Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against ...oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs), which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress.
•Antioxidant response elements (ARE) orchestrate the expression of a myriad of genes.•Since its discovery, numerous experimentally functional AREs have been identified.•Transcription factors act on the AREs to regulate the cytoprotective genes.•Applications based on AREs are employed to detect and monitor chemicals/drugs.•Computational methods and analysis of AREs are still in its infancy.
The Keap1–Nrf2–ARE ((Kelch‐like ECH‐Associating protein 1) nuclear factor erythroid 2 related factor 2‐antioxidant response element) pathway is one of the most important defense mechanisms against ...oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1–Nrf2–ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first‐line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO‐Me, was terminated for safety reasons. Directly inhibiting Keap1–Nrf2 protein–protein interactions as a novel Nrf2‐modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1–Nrf2 protein–protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1–Nrf2–ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1–Nrf2–ARE pathway and the therapeutic applications of such agents.
Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. ...Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3′-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury.
•miR-140-5p expression was up-regulated in Cisplatin induced AKI.•miR-140-5p directly targeted the 3′-UTR of Nrf2 mRNA.•miR-140-5p activated the Nrf2/ARE signaling pathway and served as an early protective response against oxidative stress.
ROS and ROS-Mediated Cellular Signaling Zhang, Jixiang; Wang, Xiaoli; Vikash, Vikash ...
Oxidative medicine and cellular longevity,
01/2016, Volume:
2016, Issue:
1
Journal Article
Peer reviewed
Open access
It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological ...processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell-signaling proteins (NF-κB, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca2+ and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System.
Redox homeostasis is a lifelong pursuit of cancer cells. Depending on the context, reactive oxygen species (ROS) exert paradoxical effects on cancers; an appropriate concentration stimulates ...tumorigenesis and supports the progression of cancer cells, while an excessive concentration leads to cell death. The upregulated antioxidant system in cancer cells limits ROS to a tumor-promoting level. In cancers, redox regulation interacts with tumor initiation, proliferation, metastasis, programmed cell death, autophagy, metabolic reprogramming, the tumor microenvironment, therapies, and therapeutic resistance to facilitate cancer development. This review discusses redox control and the major hallmarks of cancer.
Ulcerative colitis (UC), which affects millions of people worldwide, is characterized by extensive colonic injury involving mucosal and submucosal layers of the colon. Nuclear factor E2-related ...factor 2 (Nrf2) plays a critical role in cellular protection against oxidant-induced stress. Antioxidant response element (ARE) is the binding site recognized by Nrf2 and leads to the expression of phase II detoxifying enzymes and antioxidant proteins. The Nrf2/ARE system is a key factor for preventing and resolving tissue injury and inflammation in disease conditions such as UC. Researchers have proposed that both Keap1-dependent and Keap1-independent cascades contribute positive effects on activation of the Nrf2/ARE pathway. In this review, we summarize the present knowledge on mechanisms controlling the activation process. We will further review nutritional compounds that can modulate activation of the Nrf2/ARE pathway and may be used as potential therapeutic application of UC. These comprehensive data will help us to better understand the Nrf2/ARE signaling pathway and promote its effective application in response to common diseases induced by oxidative stress and inflammation.
At the onset of lactation in dairy cows, inflammation and oxidative stress may occur and result in a risk of pathologies and lower milk yield. To propose an innovative management strategy for cows ...during this period, it is essential to better understand these physiological variations. Our objective was to evaluate the metabolic, redox and immune status of 7 primiparous and 8 multiparous Holstein cows during late gestation and the first months of lactation. Blood samples were collected between 3 weeks before calving until 12 weeks postpartum. Milk samples were also collected, but only at the time points after calving. The metabolic (nonesterified fatty acids (NEFA), BHB, glucose, urea, calcium) and redox (reactive oxygen metabolites (ROM), oxidative stress index (OSI), glutathione peroxidase activity, vitamin E) statuses were analyzed in plasma or erythrocytes. The expression of genes related to antioxidant functions was determined in leukocytes collected from milk. For immune status, plasma cytokine levels and the production of reactive oxygen species (ROS) in classical and regulatory neutrophils were measured in 2 whole blood ex vivo challenges. The data were analyzed using a mixed model that included the fixed effects of parity and week and their interaction. Milk yield, plasma NEFA and BHB in wk 2 and 4 after calving were higher in multiparous cows than in primiparous cows, whereas glucose and calcium tended to be lower. Plasma ROM and OSI levels in wk 8 were higher in multiparous than in primiparous cows. Multiparous cows also displayed higher glutathione peroxidase activity in erythrocytes, and antioxidant transcription factor and superoxide dismutase-1 expression levels in milk leukocytes. Moreover, multiparous cows had higher plasma concentrations of vitamin E but lower plasma levels of cytokines CXCL10, CCL2, IL1Rα and IFNγ. Following ex vivo whole blood stimulation with Escherichia coli, lower IL1α and TNFα levels were measured in multiparous than in primiparous cows. Intracellular ROS production by neutrophils was lower in multiparous than in primiparous cows. These results thus indicated marked physiological changes in wk 8 compared with wk 2 and 4 of lactation. These differences in the physiological status of primiparous and multiparous cows offer interesting perspectives for potential dietary strategies to prevent pathologies which take account of parity and week relative to calving.
NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, ...chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3β and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.
Exposure to excess ammonia-N (NH3/NH4+) in aquaculture can disrupt physiological function in shrimp leading to enhanced oxidative stress and apoptosis, but little is known concerning the ...post-transcriptional regulation mechanism. In this study, the first miR-200 family member in crustacean was identified and characterized from Litopenaeus vannamei (designed as Lva-miR-8-3p). Lva-miR-8-3p was highly expressed in eyestalks, brainganglion, and gills. The expression of Lva-miR-8-3p in gills significantly decreased after ammonia-N stress, and Lva-miR-8-3p was confirmed to target IKKβ 3’UTR for negatively regulating IKKβ/NF-κB pathway. Overexpression of miR-8-3p promoted the hemolymph ammonia-N accumulation, total hemocyte count (THC) decrease, and gills tissue damage, thus resulting in a decreased survival rate of ammonia-exposed shrimp. Besides, Lva-miR-8-3p silencing could enhance the antioxidant enzymes activities and reduce the oxidative damage, whereas overexpression of Lva-miR-8-3p exerted the opposite effects. Furthermore, Lva-miR-8-3p overexpression was found to aggravate ammonia-N induced apoptosis in gills. In primarily cultured hemocytes, the cell viability decreased, the ROS content and caspase-3 activity increased after agomiR-8-3p transfection, while antagomiR-8-3p transfection caused the opposite change except the cell viability. These findings indicate that Lva-miR-8-3p acts as a post-transcriptional regulator in ammonia-N induced antioxidant response and apoptosis by negatively regulating IKKβ/NF-κB pathway.
•Lva-miR-8-3p is a unique miR-200 family member firstly characterized in crustacean.•Lva-miR-8-3p regulates the NF-κB activation through binding to 3′ UTR of IKKβ mRNA.•Negative regulation relationship between Lva-miR-8-3p and IKKβ/NF-κB was revealed.•Lva-miR-8-3p plays a role in antioxidant defense and apoptosis under ammonia-N stress.
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