Drug targeting to sites of oxidative stress using the Baeyer-Villiger reaction

The antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) is a desirable therapeutic target for a broad range of pathologies, including chronic diseases of the lung and liver, and autoimmune, neurodegenerative, and cardiovascular disorders. However, current Nrf2 activators are limited by unwanted effects due to non-specificity, and systemic distribution and action. Here we report that a 1,2-dicarbonyl moiety masks the electrophilic reactivity of the Nrf2 activator monomethyl fumarate (MMF), otherwise responsible for its non-specific effects. The 1,2-dicarbonyl compound is highly susceptible to Baeyer-Villiger oxidation, with generation of MMF specifically on exposure to pathological levels of hydrogen peroxide or peroxynitrite. Oral treatment with the MMF generating 1,2-dicarbonyl compound reversed chronic neuropathic and osteoarthritis pain in mice, and selectively activated Nrf2 at sites of oxidative stress. This 1,2-dicarbonyl platform may be used to treat additional disorders of oxidative stress, and to selectively target other therapeutics to sites of redox imbalance.

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Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7469326 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 26

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.

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A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy

Clinical Science ◽

10.1042/cs20160068 ◽

2016 ◽

Vol 130 (15) ◽

pp. 1375-1387 ◽

Cited By ~ 14

Author(s):

Devy Deliyanti ◽

Jae Young Lee ◽

Steven Petratos ◽

Colin J. Meyer ◽

Keith W. Ward ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Capacity ◽

Glial Cells ◽

Related Factor ◽

Nuclear Factor ◽

Effective Strategy ◽

Vascular Cell ◽

Nrf2 Activator

A novel and potent nuclear factor erythroid-2 related factor 2 (Nrf2) activator, dh404, attenuates retinal vasculopathy by reducing oxidative stress-mediated damage to glia. Nrf2 agonists represent an effective strategy to improve vision-threatening glial and vascular cell pathology in ischaemic retinopathies.

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Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease

Antioxidants ◽

10.3390/antiox9090783 ◽

2020 ◽

Vol 9 (9) ◽

pp. 783

Author(s):

Bowen Sun ◽

Xifan Wang ◽

Xiaoxue Liu ◽

Longjiao Wang ◽

Fazheng Ren ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Hippuric Acid ◽

Redox Homeostasis ◽

Pathological Process ◽

Related Factor ◽

Kidney Fibrosis ◽

Nrf2 Activator

Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD.

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1-O-Hexyl-2,3,5-Trimethylhydroquinone Ameliorates the Development of Preeclampsia through Suppression of Oxidative Stress and Endothelial Cell Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8839394 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Lai Jiang ◽

Yanping Gong ◽

Jie Rao ◽

Qiuhong Yang ◽

Na Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cell ◽

Cell Apoptosis ◽

Umbilical Vein ◽

Fetal Weight ◽

Related Factor ◽

Endothelial Cell Apoptosis ◽

High Systolic Blood Pressure ◽

Nrf2 Activator

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ), a potent nuclear factor-E2-related factor 2 (Nrf2) activator, has potent antioxidant activity by scavenging reactive oxygen species (ROS). However, the role of HTHQ on the development of preeclampsia (PE) and the underlying mechanisms have barely been explored. In the present study, PE model was induced by adenovirus-mediated overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1) in pregnant mice. The results showed that HTHQ treatment significantly relieved the high systolic blood pressure (SBP) and proteinuria and increased the fetal weight and fetal weight/placenta weight in preeclamptic mice. Furthermore, we found that HTHQ treatment significantly decreased soluble endoglin (sEng), endothelin-1 (ET-1), and activin A and restored vascular endothelial growth factor (VEGF) in preeclamptic mice. In addition, HTHQ treatment inhibited oxidative stress and endothelial cell apoptosis by increasing the levels of Nrf2 and its downstream haemoxygenase-1 (HO-1) protein. In line with the data in vivo, we discovered that HTHQ treatment attenuated oxidative stress and cell apoptosis in human umbilical vein endothelial cells (HUVECs) following hypoxia and reperfusion (H/R), and the HTHQ-mediated protection was lost after transfected with siNrf2. In conclusion, these results suggested that HTHQ ameliorates the development of preeclampsia through suppression of oxidative stress and endothelial cell apoptosis.

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Sulforaphane inhibits the production of Aβ partially through activation of Nrf2-regulated Oxidative Stress

Food & Function ◽

10.1039/d1fo02651h ◽

2021 ◽

Author(s):

Shunxi Zhang ◽

Jia He Zhao ◽

Zhihuai Bai ◽

Fan Wu ◽

Lina Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Potential Role ◽

Regulation Mechanism ◽

Related Factor ◽

Nuclear Factor ◽

Nrf2 Activator ◽

Specific Symptoms

Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, presents a very potential role in improving the Alzheimer's disease (AD)-specific symptoms. However, the regulation mechanism of SFN...

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Anti-Viral Potential and Modulation of Nrf2 by Curcumin: Pharmacological Implications

Antioxidants ◽

10.3390/antiox9121228 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1228

Author(s):

Mahdie Rahban ◽

Mehran Habibi-Rezaei ◽

Mansoureh Mazaheri ◽

Luciano Saso ◽

Ali A. Moosavi-Movahedi

Keyword(s):

Oxidative Stress ◽

Viral Infections ◽

Biological Effects ◽

Curcuma Longa ◽

Redox Balance ◽

Antioxidant Response ◽

Potential Effect ◽

Related Factor ◽

Balance State ◽

Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that maintains the cell’s redox balance state and reduces inflammation in different adverse stresses. Under the oxidative stress, Nrf2 is separated from Kelch-like ECH-associated protein 1 (Keap1), which is a key sensor of oxidative stress, translocated to the nucleus, interacts with the antioxidant response element (ARE) in the target gene, and then activates the transcriptional pathway to ameliorate the cellular redox condition. Curcumin is a yellow polyphenolic curcuminoid from Curcuma longa (turmeric) that has revealed a broad spectrum of bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Curcumin significantly increases the nuclear expression levels and promotes the biological effects of Nrf2 via the interaction with Cys151 in Keap1, which makes it a marvelous therapeutic candidate against a broad range of oxidative stress-related diseases, including type 2 diabetes (T2D), neurodegenerative diseases (NDs), cardiovascular diseases (CVDs), cancers, viral infections, and more recently SARS-CoV-2. Currently, the multifactorial property of the diseases and lack of adequate medical treatment, especially in viral diseases, result in developing new strategies to finding potential drugs. Curcumin potentially opens up new views as possible Nrf2 activator. However, its low bioavailability that is due to low solubility and low stability in the physiological conditions is a significant challenge in the field of its efficient and effective utilization in medicinal purposes. In this review, we summarized recent studies on the potential effect of curcumin to activate Nrf2 as the design of potential drugs for a viral infection like SARS-Cov2 and acute and chronic inflammation diseases in order to improve the cells’ protection.

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Ingredients from Litsea garrettii as Potential Preventive Agents against Oxidative Insult and Inflammatory Response

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7616852 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Yan-Ru Li ◽

Guo-Hui Li ◽

Lin Sun ◽

Lin Li ◽

Yue Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Regulatory Subunit ◽

No Production ◽

Related Factor ◽

Etoh Extract ◽

Protein Levels ◽

Phytochemical Investigation ◽

Nrf2 Activator ◽

Oxidative Insult

Oxidative stress and inflammation undoubtedly contribute to the pathogenesis of many human diseases. The nuclear transcription factor erythroid 2-related factor (Nrf2) and the nuclear factor κB (NF-κB) play central roles in regulation of oxidative stress and inflammation and thus are targets for developing agents against oxidative stress- and inflammation-related diseases. Our previous study indicated that the EtOH extract of Litsea garrettii protected human bronchial epithelial cells against oxidative insult via the activation of Nrf2. In the present study, a systemic phytochemical investigation of L. garrettii led to the isolation of twenty-one chemical ingredients, which were further evaluated for their inhibitions on oxidative stress and inflammation using NAD(P)H:quinone reductase (QR) assay and nitric oxide (NO) production assay. Of these ingredients, 3-methoxy-5-pentyl-phenol (MPP, 5) was identified as an Nrf2 activator and an NF-κB inhibitor. Further studies demonstrated the following: (i) MPP upregulated the protein levels of Nrf2, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase regulatory subunit (GCLM); enhanced the nuclear translocation and stabilization of Nrf2; and inhibited arsenic [As(III)]-induced oxidative insult in normal human lung epithelial Beas-2B cells. And (ii) MPP suppressed the nuclear translocation of NF-κB p65 subunit; inhibited the lipopolysaccharide- (LPS-) stimulated increases of NF-κB p65 subunit, COX-2, iNOS, TNF-α, and IL-1β; and blocked the LPS-induced biodegrade of IκB-α in RAW 264.7 murine macrophages. Taken together, MPP displayed potential preventive effects against inflammation- and oxidative stress-related diseases.

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Protective Effect of Swertiamarin on Myocardial Injury Through Activation of Nrf2/HO-1 Pathway in Heart Failure Model of Rats

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:260-265 ◽

2020 ◽

Vol 18 (3) ◽

pp. 260-265

Author(s):

Xu Lin ◽

Zheng Xiaojun ◽

Lv Heng ◽

Mo Yipeng ◽

Tong Hong

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Ejection Fraction ◽

Protective Effect ◽

Infarct Size ◽

Rat Model ◽

Left Ventricular ◽

Related Factor ◽

Nuclear Factor ◽

Internal Dimension

The purpose of this study was to evaluate the protective effect of swertiamarin on heart failure. To this end, a rat model of heart failure was established via left coronary artery ligation. Infarct size of heart tissues was determined using triphenyl tetrazolium chloride staining. Echocardiography was performed to evaluate cardiac function by the determination of ejection fraction, left ventricular internal dimension in diastole and left ventricular internal dimension in systole. The effect of swertiamarin on oxidative stress was evaluated via enzyme-linked immunosorbent assay. The mechanism was evaluated using western blot. Administration of swertiamarin reduced the infarct size of heart tissues in rat models with heart failure. Moreover, swertiamarin treatment ameliorated the cardiac function, increased ejection fraction and fractional shortening, decreased left ventricular internal dimension in diastole and left ventricular internal dimension in systole. Swertiamarin improved oxidative stress with reduced malondialdehyde, while increased superoxide dismutase, glutathione, and GSH peroxidase. Furthermore, nuclear-factor erythroid 2-related factor 2, heme oxygenase and NAD(P)H dehydrogenase (quinone 1) were elevated by swertiamarin treatment in heart tissues of rat model with heart failure. Swertiamarin alleviated heart failure through suppression of oxidative stress response via nuclear-factor erythroid 2-related factor 2/heme oxygenase-1 pathway providing a novel therapeutic strategy for heart failure.

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