Tanshinone IIA Activates Nuclear Factor-Erythroid 2-Related Factor 2 to Restrain Pulmonary Fibrosis via Regulation of Redox Homeostasis and Glutaminolysis

Background/Aims: Diabetes is associated with increased incidence of myocardial dysfunction, which is partly characterized by interstitial and perivascular fibrosis. Cardiac fibroblasts have been identified as an important participant in the development of cardiac fibrosis. Exposure of cultured cardiac fibroblasts to high glucose resulted in increased collagen synthesis. Tanshinone IIA can alleviate the ventricular fibrosis that develops in a number of different experimental conditions. However, whether tanshinone IIA can prevent high glucose-induced collagen synthesis in cardiac fibroblasts remains unknown. The aim of this study was to evaluate the effects of tanshinone IIA on high glucose-induced collagen synthesis in cardiac fibroblasts. Methods: Rat cardiac fibroblasts were cultured in high glucose (25 mM) media in the absence or presence of tanshinone IIA and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production and related signaling molecules were assessed by 3H-proline incorporation, quantitative polymerase chain reaction, enzyme linked immunosorbent assay, and Western blotting. Results: The results indicate cardiac fibroblasts exposed to high glucose condition show increased cell proliferation and collagen synthesis and these effects were abolished by tanshinone IIA treatment. Furthermore, the inhibitory effect of tanshinone IIA on high glucose induced cell proliferation and collagen synthesis may be associated with its activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of TGF-β1 production and Smad2/3 phosphorylation. Conclusion: In summary, our results highlights the critical role tanshinone IIA plays as an antioxidant in attenuating high glucose-mediated collagen synthesis through inhibiting TGF-β1/Smad signaling in cardiac fibroblasts which provide a mechanistic basis for the clinical application of tanshinone IIA in the treating diabetic-related cardiac fibrosis.

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Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance

Cells ◽

10.3390/cells10040758 ◽

2021 ◽

Vol 10 (4) ◽

pp. 758

Author(s):

Kyung-Soo Chun ◽

Do-Hee Kim ◽

Young-Joon Surh

Keyword(s):

Cancer Cells ◽

Metabolic Pathways ◽

Redox Homeostasis ◽

Redox Balance ◽

Therapy Resistance ◽

Related Factor ◽

Nuclear Factor ◽

Cellular Redox ◽

Reductive Stress

Redox homeostasis is not only essential for the maintenance of normal physiological functions, but also plays an important role in the growth, survival, and therapy resistance of cancer cells. Altered redox balance and consequent disruption of redox signaling are implicated in the proliferation and progression of cancer cells and their resistance to chemo- and radiotherapy. The nuclear factor erythroid 2 p45-related factor (Nrf2) is the principal stress-responsive transcription factor that plays a pivotal role in maintaining cellular redox homeostasis. Aberrant Nrf2 overactivation has been observed in many cancerous and transformed cells. Uncontrolled amplification of Nrf2-mediated antioxidant signaling results in reductive stress. Some metabolic pathways altered due to reductive stress have been identified as major contributors to tumorigenesis. This review highlights the multifaceted role of reductive stress in cancer development and progression.

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Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats

Scientific Reports ◽

10.1038/s41598-020-78735-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Larissa Daniele Bobermin ◽

André Quincozes-Santos ◽

Camila Leite Santos ◽

Ana Paula M. Varela ◽

Thais F. Teixeira ◽

...

Keyword(s):

Zika Virus ◽

Neuronal Damage ◽

Redox Homeostasis ◽

Hippocampal Slices ◽

Neuron Specific Enolase ◽

Nuclear Factor Κb ◽

Related Factor ◽

Nuclear Factor ◽

Zikv Infection ◽

Adult Rats

AbstractZika virus (ZIKV) infection during pregnancy was associated with microcephaly in neonates, but clinical and experimental evidence indicate that ZIKV also causes neurological complications in adults. However, the changes in neuron-glial communication, which is essential for brain homeostasis, are still unknown. Here, we report that hippocampal slices from adult rats exposed acutely to ZIKV showed significant cellular alterations regarding to redox homeostasis, inflammatory process, neurotrophic functions and molecular signalling pathways associated with neurons and glial cells. Our findings support the hypothesis that ZIKV is highly neurotropic and its infection readily induces an inflammatory response, characterized by an increased expression and/or release of pro-inflammatory cytokines. We also observed changes in neural parameters, such as adenosine receptor A2a expression, as well as in the release of brain-derived neurotrophic factor and neuron-specific enolase, indicating plasticity synaptic impairment/neuronal damage. In addition, ZIKV induced a glial commitment, with alterations in specific and functional parameters such as aquaporin 4 expression, S100B secretion and glutathione synthesis. ZIKV also induced p21 senescence-associated gene expression, indicating that ZIKV may induce early senescence. Taken together, our results indicate that ZIKV-induced neuroinflammation, involving nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NFκB) pathways, affects important aspects of neuron-glia communication. Therefore, although ZIKV infection is transient, long-term consequences might be associated with neurological and/or neurodegenerative diseases.

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Quercetin Alleviates Oxidative Damage by Activating Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Porcine Enterocytes

Nutrients ◽

10.3390/nu13020375 ◽

2021 ◽

Vol 13 (2) ◽

pp. 375

Author(s):

Hai Jia ◽

Yunchang Zhang ◽

Xuemeng Si ◽

Yuhang Jin ◽

Da Jiang ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Cell Injury ◽

Redox Homeostasis ◽

Specific Inhibitor ◽

Epithelial Cell Line ◽

Related Factor ◽

Protein Abundance ◽

Dependent Manner ◽

Nuclear Factor

Oxidative stress has been implicated in the etiology of multiple gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease. This study was conducted to evaluate effects of natural product quercetin on diquat-induced oxidative stress in porcine enterocytes and underlying mechanisms. Intestinal porcine epithelial cell line 1 (IPEC-1) cells pretreated with or without quercetin (5 μM, 24 h) were incubated with vehicle or diquat (100 μM) for 6 h. The results showed that diquat treatment induced apoptosis in a caspase-3-dependent manner, as accompanied by elevated reactive oxygen species (ROS) production, increased mitochondrial depolarization, and reduced the abundance of tight junction proteins. These adverse effects of diquat were remarkably abrogated by quercetin administration. Further study indicated that the protective effect of quercetin was associated with elevated protein abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased intracellular glutathione (GSH) content. Interestingly, the beneficial effects of quercetin on diquat-induced oxidative damage were abolished by all-trans-retinoic acid (Atra), a specific inhibitor of Nrf2, indicating a Nrf2-dependent regulation manner. The results show that quercetin attenuates diquat-induced cell injury by promoting protein abundance of Nrf2 and regulating GSH-related redox homeostasis in enterocytes. These findings provide new insights into a function role of quercetin in maintaining intestinal homeostasis.

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Nuclear Factor Erythroid-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.785057 ◽

2021 ◽

Vol 15 ◽

Author(s):

Bianca Seminotti ◽

Mateus Grings ◽

Paolo Tucci ◽

Guilhian Leipnitz ◽

Luciano Saso

Keyword(s):

Oxidative Stress ◽

Transcription Factor ◽

Metabolic Disorders ◽

Current Knowledge ◽

Redox Homeostasis ◽

Neurological Dysfunction ◽

Related Factor ◽

Type I ◽

Nuclear Factor ◽

Inherited Metabolic Disorders

Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

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The Role of Nrf2 in Skeletal Muscle on Exercise Capacity

Antioxidants ◽

10.3390/antiox10111712 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1712

Author(s):

Yu Kitaoka

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Physiology ◽

Redox Homeostasis ◽

Muscle Metabolism ◽

Related Factor ◽

Nuclear Factor ◽

Nitrogen Species ◽

Special Issue

Nuclear factor erythroid 2-related factor 2 Nfe2l2 (Nrf2) is believed to play a crucial role in protecting cells against oxidative stress. In addition to its primary function of maintaining redox homeostasis, there is emerging evidence that Nrf2 is also involved in energy metabolism. In this review, we briefly discuss the role of Nrf2 in skeletal muscle metabolism from the perspective of exercise physiology. This article is part of a special issue “Mitochondrial Function, Reactive Oxygen/Nitrogen Species and Skeletal Muscle” edited by Håkan Westerblad and Takashi Yamada.

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The Protective Effects of Flavonoids in Cataract Formation through the Activation of Nrf2 and the Inhibition of MMP-9

Nutrients ◽

10.3390/nu12123651 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3651

Author(s):

Aaron Hilliard ◽

Patricia Mendonca ◽

Tanya D. Russell ◽

Karam F. A. Soliman

Keyword(s):

Oxidative Stress ◽

Redox Homeostasis ◽

Nuclear Factor Κb ◽

Protective Role ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects ◽

Cataract Formation ◽

Contributing Factors ◽

Cataract Development

Cataracts account for over half of global blindness. Cataracts formations occur mainly due to aging and to the direct insults of oxidative stress and inflammation to the eye lens. The nuclear factor-erythroid-2-related factor 2 (Nrf2), a transcriptional factor for cell cytoprotection, is known as the master regulator of redox homeostasis. Nrf2 regulates nearly 600 genes involved in cellular protection against contributing factors of oxidative stress, including aging, disease, and inflammation. Nrf2 was reported to disrupt the oxidative stress that activates Nuclear factor-κB (NFκB) and proinflammatory cytokines. One of these cytokines is matrix metalloproteinase 9 (MMP-9), which participates in the decomposition of lens epithelial cells (LECs) extracellular matrix and has been correlated with cataract development. Thus, during inflammatory processes, MMP production may be attenuated by the Nrf2 pathway or by the Nrf2 inhibition of NFκB pathway activation. Moreover, plant-based polyphenols have garnered attention due to their presumed safety and efficacy, nutritional, and antioxidant effects. Polyphenol compounds can activate Nrf2 and inhibit MMP-9. Therefore, this review focuses on discussing Nrf2’s role in oxidative stress and cataract formation, epigenetic effect in Nrf2 activity, and the association between Nrf2 and MMP-9 in cataract development. Moreover, we describe the protective role of flavonoids in cataract formation, targeting Nrf2 activation and MMP-9 synthesis inhibition as potential molecular targets in preventing cataracts.

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Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases

Antioxidants ◽

10.3390/antiox9070617 ◽

2020 ◽

Vol 9 (7) ◽

pp. 617 ◽

Cited By ~ 5

Author(s):

Tae-Cheon Kang

Keyword(s):

Quality Control ◽

Antioxidant Defense ◽

Mitochondrial Dynamics ◽

Neurological Diseases ◽

Redox Homeostasis ◽

Related Factor ◽

Nuclear Factor ◽

Antioxidant Defense Enzymes ◽

Antioxidant Defense Systems ◽

The Relationship

Mitochondria play an essential role in bioenergetics and respiratory functions for cell viability through numerous biochemical processes. To maintain mitochondria quality control and homeostasis, mitochondrial morphologies change rapidly in response to external insults and changes in metabolic status through fusion and fission (so called mitochondrial dynamics). Furthermore, damaged mitochondria are removed via a selective autophagosomal process, referred to as mitophagy. Although mitochondria are one of the sources of reactive oxygen species (ROS), they are themselves vulnerable to oxidative stress. Thus, endogenous antioxidant defense systems play an important role in cell survival under physiological and pathological conditions. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that maintains redox homeostasis by regulating antioxidant-response element (ARE)-dependent transcription and the expression of antioxidant defense enzymes. Although the Nrf2 system is positively associated with mitochondrial biogenesis and mitochondrial quality control, the relationship between Nrf2 signaling and mitochondrial dynamics/mitophagy has not been sufficiently addressed in the literature. This review article describes recent clinical and experimental observations on the relationship between Nrf2 and mitochondrial dynamics/mitophagy in various neurological diseases.

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