Dimethyl fumarate protects against intestinal ischemia/reperfusion lesion: Participation of Nrf2/HO-1, GSK-3β and Wnt/β-catenin pathway

Gendy, Abdallah M.; Soubh, Ayman A.; Al-Mokaddem, Asmaa K.; El-Sayed, Mohamed Kotb

doi:10.1016/j.biopha.2020.111130

Cited by 18 publications

(10 citation statements)

References 47 publications

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“…According to Wagner, Stegmaier and colleagues, BRD0705, the GSK3α-selective inhibitor, did not affect β-catenin stabilization and was associated with interrupted β-catenin signaling [41]. Given the reported coincidence of β-catenin and Nrf2 deregulation in a number of neurodegenerative contexts [52], documented co-dependency [15], the interplay between the Wnt/β-catenin and NF-κB signaling [53], and another loop involving the LPS-responsive TLR4 [54] -particularly in our investigated pathological context [55,56] and proposed mechanistic model [52] we opted to investigate the activity of this transcription factor in response to our treatments. We aimed to verify the variability between the GSK3 isoforms which pose an added advantage in a number of disease groups, in which co-morbidities can be of concern.…”

Section: Discussionmentioning

confidence: 99%

Selective GSK3β Inhibition Mediates an Nrf2-Independent Anti-inflammatory Microglial Response

et al. 2022

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Glycogen synthase kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with nuclear factor kappa B (NF-κB). GSK3 is also a suppressor of nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies. Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition. The anti-inflammatory effects of paralog-selective GSK3 inhibitors were evaluated as a function of the reductive capacity of each to mitigate LPS-induced activation of SIM-A9 microglia. The Griess method was employed to detect the nitrate-lowering capacity of selective GSK3 inhibition. Real-time PCR was used to assess post-treatment expression levels of pro-inflammatory markers and antioxidant genes; pro-inflammatory cytokines were assayed by ELISA. Nuclear lysates of treated cells were examined for Nrf2 and NF-κB accumulation by immunoblotting. Finally, to infer whether the counter-inflammatory activity of GSK3 inhibition was Nrf2-dependent, DsiRNA-mediated knockdown of Nrf2 was attempted. Results from our experiments reveal a superior anti-inflammatory and anti-oxidative efficacy for GSK3β-selective inhibition, compared to GSK3α-selective and non-selective pan-inhibition; hence, use of selective GSK3β inhibitors is likely to be more propitious than non-selective dual inhibitors administered at comparable doses. Moreover, our results suggest that the anti-inflammatory effects of GSK3 inhibition are not Nrf2 dependent. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Selective GSK3β Inhibition Mediates an Nrf2-Independent Anti-inflammatory Microglial Response

et al. 2022

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“…DMF also inhibited the expression of the costimulatory molecule CD86, the chemokine receptor CCR7, and the C-X-C motif chemokine receptor 4 (CXCR4). DMF has also exhibited a protective role in ischemic injury of organs such as the lungs, liver, and kidneys [ 63 , 64 , 65 ]. Timely reperfusion and the inhibition of I/R injury are crucial for the management of myocardial ischemia.…”

Section: Therapeutic Potential Of Dmf In Cardiovascular Diseasesmentioning

confidence: 99%

Repurposing Dimethyl Fumarate for Cardiovascular Diseases: Pharmacological Effects, Molecular Mechanisms, and Therapeutic Promise

et al. 2022

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Dimethyl fumarate (DMF) is a small molecule that has been shown to assert potent in vivo immunoregulatory and anti-inflammatory therapeutic actions. The drug has been approved and is currently in use for treating multiple sclerosis and psoriasis in the USA and Europe. Since inflammatory reactions have been significantly implicated in the etiology and progression of diverse disease states, the pharmacological actions of DMF are presently being explored and generalized to other diseases where inflammation needs to be suppressed and immunoregulation is desirable, either as a monotherapeutic agent or as an adjuvant. In this review, we focus on DMF, and present an overview of its mechanism of action while briefly discussing its pharmacokinetic profile. We further discuss in detail its pharmacological uses and highlight its potential applications in the treatment of cardiovascular diseases. DMF, with its unique combination of anti-inflammatory and vasculoprotective effects, has the potential to be repurposed as a therapeutic agent in patients with atherosclerotic cardiovascular disease. The clinical studies mentioned in this review with respect to the beneficial effects of DMF in atherosclerosis involve observations in patients with multiple sclerosis and psoriasis in small cohorts and for short durations. The findings of these studies need to be assessed in larger prospective clinical trials, ideally with a double-blind randomized study design, investigating the effects on cardiovascular endpoints as well as morbidity and mortality. The long-term impact of DMF therapy on cardiovascular diseases also needs to be confirmed.

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“…Irisin, a new peptide, promotes heat production, ameliorates obesity, and regulates glucose homeostasis to improve I/R-induced intestinal inflammatory response, reduce oxidative stress, and inhibits apoptosis, which could be associated with the Nrf2 pathway activation [ 114 ]. Dimethyl fumarate activates antioxidant pathways, induces Nrf2/HO-1, GSK-3β Wnt/β-catenin signaling pathways, and improves I/R-induced intestinal inflammatory response [ 115 ]. Salvianolic acid A ameliorated oxidation inhibited the release of pro-inflammatory cytokines, and alleviated apoptosis in I/R-induced injury through the regulation of Nrf2/ HO-1 pathways [ 116 ].…”

Section: Nrf2/keap1/are Pathway As a Potential Target In Iri Therapymentioning

confidence: 99%

Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway

Uçar

Saha³

et al. 2021

Antioxidants

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Ischemia/reperfusion (I/R) injury is associated with substantial clinical implications, including a wide range of organs such as the brain, kidneys, lungs, heart, and many others. I/R injury (IRI) occurs due to the tissue injury following the reestablishment of blood supply to ischemic tissues, leading to enhanced aseptic inflammation and stimulation of oxidative stress via reactive oxygen and nitrogen species (ROS/RNS). Since ROS causes membrane lipids’ peroxidation, triggers loss of membrane integrity, denaturation of proteins, DNA damage, and cell death, oxidative stress plays a critical part in I/R pathogenesis. Therefore, ROS regulation could be a promising therapeutic strategy for IRI. In this context, Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates the expression of several factors involved in the cellular defense against oxidative stress and inflammation, including heme oxygenase-1 (HO-1). Numerous studies have shown the potential role of the Nrf2/HO-1 pathway in IRI; thus, we will review the molecular aspects of Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE) signaling pathway in I/R, and we will also highlight the recent insights into targeting this pathway as a promising therapeutic strategy for preventing IRI.

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Dimethyl fumarate protects against intestinal ischemia/reperfusion lesion: Participation of Nrf2/HO-1, GSK-3β and Wnt/β-catenin pathway

Cited by 18 publications

References 47 publications

Selective GSK3β Inhibition Mediates an Nrf2-Independent Anti-inflammatory Microglial Response

Selective GSK3β Inhibition Mediates an Nrf2-Independent Anti-inflammatory Microglial Response

Repurposing Dimethyl Fumarate for Cardiovascular Diseases: Pharmacological Effects, Molecular Mechanisms, and Therapeutic Promise

Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway

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