scholarly journals The Interaction of lncRNA XLOC-2222497, AKR1C1, and Progesterone in Porcine Endometrium and Pregnancy

2020 ◽  
Vol 21 (9) ◽  
pp. 3232
Author(s):  
Tao Su ◽  
Haile Yu ◽  
Gan Luo ◽  
Mengxia Wang ◽  
Changfan Zhou ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Core Promoter ◽  
Differentially Expressed Gene ◽  
Antioxidant Response ◽  
Differentially Expressed ◽  
Related Factor ◽  
Luciferase Activity Assay ◽  
Antioxidant Response Elements ◽  
Yorkshire Pigs ◽  
The Difference

The endometrium is an important tissue for pregnancy and plays an important role in reproduction. In this study, high-throughput transcriptome sequencing was performed in endometrium samples of Meishan and Yorkshire pigs on days 18 and 32 of pregnancy. Aldo-keto reductase family 1 member C1 (AKR1C1) was found to be a differentially expressed gene, and was identified by quantitative real-time PCR (qRT-PCR) and Western blot. Immunohistochemistry results revealed the cellular localization of the AKR1C1 protein in the endometrium. Luciferase activity assay demonstrated that the AKR1C1 core promoter region was located in the region from −706 to −564, containing two nuclear factor erythroid 2-related factor 2 (NRF2) binding sites (antioxidant response elements, AREs). XLOC-2222497 was identified as a nuclear long non-coding RNA (lncRNA) highly expressed in the endometrium. XLOC-2222497 overexpression and knockdown have an effect on the expression of AKR1C1. Endocrinologic measurement showed the difference in progesterone levels between Meishan and Yorkshire pigs. Progesterone treatment upregulated AKR1C1 and XLOC-2222497 expression in porcine endometrial epithelial cells. In conclusion, transcriptome analysis revealed differentially expressed transcripts during the early pregnancy process. Further experiments demonstrated the interaction of XLOC-2222497/AKR1C1/progesterone in the endometrium and provided new potential targets for pregnancy maintenance and its control.

scholarly journals Axonal pathology in hPSC-based models of Parkinson’s disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus

2019 ◽  
Vol 116 (28) ◽  
pp. 14280-14289 ◽  
Author(s):  
Christopher Czaniecki ◽  
Tammy Ryan ◽  
Morgan G. Stykel ◽  
Jennifer Drolet ◽  
Juliane Heide ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Differentially Expressed Gene ◽  
Antioxidant Response ◽  
Differentially Expressed ◽  
Axonal Pathology ◽  
Gene Enhancer ◽  
Antioxidant Response Elements ◽  
Gene Ontologies

While mutations in theSNCAgene (α-synuclein [α-syn]) are causal in rare familial forms of Parkinson’s disease (PD), the prevalence of α-syn aggregates in the cortices of sporadic disease cases emphasizes the need to understand the link between α-syn accumulation and disease pathogenesis. By employing a combination of human pluripotent stem cells (hPSCs) that harbor theSNCA-A53T mutation contrasted against isogenic controls, we evaluated the consequences of α-syn accumulation in human A9-type dopaminergic (DA) neurons (hNs). We show that the early accumulation of α-syn inSNCA-A53T hNs results in changes in gene expression consistent with the expression profile of the substantia nigra (SN) from PD patients, analyzed post mortem. Differentially expressed genes from both PD patient SN andSNCA-A53T hNs were associated with regulatory motifs transcriptionally activated by the antioxidant response pathway, particularly Nrf2 gene targets. Differentially expressed gene targets were also enriched for gene ontologies related to microtubule binding processes. We thus assessed the relationship between Nrf2-mediated gene expression and neuritic pathology inSNCA-A53T hNs. We show thatSNCA-mutant hNs have deficits in neuritic length and complexity relative to isogenic controls as well as contorted axons with Tau-positive varicosities. Furthermore, we show that mutant α-syn fails to complex with protein kinase C (PKC), which, in turn, results in impaired activation of Nrf2. These neuritic defects result from impaired Nrf2 activity on antioxidant response elements (AREs) localized to a microtubule-associated protein (Map1b) gene enhancer and are rescued by forced expression of Map1b as well as by both Nrf2 overexpression and pharmaceutical activation in PD neurons.

scholarly journals Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yasuhiro Nakagami
Keyword(s):  
Oxidative Stress ◽  
Neuronal Degeneration ◽  
Antioxidant Response ◽  
Related Factor ◽  
Retinal Diseases ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Genes Encoding ◽  
Antioxidant Response Elements ◽  
Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

scholarly journals The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury

2017 ◽  
Vol 312 (2) ◽  
pp. L155-L162 ◽  
Author(s):  
Hailin Zhao ◽  
Shiori Eguchi ◽  
Azeem Alam ◽  
Daqing Ma
Keyword(s):  
Lung Injury ◽  
Therapeutic Potential ◽  
Antioxidant Response ◽  
Protective Role ◽  
Chronic Obstructive ◽  
Related Factor ◽  
Nuclear Factor ◽  
Obstructive Pulmonary Disease ◽  
Antioxidant Response Elements

Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that upregulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. Activation of Nrf2 has been shown to be protective against lung injury. In the lung, diverse stimuli including environmental oxidants, medicinal agents, and pathogens can activate Nrf2. Nrf2 translocates to the nucleus and binds to an ARE. Through transcriptional induction of ARE-bearing genes encoding antioxidant-detoxifying proteins, Nrf2 induces cellular rescue pathways against oxidative pulmonary injury, abnormal inflammatory and immune responses, and apoptosis. The Nrf2-antioxidant pathway has been shown to be important in the protection against various lung injuries including acute lung injury/acute respiratory distress syndrome and bronchopulmonary dysplasia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, and allergy and was widely examined for new therapeutic targets. The present review explores the protective role of Nrf-2 against lung injury and the therapeutic potential in targeting Nrf-2.

scholarly journals NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models

2019 ◽  
Vol 116 (25) ◽  
pp. 12516-12523 ◽  
Author(s):  
Gahee Bahn ◽  
Jong-Sung Park ◽  
Ui Jeong Yun ◽  
Yoon Jee Lee ◽  
Yuri Choi ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Redox Regulation ◽  
Amyloid Β ◽  
Antioxidant Response ◽  
Related Factor ◽  
Bace1 Expression ◽  
Nrf2 Activation ◽  
Antioxidant Response Elements ◽  
Aβ Generation ◽  
Aβ Production

BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer’s disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

Peptide and small molecule inhibitors of the Keap1–Nrf2 protein–protein interaction

2015 ◽  
Vol 43 (4) ◽  
pp. 674-679 ◽  
Author(s):  
Geoff Wells
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitors ◽  
Biological Activities ◽  
Cancer Chemoprevention ◽  
Antioxidant Response ◽  
Related Factor ◽  
Promoter Regions ◽  
Protein Protein Interaction ◽  
Antioxidant Response Elements

The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) up-regulates the expression of a range of cytoprotective enzymes with antioxidant response elements in their promoter regions and thus can protect cells against oxidative damage. Increasing Nrf2 activity has been proposed as a therapeutic intervention in a range of chronic neurodegenerative conditions and cancer chemoprevention. One of the main mechanisms by which Nrf2 is negatively regulated involves an interaction with the ubiquitination facilitator protein, Kelch-like ECH-associated protein 1 (Keap1) that facilitates degradation of Nrf2. Inhibition of this process underlies the mode of action of a broad group of compounds that increase Nrf2 activity. A number of natural products, including the isothiocyanate sulforaphane, up-regulate Nrf2 by interacting with Keap1 in a covalent manner to stall its activity. Recently, a number of peptide and small molecule inhibitors of the protein-protein interaction (PPI) between Keap1 and Nrf2 have been described. These classes of compound have contrasting modes of action at the molecular level and there is emerging evidence that their biological activities have similarities and differences. This review describes the various classes of PPI inhibitor that have been described in the literature and the biological evaluations that have been performed.

scholarly journals The Neuroprotective Role of Polydatin: Neuropharmacological Mechanisms, Molecular Targets, Therapeutic Potentials, and Clinical Perspective

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5985
Author(s):  
Sajad Fakhri ◽  
Mohammad Mehdi Gravandi ◽  
Sadaf Abdian ◽  
Esra Küpeli Akkol ◽  
Mohammad Hosein Farzaei ◽  
...  
Keyword(s):  
Side Effects ◽  
Protein Kinase ◽  
Spinal Cord Injuries ◽  
Plant Secondary Metabolites ◽  
Antioxidant Response ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Mitogen Activated Protein ◽  
Antioxidant Response Elements

Neurodegenerative diseases (NDDs) are one of the leading causes of death and disability in humans. From a mechanistic perspective, the complexity of pathophysiological mechanisms contributes to NDDs. Therefore, there is an urgency to provide novel multi-target agents towards the simultaneous modulation of dysregulated pathways against NDDs. Besides, their lack of effectiveness and associated side effects have contributed to the lack of conventional therapies as suitable therapeutic agents. Prevailing reports have introduced plant secondary metabolites as promising multi-target agents in combating NDDs. Polydatin is a natural phenolic compound, employing potential mechanisms in fighting NDDs. It is considered an auspicious phytochemical in modulating neuroinflammatory/apoptotic/autophagy/oxidative stress signaling mediators such as nuclear factor-κB (NF-κB), NF-E2–related factor 2 (Nrf2)/antioxidant response elements (ARE), matrix metalloproteinase (MMPs), interleukins (ILs), phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt), and the extracellular regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Accordingly, polydatin potentially counteracts Alzheimer’s disease, cognition/memory dysfunction, Parkinson’s disease, brain/spinal cord injuries, ischemic stroke, and miscellaneous neuronal dysfunctionalities. The present study provides all of the neuroprotective mechanisms of polydatin in various NDDs. Additionally, the novel delivery systems of polydatin are provided regarding increasing its safety, solubility, bioavailability, and efficacy, as well as developing a long-lasting therapeutic concentration of polydatin in the central nervous system, possessing fewer side effects.

scholarly journals Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Angelo Sparaneo ◽  
Federico Pio Fabrizio ◽  
Lucia Anna Muscarella
Keyword(s):  
Current Knowledge ◽  
Notch Pathway ◽  
Antioxidant Response ◽  
Related Factor ◽  
Oncogenic Signaling ◽  
Tissue Organization ◽  
Tumorigenesis And Progression ◽  
Antioxidant Response Elements ◽  
Notch Pathways ◽  
Oncogenic Signaling Pathways

The transcription factor Nrf2 (NF-E2 related factor 2) is a master regulator of the cell antioxidant response associated with tumor growth and resistance to cytotoxic treatments. In particular, Nrf2 induces upregulation of cytoprotective genes by interacting with the closely situated AREs (Antioxidant Response Elements) in response to endogenous or exogenous stress stimuli and takes part to several oncogenic signaling pathways. Among these, the crosstalk with Notch pathway has been shown to enhance cytoprotection and maintenance of cellular homeostasis, tissue organization by modulating cell proliferation kinetics, and stem cell self-renewal in several organs. The role of Notch and Nrf2 related pathways in tumorigenesis is highly variable and when they are both abnormally activated they can synergistically cause neoplastic proliferation by promoting cell survival, differentiation, invasion, and metastases. NFE2L2, KEAP1, and NOTCH genes family appear in the list of significantly mutated genes in tumors in both combined and individual sets, supporting the crucial role that the aberrant Nrf2-Notch crosstalk might have in cancerogenesis. In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.

scholarly journals Alleviation of Oxidative Damage and Involvement of Nrf2-ARE Pathway in Mesodopaminergic System and Hippocampus of Status Epilepticus Rats Pretreated by Intranasal Pentoxifylline

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Yunxiao Kang ◽  
Wensheng Yan ◽  
Hui Fang ◽  
Guoliang Zhang ◽  
Yakun Du ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Oxidative Damage ◽  
Lipid Peroxide ◽  
Epileptic Seizures ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Visuospatial Memory ◽  
Related Factor ◽  
Transient Activation ◽  
Antioxidant Response Elements

The current studies were aimed at evaluating the efficacy of intranasal pentoxifylline (Ptx) pretreatment in protecting mesodopaminergic system and hippocampus from oxidative damage of lithium-pilocarpine induced status epilepticus (SE) and the involvement of nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response elements pathway. Pentoxifylline was administered to rats intranasally or intraperitoneally 30 minutes before inducing SE. Our results showed the impaired visuospatial memory, the defected mesodopaminergic system, and the oxidative damage and the transient activation of Nrf2 in SE rats. The transient activation of Nrf2 in SE rats was enhanced by Ptx pretreatment, which was followed by the upregulation of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Ptx pretreatment to SE rats significantly suppressed the epileptic seizures, decreased the levels of lipid peroxide and malondialdehyde, and elevated the ratio of reduced glutathione/oxidized glutathione. Compared with intraperitoneal injection, intranasal Ptx delivery completely restored the visuospatial memory and the activity of mesodopaminergic system in SE rats. Intranasal administration of Ptx may hopefully become a noninvasive, painless, and easily administered option for epileptic patients.

scholarly journals A Review on Oxidative Stress, Diabetic Complications, and the Roles of Honey Polyphenols

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Visweswara Rao Pasupuleti ◽  
Chandra Sekhar Arigela ◽  
Siew Hua Gan ◽  
Sirajudeen Kuttulebbai Nainamohamed Salam ◽  
Kumara Thevan Krishnan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Antioxidant Response ◽  
Dietary Factors ◽  
The Body ◽  
Related Factor ◽  
Antidiabetic Agent ◽  
Antioxidant Response Elements

Despite the availability of various antidiabetic drugs, diabetes mellitus (DM) remains one of the world’s most prevalent chronic diseases and is a global burden. Hyperglycaemia, a characteristic of type 2 diabetes mellitus (T2DM), substantially leads to the generation of reactive oxygen species (ROS), triggering oxidative stress as well as numerous cellular and molecular modifications such as mitochondrial dysfunction affecting normal physiological functions in the body. In mitochondrial-mediated processes, oxidative pathways play an important role, although the responsible molecular mechanisms remain unclear. The impaired mitochondrial function is evidenced by insulin insensitivity in various cell types. In addition, the roles of master antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response elements (ARE) are being deciphered to explain various molecular pathways involved in diabetes. Dietary factors are known to influence diabetes, and many natural dietary factors have been studied to improve diabetes. Honey is primarily rich in carbohydrates and is also abundant in flavonoids and phenolic acids; thus, it is a promising therapeutic antioxidant for various disorders. Various research has indicated that honey has strong wound-healing properties and has antibacterial, anti-inflammatory, antifungal, and antiviral effects; thus, it is a promising antidiabetic agent. The potential antidiabetic mechanisms of honey were proposed based on its major constituents. This review focuses on the various prospects of using honey as an antidiabetic agent and the potential insights.

Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity

2016 ◽  
Vol 473 (8) ◽  
pp. 961-1000 ◽  
Author(s):  
Yiguo Zhang ◽  
Yuancai Xiang
Keyword(s):  
Biological Activities ◽  
Antioxidant Response ◽  
Water Soluble ◽  
Related Factor ◽  
Activator Protein 1 ◽  
Specific Expression ◽  
Response Elements ◽  
Cellular Basis ◽  
Antioxidant Response Elements ◽  
Membrane Bound

The consensus cis-regulatory AP-1 (activator protein-1)-like AREs (antioxidant-response elements) and/or EpREs (electrophile-response elements) allow for differential recruitment of Nrf1 [NF-E2 (nuclear factor-erythroid 2)-related factor 1], Nrf2 and Nrf3, together with each of their heterodimeric partners (e.g. sMaf, c-Jun, JunD or c-Fos), to regulate different sets of cognate genes. Among them, NF-E2 p45 and Nrf3 are subject to tissue-specific expression in haemopoietic and placental cell lineages respectively. By contrast, Nrf1 and Nrf2 are two important transcription factors expressed ubiquitously in various vertebrate tissues and hence may elicit putative combinational or competitive functions. Nevertheless, they have de facto distinct biological activities because knockout of their genes in mice leads to distinguishable phenotypes. Of note, Nrf2 is dispensable during development and growth, albeit it is accepted as a master regulator of antioxidant, detoxification and cytoprotective genes against cellular stress. Relative to the water-soluble Nrf2, less attention has hitherto been drawn to the membrane-bound Nrf1, even though it has been shown to be indispensable for embryonic development and organ integrity. The biological discrepancy between Nrf1 and Nrf2 is determined by differences in both their primary structures and topovectorial subcellular locations, in which they are subjected to distinct post-translational processing so as to mediate differential expression of ARE-driven cytoprotective genes. In the present review, we focus on the molecular and cellular basis for Nrf1 and its isoforms, which together exert its essential functions for maintaining cellular homoeostasis, normal organ development and growth during life processes. Conversely, dysfunction of Nrf1 results in spontaneous development of non-alcoholic steatohepatitis, hepatoma, diabetes and neurodegenerative diseases in animal models.

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