Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy

Yerra, Veera Ganesh; Negi, Geeta; Sharma, Shyam Sunder; Kumar, Ashutosh

doi:10.1016/j.redox.2013.07.005

Cited by 337 publications

(201 citation statements)

References 20 publications

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“…found that NF-κB generates TNF-α and IL-6 expression. Activation of NF-κB suppresses antioxidant genes by inhibiting the Nrf2 pathway, thereby disrupting the antioxidant defence system [34,35]. In the present study, DN was induced in diabetic rats, along with activation of both the Nrf2 and NF-κB pathways.…”

Section: Discussionmentioning

confidence: 48%

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway

Chen

Liu

Han

et al. 2018

Cell Physiol Biochem

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Background/Aims: Deguelin is a natural rotenoid that shows anti-inflammatory and antimicrobial activities. Rotenoids prevent oxidative damage and potentiate natural antioxidant activity in diabetic conditions, suggesting utility in treating diabetes and its complications. Here, we evaluate the potential efficacy of deguelin against diabetic neuropathy (DN). Methods: DN was induced by streptozotocin followed by daily treatment with deguelin (4, 6 or 8 mg/kg) for 14 days. Blood glucose was measured, neurobehavioral tests for nociception and motor coordination were performed, and neuron conduction velocities were analysed electrophysiologically. We also assessed (Na⁺-K⁺) ATPase activity, performed a reactive oxygen species assay, measured the levels of various markers of oxidative stress, and of hydrogen sulphide (H₂S) in dorsal root ganglion (DRG) neurons, conducted immunoblotting studies for proteins and ELISA for inflammatory cytokines. Results: Deguelin significantly suppressed mechanical and thermal hyperalgesia, as well as cold allodynia, and partially restored the conduction velocities of neurons in DN rats. Significantly decreased expression levels of capspase-3 in DRG neurons, and increased (Na⁺-K⁺) ATPase activity in sciatic nerves, were observed. In addition, deguelin decreased glucose levels, attenuated oxidative stress and neuroinflammation, and elevated levels of H₂S, nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1, suggesting a disease-attenuating effect of deguelin in DN rats. To shed light on the underlying mechanism of action of deguelin, insulin- and dimethyl fumarate (BG-12)-treated groups were also included. Insulin suppressed glucose levels and BG-12 produced effects on Nrf2 levels similar to 8 mg/kg deguelin, confirming involvement of the Nrf2 pathway in the beneficial effects of deguelin against DN. Conclusions: Deguelin attenuated DN by decreasing oxidative stress and plasma glucose levels via the Nrf2 signalling pathway.

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Section: Discussionmentioning

confidence: 48%

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway

Chen

Liu

Han

et al. 2018

Cell Physiol Biochem

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“…As transfection efficiency varies between cell types, viral pTRAF vectors may become useful and should be assessed in future development of the method. However, it should be underlined that even in cells hard to transfect, the fact that three response elements are present in the same plasmid backbone to Interactions between Nrf2 and NF-κB, in particular, in different pathological conditions have been much discussed, both in terms of possible molecular mechanisms for the cross talk and pathophysiological consequences (6,14). Interactions between NF-κB and HIF (2,5) and between Nrf2 and HIF have also been reported (29).…”

Section: Discussionmentioning

confidence: 99%

Cross Talk in HEK293 Cells Between Nrf2, HIF, and NF-κB Activities upon Challenges with Redox Therapeutics Characterized with Single-Cell Resolution

Johansson

Cebula

Rengby

et al. 2017

Antioxidants & Redox Signaling

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“…The MAPK is promoted by hyperglycemia through apoptosis signaling kinase 1 or directly by ROS and causes activation of cytosolic NF- κ B [61]. It is known that Nrf2 consist in the counterpart of NF- κ B maintaining a cellular homeostasis, but ROS overproduction can generate an imbalance between them and associates with nerve damage [62, 63]. …”

Section: Diabetic Polyneuropathymentioning

confidence: 99%

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function

Román-Pintos

Villegas-Rivera

Rodríguez-Carrizález

et al. 2016

Journal of Diabetes Research

181

152

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Diabetic polyneuropathy (DPN) is defined as peripheral nerve dysfunction. There are three main alterations involved in the pathologic changes of DPN: inflammation, oxidative stress, and mitochondrial dysfunction. Inflammation induces activation of nuclear factor kappa B, activator protein 1, and mitogen-activated protein kinases. Oxidative stress induced by hyperglycemia is mediated by several identified pathways: polyol, hexosamine, protein kinase C, advanced glycosylation end-products, and glycolysis. In addition, mitochondrial dysfunction accounts for most of the production of reactive oxygen and nitrosative species. These free radicals cause lipid peroxidation, protein modification, and nucleic acid damage, to finally induce axonal degeneration and segmental demyelination. The prevalence of DPN ranges from 2.4% to 78.8% worldwide, depending on the diagnostic method and the population assessed (hospital-based or outpatients). Risk factors include age, male gender, duration of diabetes, uncontrolled glycaemia, height, overweight and obesity, and insulin treatment. Several diagnostic methods have been developed, and composite scores combined with nerve conduction studies are the most reliable to identify early DPN. Treatment should be directed to improve etiologic factors besides reducing symptoms; several approaches have been evaluated to reduce neuropathic impairments and improve nerve conduction, such as oral antidiabetics, statins, and antioxidants (alpha-lipoic acid, ubiquinone, and flavonoids).

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Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy

Cited by 337 publications

References 20 publications

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway

Cross Talk in HEK293 Cells Between Nrf2, HIF, and NF-κB Activities upon Challenges with Redox Therapeutics Characterized with Single-Cell Resolution

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function

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