Mechanisms and Therapeutic Potential of GPX4 in Pain Modulation DOI Creative Commons

Shiwen Fan,

Kaixin Wang,

Tianhao Zhang

et al.

Pain and Therapy, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Pain, a complex symptom encompassing both sensory and emotional dimensions, constitutes significant global public health issue. Oxidative stress is pivotal factor in the pathophysiology of pain, with glutathione peroxidase 4 (GPX4) recognized as crucial antioxidant enzyme involved defense mechanisms ferroptosis pathways. This review systematically explores GPX4's functions across various pain models, including neuropathic, inflammatory, low back, cancer-related pain. Specifically, focus includes physiological roles, mechanisms, regulation ferroptosis, involvement signal transduction pathways, metabolic regulation. By summarizing current research, we highlight potential GPX4-targeted therapies management.

Language: Английский

Electroacupuncture attenuates ferroptosis by promoting Nrf2 nuclear translocation and activating Nrf2/SLC7A11/GPX4 pathway in ischemic stroke DOI Creative Commons

Xichen Yang,

Ying Jin,

Rong Ning

et al.

Chinese Medicine, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 4, 2025

Abstract Objective Electroacupuncture has been shown to play a neuroprotective role following ischemic stroke, but the underlying mechanism remains poorly understood. Ferroptosis key in injury process. In present study, we wanted explore whether electroacupuncture could inhibit ferroptosis by promoting nuclear factor erythroid-2-related 2 (Nrf2) translocation. Methods The stroke model was established middle cerebral artery occlusion/reperfusion (MCAO/R) adult rats. These rats have randomly divided into EA + MCAO/R group, Brusatol group (the inhibitor of Nrf2), and DMSO Sham group. received intervention 24 h after modeling for 7 consecutive days. behavioral function evaluated Neurologic severity score (NSS), Garcia score, Foot-fault Test, Rotarod Test. infarct volume detected TTC staining, neuronal damage observed Nissl staining. levels Fe 2+ , reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA) were measured ELISA. immunofluorescence Western blotting used detect expression Total Nrf2, p-Nrf2, Nuclear Cytoplasmic essential proteins, including glutathione peroxidase 4 (GPX4), solute carrier family member 11 (SLC7A11) ferritin heavy chain 1 (FTH1). mitochondria transmission electron microscopy (TEM). Results improved neurological deficits MCAO/R, decreased brain volume, alleviated damage, inhibited ROS, MDA accumulation, increased SOD levels, GPX4, SLC7A11 FTH1, rescued injured mitochondria. Especially, found that up-regulated promoted phosphorylation Nrf2 translocation, However, reversed effect electroacupuncture. Conclusion can alleviate I/R injury-induced It is expected these data will provide novel insights mechanisms protecting against potential targets stroke. Graphical

Language: Английский

Citations

2
Electroacupuncture suppresses neuronal ferroptosis to relieve chronic neuropathic pain DOI Creative Commons

Chunchun Xue,

Wenyun Kui,

Aiping Huang

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(7)

Published: March 20, 2024

Growing evidence supports the analgesic efficacy of electroacupuncture (EA) in managing chronic neuropathic pain (NP) both patients and NP models induced by peripheral nerve injury. However, underlying mechanisms remain incompletely understood. Ferroptosis, a novel form programmed cell death, has been found to be activated during development, while EA shown potential promoting neurological recovery following acute cerebral injury targeting ferroptosis. In this study, investigate detailed mechanism intervention on NP, male Sprague-Dawley rats with constriction (CCI)-induced model received treatment at acupoints ST36 GV20 for 14 days. Results demonstrated that effectively attenuated CCI-induced hypersensitivity mitigated neuron damage loss spinal cord rats. Moreover, reversed oxidative stress-mediated ferroptosis phenotype upregulating reduced expression xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) superoxide dismutase (SOD) levels, downregulating increased acyl-CoA synthetase long-chain family member (ACSL4), malondialdehyde levels iron overload. Furthermore, immunofluorescence co-staining GPX4 neurons cells CCI Mechanistic analysis unveiled inhibition antioxidant pathway Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal marginally diminishing effect. These findings suggest may protect inhibiting cord, partially through activation signalling.

Language: Английский

Citations

10
New Insight into Neuropathic Pain: The Relationship between α7nAChR, Ferroptosis, and Neuroinflammation DOI Open Access

Fangting Luo,

Cheng Huang

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6716 - 6716

Published: June 18, 2024

Neuropathic pain, which refers to pain caused by a lesion or disease of the somatosensory system, represents wide variety peripheral central disorders. Treating neuropathic is quite demanding, primarily because its intricate underlying etiological mechanisms. The nervous system relies on microglia maintain balance, as they are associated with serving primary immune responses in brain next cell communication. Ferroptosis, driven phospholipid peroxidation and regulated iron, vital mechanism death regulation. Neuroinflammation can be triggered ferroptosis microglia, contributes release inflammatory cytokines. Conversely, neuroinflammation induce iron accumulation resulting microglial ferroptosis. Accumulating evidence suggests that neuroinflammation, characterized glial activation substances, significantly exacerbates development pain. By inhibiting ferroptosis, it may possible prevent subsequently alleviate homopentameric α7 subtype neuronal nicotinic acetylcholine receptor (α7nAChR) has potential suppress activation, transitioning M1 an M2 phenotype, facilitating anti-inflammatory factors, ultimately reducing Recent years have witnessed growing recognition regulatory role α7nAChR could target for treating This review summarizes mechanisms related progress according recent research. Such exploration will help elucidate relationship between α7nAChR, provide new insights into management.

Language: Английский

Citations

4
Electroacupuncture Inhibits NLRP3-Mediated Microglial Pyroptosis to Ameliorate Chronic Neuropathic Pain in Rats DOI Creative Commons

Wenyun Kui,

Yanan Li,

Zhen Gu

et al.

Journal of Pain Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 1115 - 1129

Published: March 1, 2025

Patients with neuropathic pain (NP), caused by injury or disease of the somatosensory nervous system, usually suffer from severe pain. Our previous studies revealed that electroacupuncture (EA) stimulation could effectively improve NP. However, underlying mechanisms EA have not been fully clarified. This study aimed to investigate specific in alleviating NP, focusing on pyroptosis. Chronic Constriction Injury (CCI) model was established male Sprague-Dawley rats. CCI rats were treated at acupoints GV20 and ST36 or/with NOD-like receptor protein 3 (NLRP3) antagonist MCC950. treatment administered for successive 14 days 7 after surgery. The mechanical withdrawal threshold (MWT) paw latency (PWL) performed during experiment. At end experiment, spinal cord segments serum collected, ELISA detected expression inflammatory factors, immunofluorescence microglia neuron cells pyroptosis biomarkers, Western blot NLRP3 pathway. significantly alleviated hypersensitivity increasing MWT PWL. Moreover, reduced levels pro-inflammatory cytokines IL-1β TNF-α tissue. Mechanistically, pyroptosis-related proteins, including NLRP3, N-GSDMD, Cleaved Caspase-1, IL-18 as well downregulated EA, indicating attenuated phenotype NP In particular, co-expression Caspase-1 N-GSDMD rather than neuronal astrocytic within Pharmacological inhibition inflammasome MCC950 alleviates CCI-induced while blocking EA's effect anti-pyroptosis These findings demonstrate ameliorates neuroinflammation relieve chronic suppressing activation microglia. may serve a viable therapy

Language: Английский

Citations

0
An active ingredient from the combination of Corydalis Rhizoma and Paeoniae Radix Alba relieves chronic compression injury-induced pain in rats by ameliorating AR/Mboat2-mediated ferroptosis in spinal cord neurons DOI Creative Commons
Zeming Wang, Xiao-Hong Wei,

Gui‐Yang Xia

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 25, 2025

Introduction A combination of Corydalis Rhizoma (the dried tuber yanhusuo W.T. Wang) and Paeoniae Radix Alba root Paeonia lactiflora Pall.) has been traditionally employed for analgesia. However, the underlying pharmacological mechanisms have not clarified. The aim present study was to investigate anti-inflammatory analgesic effects YB60, 60% ethanol elution fraction derived from Alba, explore mechanism. Methods Lipopolysaccharide-induced cellular inflammation model chronic compression injury (CCI) rat were used YB60. Proteomics molecular biology experiments applied potential mechanism Results results demonstrated that YB60 significantly decreased inflammatory cytokine levels both in models serum, while concurrently elevating pain thresholds CCI rats. Proteomic analysis indicated could upregulate expression Membrane Bound O-Acyltransferase Domain Containing 2 (Mboat2), a newly confirmed marker ferroptosis. Furthermore, prevented ferroptosis spinal cords Western blotting immunofluorescent dual staining further revealed increased Mboat2 its upstream signaling molecule Androgen receptor (AR). PC12 cells vitro showed reversed downregulation AR Mboat2, ameliorated induced by Erastin, knockdown eliminated above Conclusion These findings exerted effect inhibiting cord neurons via modulation AR/Mboat2 pathway.

Language: Английский

Citations

0
Exploring the spatial effects of acupuncture analgesia DOI
Zihe Wang, Peng Qin, Yuyan Chen

et al.

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Electroacupuncture Ameliorates Chronic Inflammatory Pain and Depression Comorbidity by Inhibiting Nrf2-Mediated Ferroptosis in Hippocampal Neurons DOI
Guanghua Liu, Di Liu, Dongliang Shi

et al.

Neurochemical Research, Journal Year: 2025, Volume and Issue: 50(3)

Published: April 21, 2025

Language: Английский

Citations

0
The Antinociceptive Role of Nrf2 in Neuropathic Pain: From Mechanisms to Clinical Perspectives DOI Creative Commons
Kęstutis Petrikonis, Jurga Bernatonienė, Dalia M. Kopustinskienė

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(8), P. 1068 - 1068

Published: Aug. 15, 2024

Neuropathic pain, a chronic condition resulting from nerve injury or dysfunction, presents significant therapeutic challenges and is closely associated with oxidative stress inflammation, both of which can lead to mitochondrial dysfunction. The nuclear factor erythroid 2-related 2 (Nrf2) pathway, critical cellular defense mechanism against stress, has emerged as promising target for neuropathic pain management. Nrf2 modulators enhance the expression antioxidant cytoprotective genes, thereby reducing damage, impairment. This review explores antinociceptive effects Nrf2, highlighting how pharmacological agents natural compounds may be used potential strategies pain. Although preclinical studies demonstrate reduction improved function through activation, several clinical need addressed. However, emerging evidence suggests benefits in conditions, such diabetic neuropathy multiple sclerosis. Future research should focus on further elucidating molecular role optimize its modulation efficacy maximize utility.

Language: Английский

Citations

3
Nuclear factor erythroid 2-related factor-mediated signaling alleviates ferroptosis during cerebral ischemia-reperfusion injury DOI Open Access
Zheng Li, Jihong Xing

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 180, P. 117513 - 117513

Published: Sept. 27, 2024

Language: Английский

Citations

2
Sustainable Release Selenium Laden with SiO2 Restoring Peripheral Nerve Injury via Modulating PI3K/AKT Pathway Signaling Pathway DOI Creative Commons

Song Jianguo,

Huanliang Meng, Guoying Deng

et al.

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 7851 - 7870

Published: Aug. 1, 2024

Inhibiting ROS overproduction is considered a very effective strategy for the treatment of peripheral nerve injuries, and Se has remarkable antioxidant effect; however, since difference between concentration toxic dose not large, we synthesized nanomaterial that can release slowly so it be used more effectively.

Language: Английский

Citations

1