Oxidized 5-aminosalicylic acid activates Nrf2-HO-1 pathway by covalently binding to Keap1: Implication in anti-inflammatory actions of 5-aminosalicylic acid

Kang, Sookjin; Kim, Wooseong; Jeong, Seongkeun; Lee, Yonghyun; Nam, Joon; Lee, Sun Young; Jung, Yunjin

doi:10.1016/j.freeradbiomed.2017.04.366

Cited by 26 publications

(22 citation statements)

References 30 publications

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“…The colon segments were homogenized with RIPA buffer containing protease inhibitor (1:100). After protein concentration was determined by BCR protein assay kit, Western blot assay was performed as described ( Kang et al, 2017 ). The primary antibodies against ZO-1, occludin and claudin-1 were then incubated overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Periplaneta americana Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rats by Keap1/Nrf-2 Activation, Intestinal Barrier Function, and Gut Microbiota Regulation

et al. 2018

Front. Pharmacol.

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Periplaneta americana, a magic medicinal insect being present for over 300 million years, exhibits desirable therapeutic outcome for gastrointestinal ulcer treatment. Nowadays, P. americana ethanol extract (PAE) has been shown to ameliorate ulcerative colitis (UC) by either single-use or in combination with other therapeutic agents in clinics. However, its underlying mechanisms are still seldom known. Herein, we investigated the anti-UC activity of PAE by alleviating intestinal inflammation and regulating the disturbed gut microbiota structure in dextran sulfate sodium (DSS)-induced UC rats. Based on multiple constitute analyses by HPLC for quality control, PAE was administrated to DSS-induced UC rats by oral gavage for 2 weeks. The anti-UC effect of PAE was evaluated by inflammatory cytokine production, immunohistochemical staining, and gut microbiota analysis via 16S rRNA sequencing. As a result, PAE remarkably attenuated DSS-induced UC in rats. The colonic inflammatory responses manifested as decreased colonic atrophy, intestinal histopathology scores and inflammatory cytokines. In addition, PAE improved the intestinal barrier function via activating Keap1/Nrf-2 pathway and promoting the expressions of tight junction proteins. It was observed that the UC rats showed symptoms of gut microbial disturbance, i.e., the increased Firmicutes/Bacteroidetes ratio and the significantly decreased probiotics such as Lactobacillus, Roseburia, and Pectobacterium, which were negatively correlated with these detected pro-inflammatory cytokines (secreted by immune CD4+ T cells, and including IFN-γ, TNF-α, IL-6, IL-8, IL-17, IL-1β). Besides, PAE administration regulated the abnormal intestinal microbial composition and made it similar to that in normal rats. Therefore, PAE could attenuate the DSS-induced UC in rats, by means of ameliorating intestinal inflammation, improving intestinal barrier function, and regulating the disturbed gut microbiota, especially improving beneficial intestinal flora growth, modulating the flora structure, and restoring the intestinal-immune system.

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Section: Methodsmentioning

confidence: 99%

Periplaneta americana Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rats by Keap1/Nrf-2 Activation, Intestinal Barrier Function, and Gut Microbiota Regulation

et al. 2018

Front. Pharmacol.

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“…In addition, many phytochemicals, such as quercetin, curcumin and resveratrol, are currently under investigation, due to their potential as HO-1 alternative inducers to counteract inflammation processes with lower cytotoxic secondary effects [ 95 , 96 , 97 ]. Alternatively, there are also a few approved drugs, such as 5-aminosalicylic acid (5-ASA), dimethyl fumarate (DMF), and 5-aminolevulinic acid (5-ALA), whose beneficial properties in inflammatory conditions are explained, at least in part, by their capacity to induce HO-1 [ 96 , 98 , 99 ] ( Figure 1 ). Additionally, another effective option is the use of BV/BR based therapies, which have proven to be effective for these chronic pathologies [ 100 , 101 , 102 ] and/or the direct administration of CO via inhalation, CO-releasing molecules (CORMs) or hybrid carbon monoxide-releasing molecules (HYCOs).…”

Section: Understanding the Protective Role Of Heme Oxygenasementioning

confidence: 99%

A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene?

et al. 2022

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Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe2+), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.

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“…HO-1 and NQO1 are landmark target genes in a series of antioxidant enzyme and detoxifying enzyme genes regulated in the middle and lower reaches of Nrf2 pathway. 28,29 NQO1 is ubiquitous in eukaryotic cells and has strong antioxidant properties, which can prevent oxidation-reduction reactions and oxidative stress reactions of quinones. 30 HO-1 can inhibit various inflammation and oxidation reactions, maintain platelet aggregation and vascular tension, and has protective effect on I/R.…”

Section: Dovepressmentioning

confidence: 99%

<p>Protective Effect of Pravastatin on Myocardial Ischemia Reperfusion Injury by Regulation of the miR-93/Nrf2/ARE Signal Pathway</p>

Liu¹,

Zhang²,

Zhao³

et al. 2020

DDDT

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Purpose: This research intended to study the mechanism of pravastatin in myocardial ischemia reperfusion (I/R) injury. Patients and Methods: Altogether 70 male rats were selected and grouped into Sham operation group (Sham group), ischemia reperfusion group (I/R group), pravastatin pretreatment group (I/R+P group), I/R+miR-93-mimics, I/R+P+miR-93-mimics, I/R+Nrf2 siRNA, and I/R+P+Nrf2 siRNA group. The myocardial function of each group was detected. Results: Myocardial I/R injury could lead to abnormal myocardial enzyme activity, inflammatory reaction and oxidative stress. However, pravastatin could significantly inhibit the activity of myocardial enzymes, alleviate inflammatory reaction and inhibit oxidative stress reaction, thus playing a protective role. Furthermore, cell experiments showed that pravastatin can alleviate the injury of H9C2 myocardial cells caused by I/R, inhibit the apoptosis of myocardial cells, and lead to a significant reduction in pro-apoptotic genes Bax, caspase-3 and caspase-9 transcription levels, an obvious increase in anti-apoptotic gene Bcl-2, and an increase in cell activity. After I/R induced injury, miR-93 level was significantly up-regulated and Nrf2 level was down-regulated. Over-expression of miR-93 or inhibition of Nrf2 expression would lead to further aggravation of I/R myocardial injury, increase the apoptosis rate of cells and decrease the activity of myocardial cells. Pravastatin administration could inhibit miR-93, activate and promote Nrf2 in myocardial tissue, and promote protein expression of downstream regulatory genes HO-1 and NQO1. In the I/R model, pravastatin was given. Over-expression of miR-93 or silencing Nrf2 could reverse the therapeutic effect of pravastatin on I/R. Conclusion: Pravastatin acts as a protector on myocardial ischemia reperfusion injury by regulating miR-93/Nrf2/ARE signaling pathway.

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Oxidized 5-aminosalicylic acid activates Nrf2-HO-1 pathway by covalently binding to Keap1: Implication in anti-inflammatory actions of 5-aminosalicylic acid

Cited by 26 publications

References 30 publications

Periplaneta americana Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rats by Keap1/Nrf-2 Activation, Intestinal Barrier Function, and Gut Microbiota Regulation

Periplaneta americana Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Rats by Keap1/Nrf-2 Activation, Intestinal Barrier Function, and Gut Microbiota Regulation

A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene?

<p>Protective Effect of Pravastatin on Myocardial Ischemia Reperfusion Injury by Regulation of the miR-93/Nrf2/ARE Signal Pathway</p>

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