Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain

Vasavda, Chirag; Xu, Risheng; Liew, Jason; Kothari, Ruchita; Dhindsa, Ryan S.; Semenza, Evan R.; Paul, Bindu D.; Green, Dustin P.; Sabbagh, Mark F; Shin, Joseph; Yang, Wuyang; Snowman, Adele M.; Albacarys, Lauren; Moghekar, Abhay; Pardo, Carlos A.; Luciano, Mark; Huang, Judy; Bettegowda, Chetan; Kwatra, Shawn G.; Dong, Xinzhong; Lim, Michael; Snyder, Solomon H.

doi:10.1126/sciadv.abo5633

Cited by 20 publications

(13 citation statements)

References 124 publications

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“…Furthermore, studies were also conducted to trace the possible upstream signal for the process. Previous studies have reported that 59,60 Nrf2-Keap1 signaling plays an important role in regulating the cellular oxidative stress response, 61,62 and the release of Nrf2 could activate the expression of antioxidant genes (Figure 3F). Therefore, we used Nrf2 siRNA and ML385 inhibitor to knock down or inhibit Nrf2 expression in RBL-2H3 cells to further examine the relationship between the Nrf2-Keap1 signaling pathway and selenoproteins.…”

Section: Resultsmentioning

confidence: 88%

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins

et al. 2023

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Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and Macaca fascicularis models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.

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Section: Resultsmentioning

confidence: 88%

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins

et al. 2023

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“…Furthermore, oxidative stress was evident in a murine model of TN, and activation of the antioxidant nuclear factor erythroid 2-related factor (2) transcriptional network was shown to have pain-relieving properties through a reduction in oxidative stress. 22…”

Section: Discussionmentioning

confidence: 99%

Preoperative Characteristics and Postoperative Pain Outcomes in Trigeminal Neuralgia With Concomitant Autoimmune Disease

Kalluri¹,

So²,

Ran³

et al. 2023

Neurosurgery

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BACKGROUND AND OBJECTIVES: Although the association between multiple sclerosis and trigeminal neuralgia (TN) is well established, little is known about TN pain characteristics and postoperative pain outcomes after microvascular decompression (MVD) in patients with TN and other autoimmune diseases. In this study, we aim to describe presenting characteristics and postoperative outcomes in patients with concomitant TN and autoimmune disease who underwent an MVD. METHODS: A retrospective review of all patients who underwent an MVD at our institution between 2007 and 2020 was conducted. The presence and type of autoimmune disease were recorded for each patient. Patient demographics, comorbidities, clinical characteristics, postoperative Barrow Neurological Institute (BNI) pain and numbness scores, and recurrence data were compared between groups. RESULTS: Of the 885 patients with TN identified, 32 (3.6%) were found to have concomitant autoimmune disease. Type 2 TN was more common in the autoimmune cohort (P = .01). On multivariate analysis, concomitant autoimmune disease, younger age, and female sex were found to be significantly associated with higher postoperative BNI score (P = .04, <0.001, and <0.001, respectively). In addition, patients with autoimmune disease were more likely to experience significant pain recurrence (P = .009) and had shorter time to recurrence on Kaplan-Meier analysis (P = .047), although this relationship was attenuated on multivariate Cox proportional hazards regression. CONCLUSION: Patients with concomitant TN and autoimmune disease were more likely to have Type 2 TN, had worse postoperative BNI pain scores at the final follow-up after MVD, and were more likely to experience recurrent pain than patients with TN alone. These findings may influence postoperative pain management decisions for these patients and support a possible role for neuroinflammation in TN pain.

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“…By contrast, Nrf2 knockout mice show more severe oxidative stress and neurologic dysfunction after TBI [ 73 ]. Nrf2 also links redox homeostasis to pain perception mechanisms and tolerance [ 74 ].…”

Section: Potential Mechanisms Of Tbi-mediated Increased Risk Of All F...mentioning

confidence: 99%

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

2023

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Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Alzheimer’s disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease.

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Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain

Cited by 20 publications

References 124 publications

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins

Preoperative Characteristics and Postoperative Pain Outcomes in Trigeminal Neuralgia With Concomitant Autoimmune Disease

Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury

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