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

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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Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications

Molecules ◽

10.3390/molecules27020502 ◽

2022 ◽

Vol 27 (2) ◽

pp. 502

Author(s):

Sergio Davinelli ◽

Luciano Saso ◽

Floriana D’Angeli ◽

Vittorio Calabrese ◽

Mariano Intrieri ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factors ◽

Molecular Mechanisms ◽

Nuclear Factor Κb ◽

Protective Role ◽

Related Factor ◽

Nuclear Factor ◽

Molecular Features ◽

Wide Range ◽

Pharmaceutical Industries

Astaxanthin (AST) is a dietary xanthophyll predominantly found in marine organisms and seafood. Due to its unique molecular features, AST has an excellent antioxidant activity with a wide range of applications in the nutraceutical and pharmaceutical industries. In the past decade, mounting evidence has suggested a protective role for AST against a wide range of diseases where oxidative stress and inflammation participate in a self-perpetuating cycle. Here, we review the underlying molecular mechanisms by which AST regulates two relevant redox-sensitive transcription factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB). Nrf2 is a cellular sensor of electrophilic stress that coordinates the expression of a battery of defensive genes encoding antioxidant proteins and detoxifying enzymes. Likewise, NF-κB acts as a mediator of cellular stress and induces the expression of various pro-inflammatory genes, including those encoding cytokines, chemokines, and adhesion molecules. The effects of AST on the crosstalk between these transcription factors have also been discussed. Besides this, we summarize the current clinical studies elucidating how AST may alleviate the etiopathogenesis of oxidative stress and inflammation.

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(–)-Loliolide Isolated from Sargassum horneri Suppressed Oxidative Stress and Inflammation by Activating Nrf2/HO-1 Signaling in IFN-γ/TNF-α-Stimulated HaCaT Keratinocytes

Antioxidants ◽

10.3390/antiox10060856 ◽

2021 ◽

Vol 10 (6) ◽

pp. 856

Author(s):

Eui-Jeong Han ◽

Ilekuttige Priyan Shanura Fernando ◽

Hyun-Soo Kim ◽

Dae-Sung Lee ◽

Areum Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Factor Κb ◽

Sargassum Horneri ◽

Mitogen Activated Protein Kinase ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Hacat Keratinocytes ◽

Tnf Α ◽

Ifn Γ

The present study evaluated the effects of (–)-loliolide isolated from Sargassum horneri (S. horneri) against oxidative stress and inflammation, and its biological mechanism in interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated HaCaT keratinocytes. The results showed that (–)-loliolide improved the cell viability by reducing the production of intracellular reactive oxygen species (ROS) in IFN-γ/TNF-α-stimulated HaCaT keratinocytes. In addition, (–)-loliolide effectively decreased the expression of inflammatory cytokines (interleukin (IL)-4 IL-6, IL-13, IFN-γ and TNF-α) and chemokines (CCL11 (Eotaxin), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC)), by downregulating the expression of epidermal-derived initial cytokines (IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)). Furthermore, (–)-loliolide suppressed the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling, whereas it activated nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Interestingly, the cytoprotective effects of (–)-loliolide against IFN-γ/TNF-α stimulation were significantly blocked upon inhibition of HO-1. Taken together, these results suggest that (–)-loliolide effectively suppressed the oxidative stress and inflammation by activating the Nrf2/HO-1 signaling in IFN-γ/TNF-α-stimulated HaCaT keratinocytes.

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The Protective Role of Feruloylserotonin in LPS-Induced HaCaT Cells

Molecules ◽

10.3390/molecules24173064 ◽

2019 ◽

Vol 24 (17) ◽

pp. 3064 ◽

Cited By ~ 3

Author(s):

Yuzhu He ◽

Byung-gook Kim ◽

Hye-Eun Kim ◽

Qiaochu Sun ◽

Shuhan Shi ◽

...

Keyword(s):

Antioxidant Activities ◽

Protective Role ◽

Related Factor ◽

Nuclear Factor ◽

Hacat Cells ◽

Protective Effects ◽

Hydroxycinnamic Acid Amides ◽

Anti Inflammatory ◽

Underlying Mechanisms

Epidermal inflammation is caused by various bacterial infectious diseases that impair the skin health. Feruloylserotonin (FS) belongs to the hydroxycinnamic acid amides of serotonin, which mainly exists in safflower seeds and has been proven to have anti-inflammatory and antioxidant activities. Human epidermis mainly comprises keratinocytes whose inflammation causes skin problems. This study investigated the protective effects of FS on the keratinocyte with lipopolysaccharides (LPS)-induced human HaCaT cells and elucidated its underlying mechanisms of action. The mechanism was investigated by analyzing cell viability, PGE2 levels, cell apoptosis, nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, and TLR4/NF-κB pathway. The anti-inflammatory effects of FS were assessed by inhibiting the inflammation via down-regulating the TLR4/NF-κB pathway. Additionally, FS promoted Nrf2 translocation to the nucleus, indicating that FS showed anti-oxidative activities. Furthermore, the antioxidative and anti-inflammatory effects of FS were found to benefit each other, but were independent. Thus, FS can be used as a component to manage epidermal inflammation due to its anti-inflammatory and anti-oxidative properties.

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Protective effects of nuclear factor erythroid 2-related factor on oxidative stress and apoptosis in the testis of mice before adulthood

Theriogenology ◽

10.1016/j.theriogenology.2020.03.002 ◽

2020 ◽

Vol 148 ◽

pp. 112-121 ◽

Cited By ~ 2

Author(s):

Jin Feng ◽

Yuxuan He ◽

Yulong Shen ◽

Guanglin Zhang ◽

Shaotao Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects

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Gentiopicroside Ameliorates Oxidative Stress and Lipid Accumulation through Nuclear Factor Erythroid 2-Related Factor 2 Activation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/2940746 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Meiyu Jin ◽

Haihua Feng ◽

Yue Wang ◽

Siru Yan ◽

Bingyu Shen ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Regulatory Element ◽

Cell Counting ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects ◽

Akt Inhibitor

The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is closely related to the alleviation of nonalcoholic fatty liver disease (NAFLD) by regulating oxidative stress and lipid homeostasis. Gentiopicroside (GPS), an iridoid glycoside found in the Gentianaceae, possesses anti-inflammatory and antioxidant effects. However, the protective effects of GPS on lipid accumulation and oxidative damage have not been investigated thoroughly in free fatty acid- (FFA-) induced HepG2 cells and tyloxapol- (Ty-) induced hyperlipidemia mice. Cell counting kit-8 assays, Oil Red O staining, Western blotting analysis, extraction of nuclear and cytosolic proteins, and biochemical index assay were employed to explore the mechanisms by which GPS exerts a protective effect on FFA-induced HepG2 cells and Ty-induced hyperlipidemia mouse model. This paper demonstrates that GPS could effectively alleviate NAFLD by elevating cell viability, reducing fatty deposition, downregulating TG, and activating nucleus Nrf2 in FFA-induced HepG2 cells. Meanwhile, GPS significantly regulated the activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, Nrf2 antioxidant pathway, peroxisome proliferator-activated receptor α (PPARα), and GPS-inhibited sterol regulatory element-binding protein-1c (SREBP-1c) expression in FFA-stimulated lipid accumulation of HepG2 cells and Ty-treated mice. Interestingly, we highlight that PI3K/AKT inhibitor (LY294002) markedly increased the expression of Nrf2 antioxidant pathway, PPARα, and downregulated SREBP-1c in FFA-stimulated HepG2 cells. For these reasons, we found that the deletion of Nrf2 could lose the protective effects of GPS on the Nrf2 antioxidant pathway and PPARα activation and SREBP-1c inactivation in FFA-stimulated HepG2 cells and Ty-treated mice. GPS treatment had no effect on abnormal lipogenesis and antioxidant enzymes in Ty-induced Nrf2-/- mice. This work gives a new explanation that GPS may be a useful therapeutic strategy for NAFLD through upregulation of the Nrf2 antioxidant pathway, which can alleviate oxidative damage and lipid accumulation.

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PEA/Polydatin: Anti-Inflammatory and Antioxidant Approach to Counteract DNBS-Induced Colitis

Antioxidants ◽

10.3390/antiox10030464 ◽

2021 ◽

Vol 10 (3) ◽

pp. 464

Author(s):

Alessio Filippo Peritore ◽

Ramona D’Amico ◽

Marika Cordaro ◽

Rosalba Siracusa ◽

Roberta Fusco ◽

...

Keyword(s):

Oxidative Stress ◽

Clinical Signs ◽

Neutrophil Infiltration ◽

Sirtuin 1 ◽

Positive Staining ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects ◽

Inflammatory Processes ◽

Anti Inflammatory

Palmitoylethanolamide (PEA) has well-known anti-inflammatory effects. However, PEA does not possess an antioxidant ability. A comicronized formulation of ultramicronized PEA (um-PEA) and polydatin (Pol) PEA/Pol, a biological precursor of resveratrol with antioxidant activity, could have protective effects on oxidative stress produced by inflammatory processes. We evaluated the effects of a comicronized PEA/Pol 10 mg/kg (9 mg of um-PEA+1 mg of polydatin) in a model of Dinitrobenzene sulfonic acid (DNBS)-induced colitis. Ulcerative colitis was induced in mice by intrarectally injection of DNBS (4 mg in 100 µL of 50% ethanol per mouse). Macroscopic and histologic colon alterations and marked clinical signs were observed four days after DNBS and elevated cytokine production. The myeloperoxidase (MPO) activity assessed for neutrophil infiltration was associated with ICAM-1 and P-selectin adhesion controls in colons. Oxidative stress was detected with increased poly ADP-ribose polymerase (PARP) and nitrotyrosine positive staining and malondialdehyde (MDA) levels in inflamed colons. Macroscopic and histologic alterations minimized by oral PEA/Pol, as well as neutrophil infiltration, inflammatory cytokine release, MDA, nitrotyrosine, PARP and ICAM-1, and P-selectin expressions. The mechanism of action of PEA/Pol could be related to the sirtuin 1/nuclear factor erythroid 2-related factor 2 (SIRT-1/Nrf2) pathway and nuclear factor (NF)-κB. PEA/Pol administration inhibited NF-κB and increased SIRT-1/Nrf2 expressions. Our results show that PEA/Pol is capable of decreasing inflammatory bowel disease (IBD) DNBS-induced in mice.

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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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Oxidative Stress, NF-κB-Mediated Inflammation and Apoptosis in the Testes of Streptozotocin–Induced Diabetic Rats: Combined Protective Effects of Malaysian Propolis and Metformin

Antioxidants ◽

10.3390/antiox8100465 ◽

2019 ◽

Vol 8 (10) ◽

pp. 465 ◽

Cited By ~ 15

Author(s):

Victor Udo Nna ◽

Ainul Bahiyah Abu Bakar ◽

Azlina Ahmad ◽

Chinedum Ogbonnaya Eleazu ◽

Mahaneem Mohamed

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Reproductive System ◽

Diabetic Rats ◽

Male Reproductive System ◽

Related Factor ◽

Mrna Levels ◽

Nuclear Factor ◽

Protective Effects ◽

Protein Levels

Oxidative stress, inflammation and apoptosis are major complications that trigger organ failure in diabetes mellitus (DM), and are proven to adversely affect the male reproductive system. Clinical and experimental studies have demonstrated the promising protective effects of propolis in DM and its associated systemic effects. Herein, we investigated the effect of Malaysian propolis (MP) on testicular oxidative stress, inflammation and apoptosis in diabetic rats. Further, the possibility of a complementary effect of MP with the anti-hyperglycaemic agent, metformin (Met), was studied with the idea of recommending its use in the event that Met alone is unable to contain the negative effects of DM on the male reproductive system in mind. Male Sprague-Dawley rats were either gavaged distilled water (normoglycaemic control and diabetic control groups), MP (diabetic rats on MP), Met (diabetic rats on Met) or MP+Met (diabetic rats on MP+Met), for 4 weeks. MP decreased oxidative stress by up-regulating (p < 0.05) testicular mRNA levels of nuclear factor erythroid 2-related factor 2, superoxide dismutase, catalase and glutathione peroxidase; increasing (p < 0.05) the activities of antioxidant enzymes; and decreasing (p < 0.05) lipid peroxidation in the testes and epididymis of diabetic rats. Further, MP down-regulated (p < 0.05) testicular mRNA and protein levels of pro-inflammatory mediators (nuclear factor kappa B, inducible nitric oxide synthase, tumour necrosis factor-α and interleukin (IL)-1β), decreased (p < 0.05) the nitric oxide level, and increased (p < 0.05) IL-10 mRNA and protein levels. MP also down-regulated (p < 0.05) Bax/Bcl-2, p53, casapase-8, caspase-9 and caspase-3 genes, and increased (p < 0.05) testicular germ cell proliferation. MP’s effects were comparable to Met. However, the best results were achieved following co-administration of MP and Met. Therefore, we concluded that administration of the MP+Met combination better attenuates testicular oxidative stress, inflammation and apoptosis in DM, relative to MP or Met monotherapy, and may improve the fertility of males with DM.

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GLUTATHIONE TRANSFERASES

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev.pharmtox.45.120403.095857 ◽

2005 ◽

Vol 45 (1) ◽

pp. 51-88 ◽

Cited By ~ 2233

Author(s):

John D. Hayes ◽

Jack U. Flanagan ◽

Ian R. Jowsey

Keyword(s):

Oxidative Stress ◽

Antitumor Agents ◽

Glutathione Transferase ◽

Degradation Products ◽

Nuclear Factor Κb ◽

Peroxisome Proliferator ◽

Related Factor ◽

Nuclear Factor ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous α,β-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-κB (NF-κB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.

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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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