Abstract:
: Aims: Lifelong pain is a hallmark feature of sickle cell disease (SCD). How sickle pathobiology evokes pain remains unknown. We hypothesize that increased cell-free heme due to ongoing hemolysis activates toll-like receptor 4 (TLR4), leading to the formation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Together, these processes lead to spinal microglial activation and neuroinflammation, culminating in acute and chronic pain. Results: Spinal heme levels, TLR4 transcripts, oxidative stress, and ER stress were significantly higher in sickle mice than controls. In vitro, TLR4 inhibition in spinal cord microglial cells attenuated heme-induced ROS and ER stress. Heme treatment led to a time-dependent increase in the characteristic features of sickle pain (mechanical and thermal hyperalgesia) in both sickle and control mice; this effect was absent in TLR4-knockout sickle and control mice. TLR4 deletion in sickle mice attenuated chronic and hypoxia/reoxygenation (H/R)-evoked acute hyperalgesia. Sickle mice treated with the TLR4 inhibitor resatorvid; selective small-molecule inhibitor of TLR4 (TAK242) had significantly reduced chronic hyperalgesia and had less severe H/R-evoked acute pain with quicker recovery. Notably, reducing ER stress with salubrinal ameliorated chronic hyperalgesia in sickle mice. Innovation: Our findings demonstrate the causal role of free heme in the genesis of acute and chronic sickle pain and suggest that TLR4 and/or ER stress are novel therapeutic targets for treating pain in SCD. Conclusion: Heme-induced microglial activation via TLR4 in the central nervous system contributes to the initiation and maintenance of sickle pain via ER stress in SCD. Antioxid. Redox Signal. 34, 279-293.
journal_name
Antioxid Redox Signaljournal_title
Antioxidants & redox signalingauthors
Lei J,Paul J,Wang Y,Gupta M,Vang D,Thompson S,Jha R,Nguyen J,Valverde Y,Lamarre Y,Jones MK,Gupta Kdoi
10.1089/ars.2019.7913subject
Has Abstractpub_date
2021-02-01 00:00:00pages
279-293issue
4eissn
1523-0864issn
1557-7716journal_volume
34pub_type
杂志文章abstract::Exposure of neonatal rat cardiac myocytes to palmitate and glucose produces apoptosis as seen by cytochrome c release, caspase 3-like activation, DNA laddering, and poly(ADP-ribose) polymerase cleavage. The purpose of this study was to understand the role of reactive oxygen species in the initiation of programmed cell...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/152308601750100524
更新日期:2001-02-01 00:00:00
abstract::The role of free radicals in aging has been a long-standing theory that has now been extended to include both reactive oxygen and nitrogen species. The original concepts that overwhelming oxidative stress depleted antioxidants and thus damaged intracellular targets is being supplanted by the hypothesis that the reacti...
journal_title:Antioxidants & redox signaling
pub_type: 社论
doi:10.1089/15230860050192143
更新日期:2000-10-01 00:00:00
abstract:SIGNIFICANCE:The therapeutic effects of current micellar and vesicular drug formulations are restricted by slow and inefficient drug release at the pathological site. The development of smart polymeric nanocarriers that release drugs upon arriving at the target site has received a tremendous amount of attention for can...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2013.5733
更新日期:2014-08-10 00:00:00
abstract:AIMS:Intracellular amyloid beta (Aβ) oligomers and extracellular Aβ plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Aβ production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase ...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2011.4173
更新日期:2012-06-15 00:00:00
abstract::The current societal environment is marked by overabundant accessibility of food coupled with a strong trend of reduced physical activity, both leading to the development of a constellation of disorders, including central obesity, insulin resistance, dyslipidemia, and hypertension (metabolic syndrome). Prolonged calor...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2010.3253
更新日期:2011-01-15 00:00:00
abstract::Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the progressive development of involuntary choreiform movements, cognitive impairment, neuropsychiatric symptoms, and premature death. These phenotypes reflect neuronal dysfunction and ultimately death in selected brain regions, the...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2006.8.2061
更新日期:2006-11-01 00:00:00
abstract:AIMS:Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. U...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2015.6531
更新日期:2016-11-20 00:00:00
abstract::The DNA base excision-repair pathway is responsible for the repair of DNA damage caused by oxidation/alkylation and protects cells against the effects of endogenous and exogenous agents. Removal of the damaged base creates a baseless (AP) site. AP endonuclease1 (Ape1) acts on this site to continue the BER-pathway repa...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2008.2120
更新日期:2008-11-01 00:00:00
abstract::This Forum issue "Heme Oxygenase" (HO) includes original research articles and reviews that are aimed at understanding the role of HO-1 in several pathophysiological conditions, specially addressing those involving inflammation and oxidative damage. Overall, the seven contributions of this Forum highlight the dual rol...
journal_title:Antioxidants & redox signaling
pub_type: 评论,社论
doi:10.1089/ars.2020.8065
更新日期:2020-06-10 00:00:00
abstract::Hypoxia is sensed by all mammalian cells and elicits a variety of adaptive and pathophysiological responses at the molecular and cellular level. For the pulmonary vasculature, hypoxia causes increased vasoconstriction and vessel-wall remodeling. These responses are mediated by complex intracellular cascades leading to...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/152308602753666343
更新日期:2002-04-01 00:00:00
abstract::Protection of ischemic myocardium is an important unmet need in reperfusion therapy of acute myocardial infarction. Myocardial ischemia and reperfusion induce necrosis and apoptosis in cardiomyocytes. Caspase processing and activation are critical steps in most receptor and nonreceptor pathways of apoptosis. Caspase i...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/152308601750100605
更新日期:2001-02-01 00:00:00
abstract::Epithelial to mesenchymal transition (EMT) is a fundamental process, paradigmatic of the concept of cell plasticity, that leads epithelial cells to lose their polarization and specialized junctional structures, to undergo cytoskeleton reorganization, and to acquire morphological and functional features of mesenchymal-...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2009.2737
更新日期:2010-06-15 00:00:00
abstract::Studies on thioredoxin (Trx) and its related molecules have expanded dramatically recently. Proteins that share the similar active-site sequence, -Cys-Xxx-Yyy-Cys-, are called the Trx family, and the number of Trx family members is increasing. Trx reductase, which reduces oxidized Trx in cooperation with NADPH, has th...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2005.7.823
更新日期:2005-05-01 00:00:00
abstract:AIMS:Corosolic acid (CRA) is a natural triterpenoid with antioxidative activity. This study was designed to elucidate the mechanism through which CRA protected vessel endothelial homeostasis by combating oxidative stress. RESULTS:In endothelial cells, CRA induced dynamin-related protein 1 (Drp1) phosphorylation at Ser...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2015.6479
更新日期:2016-06-01 00:00:00
abstract:SIGNIFICANCE:The rising global prevalence of diabetes and its debilitating complications give rise to significant disability and premature mortality. Due to the silent nature of diabetes and its vascular complications, and limitations in current methods for detection, there is a need for novel biomarkers for early dete...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2017.7318
更新日期:2018-10-10 00:00:00
abstract:SIGNIFICANCE:Alzheimer's disease is a neurodegenerative disorder that is projected to exceed more than 100 million cases worldwide by 2050. Aging is considered the primary risk factor for some 90% of Alzheimer's cases but a significant 10% of patients suffer from aggressive, early-onset forms of the disease. There is c...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2016.6802
更新日期:2016-12-01 00:00:00
abstract:SIGNIFICANCE:MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on every realm of biomedicine is established and progressively increasing. The impact of environment on human health is enormous. Among environmental risk factors impinging on quality...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2017.7175
更新日期:2018-03-20 00:00:00
abstract::We studied the subcellular distribution of mitochondria and superoxide dismutase-1 (SOD1) in whole mounts of microdissected motor axons of rats expressing the ALS-linked SOD1-G93A mutation. The rationale was to determine whether physical interactions between the enzyme and mitochondria were linked to the axonopathy of...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2009.2614
更新日期:2009-07-01 00:00:00
abstract:AIMS:Myocardial ischemia/reperfusion (I/R) is associated with mitochondrial dysfunction and subsequent cardiomyocyte death. The generation of excessive quantities of reactive oxygen species (ROS) and resultant damage to mitochondrial enzymes is considered an important mechanism underlying reperfusion injury. Mitochondr...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2012.4698
更新日期:2013-11-01 00:00:00
abstract:SIGNIFICANCE:Half a century of research provided unambiguous proof that superoxide and species derived from it-reactive oxygen species (ROS)-play a central role in many diseases and degenerative processes. This stimulated the search for pharmaceutical agents that are capable of preventing oxidative damage, and methods ...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2013.5576
更新日期:2014-05-20 00:00:00
abstract::The 6(th) COSTAM/SFRR (ASEAN/Malaysia) workshop, "Micronutrients, Oxidative Stress, and the Environment," was held from June 29 to July 2 at Holiday Inn Damai Beach Resort in Kuching, Sarawak. Two hundred twenty participants from 17 countries presented recent advances on natural antioxidants in the area of oxidative s...
journal_title:Antioxidants & redox signaling
pub_type:
doi:10.1089/ars.2006.8.2175
更新日期:2006-11-01 00:00:00
abstract:AIMS:Astrocytes have been revealed as a controller of synaptic plasticity and memory via releasing gliotransmitters. Our recent findings showed that reactive sulfur species (RSS), including hydrogen sulfide (H2S) and polysulfide (H2Sn), regulated the availability of d-serine, which is a well-known gliotransmitter that ...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2018.7503
更新日期:2019-06-01 00:00:00
abstract:SIGNIFICANCE:Abnormal lung development in the perinatal period can result in severe neonatal complications, including persistent pulmonary hypertension (PH) of the newborn and bronchopulmonary dysplasia. Reactive oxygen species (ROS) play a substantive role in the development of PH associated with these diseases. ROS i...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2013.5785
更新日期:2014-11-01 00:00:00
abstract::It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione peroxidase activity and that these enzymes can also detoxify lipid peroxidation end products such as 4-hydroxynonenal (4-HNE). In this article, recent studies suggesting that the Alpha clas...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/152308604322899350
更新日期:2004-04-01 00:00:00
abstract:: Significance: T lymphocytes, as part of the adaptive immune system, possess the ability to activate and function in extreme cellular microenvironments, which requires these cells to remain highly malleable. One mechanism in which T lymphocytes achieve this adaptability is ...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2020.8042
更新日期:2020-04-30 00:00:00
abstract:SIGNIFICANCE:Stiffness of endothelial cells is closely linked to the function of the vasculature as it regulates the release of vasoactive substances such as nitric oxide (NO) and reactive oxygen species. The outer layer of endothelial cells, consisting of the glycocalyx above and the cortical zone beneath the plasma m...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2017.7327
更新日期:2019-03-01 00:00:00
abstract::A model has been developed for the hemopexin receptor-mediated heme transport system based on iron uptake in yeast. Two steps are required: reduction followed by oxidation by a multi-copper-oxidase. Furthermore, in the hemopexin system, the surface redox events have been linked with gene regulation. The impermeable Cu...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2000.2.4-753
更新日期:2000-01-01 00:00:00
abstract::Autophagy is a bulk degradation process in which cytosolic proteins and organelles are degraded through lysosomes. To evaluate autophagic flux in cardiac myocytes, we generated adenovirus and cardiac-specific transgenic mice harboring tandem fluorescent mRFP-GFP-LC3. Starvation significantly increased the number of mR...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2010.3488
更新日期:2011-06-01 00:00:00
abstract::This brief review first touches on the origins of the earth's oxygen. It then identifies and locates the principal oxygen sensor in vertebrates, the carotid body (CB). The CB is unique in that in human subjects, it is the only sensor of lower than normal levels in the partial pressure of oxygen (hypoxia, HH). Another ...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
doi:10.1089/ars.2007.1546
更新日期:2007-06-01 00:00:00
abstract::Hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain triggers several pathways of injury involved in the pathogenesis of diabetic complications [protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product (AGE) formation] by inhibiting glyceralde...
journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
doi:10.1089/ars.2005.7.1568
更新日期:2005-11-01 00:00:00