tBHQ as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also cannot fully compensate specific loss of Nrf1α's function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2−/−ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression and hence resulted in obvious oxidative stress, but can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG to GSH. Conversely, a remarkable increase of Nrf1 expression was resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, no matter if it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E and MT2), as well on the ROS-scavenging activities of SOD and CAT, were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2's functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2. Keywords: Nrf1; Nrf2; antioxidant; oxidative stress; reactive oxygen species; tert-butylhydroquinone (tBHQ).

scholarly journals Xanthohumol inhibits PRRSV proliferation and alleviates oxidative stress induced by PRRSV via the Nrf2–HMOX1 axis

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Xuewei Liu ◽  
Zhongbao Song ◽  
Juan Bai ◽  
Hans Nauwynck ◽  
Yongxiang Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Therapeutic Strategy ◽  
Antioxidant Response ◽  
Economic Losses ◽  
Respiratory Syndrome Virus ◽  
Related Factor ◽  
Nuclear Factor ◽  
Swine Industry ◽  
Therapeutic Drugs ◽  
Swine Pathogen

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen that causes significant economic losses in the global swine industry. Commercial vaccines provide limited protection against this virus, and no highly effective therapeutic drugs are yet available. In this study, we first screened a library of 386 natural products and found that xanthohumol (Xn), a prenylated flavonoid found in hops, displayed high anti-PRRSV activity by inhibiting PRRSV adsorption onto and internalization into cells. Transcriptome sequencing revealed that Xn treatment stimulates genes associated with the antioxidant response in the nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. Xn causes increased expression of Nrf2, HMOX1, GCLC, GCLM, and NQO1 in Marc-145 cells. The action of Xn against PRRSV proliferation depends on Nrf2 in Marc-145 cells and porcine alveolar macrophages (PAMs). This finding suggests that Xn significantly inhibits PRRSV proliferation and decreases viral-induced oxidative stress by activating the Nrf2–HMOX1 pathway. This information should be helpful for developing a novel prophylactic and therapeutic strategy against PRRSV infection.

scholarly journals Oridonin Attenuates Low Shear Stress-Induced Endothelial Cell Dysfunction and Oxidative Stress by Activating The Nuclear Factor Erythroid 2-Related Factor 2 Pathway

2021 ◽  
Author(s):  
ZHIPENG CHEN ◽  
HEQIAN LIU ◽  
SUBINUR MAMATELI ◽  
CHENG LIU ◽  
YUTONG LIU ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
Related Factor ◽  
Nuclear Factor ◽  
Expression Levels ◽  
Low Shear Stress ◽  
Ea.Hy926 Cells ◽  
And Oxidative Stress ◽  
Mrna Expression Levels ◽  
Low Shear

Abstract Background Atherosclerosis (AS) is the primary cause of cardiovascular disease and the incidence is extremely common; however, there are currently few drugs that can effectively treat AS. Although oridonin has been widely used to treat inflammation and cancer for numerous years, to the best of our knowledge, its protective effect against AS has not been reported. Therefore, the present study aimed to investigate whether oridonin attenuated AS. Methods By using text mining, chemometric and chemogenomic methods, oridonin was predicted to be a beneficial agent for the treatment of AS. A parallel flow chamber was used to establish a low shear stress (LSS)-induced endothelial cell (EC) dysfunction model. Briefly, ECs were exposed to 3 dyn/cm2 LSS for 30 min and subsequently treated with oridonin or transfected with a small interfering RNA (siRNA) targeting nuclear factor erythroid 2-related factor 2 (NRF2). Reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH) and glutathione disulfide (GSSG) in EA.hy926 cells were analyzed to determine the level of oxidative stress. The nitric oxide (NO) levels and mRNA expression levels of endothelial NO synthase (eNOS), endothelin-1 (ET-1) and prostaglandin synthase (PGIS) in EA.hy926 cells were analyzed to determine EC dysfunction. Furthermore, the mRNA expression levels of NRF2 were analyzed using reverse transcription-quantitative PCR. In addition, zebrafish were fed with a high-cholesterol diet to establish a zebrafish AS model, which was used to observe lipid accumulation and inflammation under a fluorescence microscope. Results We found LSS led to oxidative stress and EC dysfunction; this was primarily indicated through the significantly decreased SOD and GSH content, the significantly increased MDA, GSSG and ROS content, the upregulated mRNA expression levels of ET-1, and the downregulated NO levels and mRNA expression levels of eNOS and PGIS in ECs. Notably, oridonin could improve LSS-induced oxidative stress and EC dysfunction,and the effects of oridonin were reversed by the transfection with NRF2 siRNA. Oridonin also attenuated lipid accumulation and neutrophil recruitment at the LSS regions in the zebrafish AS model. Conclusions In conclusion, the results of the present study suggested that oridonin may ameliorate LSS-induced EC dysfunction and oxidative stress by activating NRF2, thereby attenuating AS.

Shenduning Granule Attenuates Renal Injury from Oxidative Stress through the Nuclear Factor Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway

Pharmacology ◽  
2019 ◽  
Vol 103 (5-6) ◽  
pp. 236-245
Author(s):  
Xiao-Jun Fu ◽  
Shuang-Yan Hu
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Response ◽  
Urinary Protein ◽  
Heme Oxygenase 1 ◽  
High Dose ◽  
Related Factor ◽  
Nuclear Factor ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Operation Group

Background: Systemic oxidative stress has been reported to play a central role in the pathogenesis of kidney function decline. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is one of the important endogenous antioxidant stress pathways in cells. This study aims to investigate whether shenduning granule can ameliorate oxidative stress in kidney tissues by activating the Nrf2/ARE pathway, and explores the detailed underlying mechanism. Methods: A total of 120 male Sprague-Dawley rats were randomly assigned to the sham-operated and operation groups. Rats in the operation group underwent 5/6 nephrectomy. Two weeks later, rats in the operation group were further randomly divided into 5 groups: model group, low-dose, medium-dose and high-dose shenduning granule groups, and losartan group. Rats in each group were given the same volume of corresponding liquid orally. Serum creatinine (SCr), blood urea nitrogen (BUN), 24-h urinary protein, malondialdehyde (MDA) and superoxide dismutase (SOD), Nrf2, heme oxygenase-1 (HO-1), and γ-glutamyl-cysteine synthetase (γ-GCS) were determined. Results: Shenduning granule could markedly elevate HO-1, NRF2, γ-GCS and SOD (p < 0.05), and significantly decreased MDA, 24-h urinary protein, SCr and BUN in rats (p < 0.05). Conclusion: Shenduning granule can improve renal antioxidative stress activity in rats, exhibiting a renoprotective effect. The potential mechanism is likely exerted by the activation of the Nrf2/ARE pathway.

scholarly journals Sulforaphane Protects the Male Reproductive System of Mice from Obesity-Induced Damage: Involvement of Oxidative Stress and Autophagy

2019 ◽  
Vol 16 (19) ◽  
pp. 3759 ◽  
Author(s):  
Li Huo ◽  
Yu Su ◽  
Gaoyang Xu ◽  
Lingling Zhai ◽  
Jian Zhao
Keyword(s):  
Oxidative Stress ◽  
Reproductive System ◽  
Sperm Count ◽  
Reproductive Toxicity ◽  
Antioxidant Response ◽  
Male Reproductive System ◽  
Related Factor ◽  
Male Hypogonadism ◽  
Nuclear Factor ◽  
Total Antioxidant

(1) Background: In recent decades, the prevalence of obesity has grown rapidly worldwide, thus causing many diseases, including male hypogonadism. Sulforaphane (SFN), an isothiocyanate compound, has been reported to protect the reproductive system. This research investigated the protective effect of SFN against obesity-induced impairment in the male reproductive system and explored the potential mechanism involved in mice. (2) Methods: One hundred thirty mice were divided into 5 groups (Control, DIO (diet-induced obesity), DIO + SFN 5 mg/kg, DIO + SFN 10 mg/kg, and DIO + SFN 20 mg/kg). The effects of SFN on the male reproductive system were determined based on the sperm count and motility, relative testes and epididymis weights, hormone levels, and pathological analyses. Oxidative stress was determined by measuring malondialdehyde (MDA), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione (GSH), H2O2, catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Protein expression of nuclear factor erythroid-2 related factor 2 (Nrf2), Kelch-like ECH-associated protein-1 (Keap1), Microtubule-associated protein light chain 3 (LC3), Beclin1, and P62 were determined by western blotting. (3) Results: High-fat diet (HFD)-induced obesity significantly decreased relative testes and epididymis weights, sperm count and motility, and testosterone levels but increased leptin and estradiol levels. SFN supplementation ameliorated these effects. Additionally, SFN administration inhibited the obesity-induced MDA accumulation and increased the SOD level. Western blot indicated that SFN had an important role in the downregulation of Keap1. Moreover, SFN treatment attenuated obesity-induced autophagy, as detected by LC3 and Beclin1. (4) Conclusions: SFN ameliorated the reproductive toxicity associated with obesity by inhibiting oxidative stress mediated by the nuclear factor erythroid-2 related factor 2/ antioxidant response element (Nrf2/ARE) signaling pathway and recovery of normal autophagy.

scholarly journals Elucidating the Role of Nrf2 Factor Interactions in Various Disorders of Human System and It’s Proteomic Approaches: A Novel Study

2021 ◽  
Vol 8 (5) ◽  
Author(s):  
Aparajita Chakraborty
Keyword(s):  
Oxidative Stress ◽  
Protein Interactions ◽  
Leucine Zipper ◽  
Antioxidant Response ◽  
Related Factor ◽  
Nuclear Factor ◽  
Basic Leucine Zipper ◽  
Ring E3 Ligase ◽  
Microbial Infections ◽  
Factor Interactions

Nuclear factor erythroid 2-related factor 2 (Nrf2), which is also known as nuclear factor erythroid-derived-like-2, is a transcription factor which is encoded by the NFE2L2 gene. It is a basic leucine zipper (bZIP) protein which coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. It modulates a cellular antioxidant response program and plays a major role in the protection against oxidants and electrophiles; extracellular and intracellular oxidant/electrophiles have great contributions to the damages in cellular macromolecules such as proteins, lipids or DNA. Keap1 protein which is a regulator of Nrf2, is a highly redox-sensitive member of BTB-Kelch family assembling with Cul3 protein to form a Cullin-RING E3 ligase complex for Nrf2 degradation. Thus, this factor is a regulator of many processes of life and it’s signalling system (Nrf2-KEAP-1-ARE pathway) has been found to participate in various ocular or eye diseases and even other systemic diseases such as respiratory disease, chronic diseases or cancer. In microbial infections, the host oxidative stress response may lead to the production of cytoprotective molecules, which in turn induces the activation of cellular Nrf2 factor. The crystallins or eye lens proteins, (?B-crystallin being one of them) may possibly interact with Nrf2 factor and regulate oxidative stress, but it is yet to be deciphered. Proteomic studies may provide valuable information, regarding such detailed protein interactions and their pathways especially in case of diseases or infections in the upcoming days.

scholarly journals Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs

2019 ◽  
Vol 20 (8) ◽  
pp. 2025 ◽  
Author(s):  
Pelin Telkoparan-Akillilar ◽  
Sibel Suzen ◽  
Luciano Saso
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorders ◽  
Antioxidant Response ◽  
Related Factor ◽  
Antineoplastic Drugs ◽  
Nuclear Factor ◽  
Antioxidant Response Element ◽  
Malignant Cells ◽  
Nrf2 Pathway ◽  
Anti Cancer

Oxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed.

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