NR4A ablation improves mitochondrial fitness for long persistence in human CAR-T cells against solid tumors.
Nakagawara K, Ando M, Srirat T, Mise-Omata S, Hayakawa T, Ito M, Fukunaga K, Yoshimura A
Deleting all three NR4A genes in human CAR-T cells makes them more resistant to exhaustion, improves their ability to kill solid tumors, and helps them survive longer in the body by boosting mitochondrial function. This approach works across different donors, including older individuals, and shows strong promise for treating solid tumors.
- NR4A gene deletion boosts CAR-T cell survival and tumor-killing ability
- Triple knockout enhances mitochondrial energy production
- Improved performance seen in cells from diverse donors, including older adults
- Results show stronger anti-tumor effects in both lab and animal models
- Targeting NR4A may lead to better CAR-T therapies for solid tumors
Author Correction: The Nurr1 ligand indole acetic acid hydrazide loaded onto ZnFe2O4 nanoparticles suppresses proinflammatory gene expressions in SimA9 microglial cells.
Qasim R, Thiab TA, Alhindi T, Al-Hunaiti A, Imraish A
A compound called indole acetic acid hydrazide, delivered via zinc ferrite nanoparticles, reduces inflammation in mouse brain cells that model microglial activity. This suggests a potential way to calm harmful brain inflammation in NR4A2-related disorders.
- A drug candidate reduces brain cell inflammation
- Nanoparticles deliver the drug effectively
- Targets microglial overactivity linked to NR4A2 issues
- May help with neuroinflammation in NR4A2 syndrome
Whole-genome sequencing identifies novel genes for autism in Chinese trios.
Chang S, Liu JJ, Zhao Y, Pang T, Zheng X, Song Z, Zhang A, Gao X, Luo L, Guo Y, Liu J, Yang L, Lu L
This study used whole-genome sequencing in Chinese autism families and identified NR4A2 as a high-confidence risk gene for autism, along with several other genes linked to brain development and gene regulation. The findings suggest that NR4A2 variants may disrupt gene expression and contribute to autism symptoms, with supporting evidence from gene networks and brain activity patterns.
- NR4A2 is a strong autism risk gene identified in Chinese families
- NR4A2 variants affect gene expression and brain-related processes
- Other genes like SHANK3 and CHD8 were also confirmed
- De novo variants increase with parental age
- Findings support NR4A2's role in neurodevelopment
ASCL1-mediated direct reprogramming: converting ventral midbrain astrocytes into dopaminergic neurons for Parkinson's disease therapy.
Yong SH, Kim SM, Kong GW, Ko SH, Lee EH, Oh Y, Park CH
This study shows that astrocytes from the ventral midbrain can be directly converted into dopamine-producing neurons using a single gene, ASCL1, which may lead to new treatments for Parkinson's disease. The reprogrammed neurons matured over two weeks and showed key markers of healthy dopamine neurons.
- ASCL1 alone reprograms ventral midbrain astrocytes into dopamine neurons
- Reprogrammed neurons express key markers of mature dopaminergic neurons
- Only ventral midbrain astrocytes, not others, can be converted this way
- This approach could lead to regenerative therapies for Parkinson's disease
- No need for additional transcription factors like NURR1 or LMX1A
CCL22 Induces the Polarization of Immature Dendritic Cells into Tolerogenic Dendritic Cells in Radiation-Induced Lung Injury through the CCR4-Dectin2-PLC-γ2-NFATC2-Nr4a2-PD-L1 Signaling Pathway.
Liu B, Wang Y, Ma L, Chen G, Yang Z, Zhu M
Ionizing radiation triggers lung cells to release CCL22, which recruits immune cells and reprograms them into tolerant cells that reduce inflammation. This process involves a specific signaling pathway that activates Nr4a2, a gene linked to immune regulation, and may offer new treatment targets for radiation lung injury.
- Radiation increases CCL22 in lung cells
- CCL22 recruits immune cells to injury sites
- CCL22 reprograms immune cells into tolerant types
- Nr4a2 is a key gene in this immune regulation pathway
- This pathway could be targeted to treat radiation lung injury
Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism.
Willems S, Busch R, Nawa F, Ballarotto M, Lillich FF, Kasch T, López-García Ú, Marschner JA, Rüger LA, Renelt B, Ohrndorf J, Arifi S, Zaienne D, Proschak E, Pabel J, Merk D
Researchers modified oxaprozin, a drug originally used for arthritis, to create new compounds that specifically target Nurr1, a protein linked to brain health and neurodegenerative diseases. These new compounds block Nurr1's constant activity and show improved strength and selectivity, offering a potential path for treating conditions like Parkinson’s and Alzheimer’s.
- Oxaprozin was redesigned to target Nurr1 more precisely
- New compounds block Nurr1’s constant activity
- Improved potency and selectivity for Nurr1 over other receptors
- Potential for treating Parkinson’s and Alzheimer’s disease
- A step toward developing therapies for NR4A2-related disorders
The roles of orphan nuclear receptor 4 group A1 and A2 in fibrosis.
Gao L, Wang H, Fang F, Liu J, Zhao C, Niu J, Wang Z, Zhong Y, Wang X
NR4A2 helps prevent fibrosis by blocking the TGF-β signaling pathway, which drives scar tissue buildup. Lower NR4A2 activity may contribute to excessive fibrosis in organs like the lungs, liver, and kidneys.
- NR4A2 reduces fibrosis by inhibiting TGF-β signaling
- Low NR4A2 levels may worsen tissue scarring
- NR4A2 protects against collagen and fibronectin buildup
- NR4A2 is a potential target for anti-fibrotic treatments
Genoarchitectural Definition of the Adult Mouse Mesocortical Ring: A Contribution to Cortical Ring Theory.
Puelles L, Alonso A, García-Calero E
This study defines the molecular boundaries of a specific brain region in mice called the mesocortex, which may help clarify the structure and function of brain areas involved in higher thinking and behavior. It shows that a region previously thought to be part of the mesocortex, the retrosplenial area, does not share its molecular signature and likely belongs elsewhere, refining how we understand brain organization.
- The mesocortex has a unique molecular profile in mice.
- The retrosplenial area is not part of the mesocortex, despite prior belief.
- NR4A2 is expressed in the retrosplenial area, not in the mesocortex.
- This study redefines brain region boundaries using gene expression data.
- Findings may help interpret human brain disorders involving NR4A2.
Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing.
Sai M, Hank EC, Tai HM, Kasch T, Lewandowski M, Vincendeau M, Marschner JA, Merk D
Researchers developed new Nurr1 agonists from the drug amodiaquine, creating potent compounds that activate Nurr1, a key protein involved in brain health. In lab-grown human brain tissue with a Parkinson’s-related mutation, the new compounds restored a critical protein, suggesting potential for treating NR4A2-related disorders.
- New Nurr1 activators were designed from amodiaquine
- Compounds show strong activity at nanomolar levels
- Restored a key brain protein in Parkinson’s-like human tissue
- These are promising tools for studying NR4A2-related conditions
- Potential for future therapies targeting Nurr1
Analysis of machine learning based integration to identify the crosslink between inflammation and immune response in non-alcoholic fatty liver disease through bioinformatic analysis.
Yu R, Huang Y, Hu X, Chen J
This study identifies NR4A2 as one of five key genes linked to nonalcoholic fatty liver disease (NAFLD), suggesting it may serve as a diagnostic marker and potential treatment target. The findings highlight NR4A2's role in immune responses and liver inflammation, offering insights into how metabolic and immune processes interact in NAFLD.
- NR4A2 is a top candidate biomarker in NAFLD
- NR4A2 is linked to immune cell activity and liver inflammation
- The gene may help diagnose or treat NAFLD
- Findings connect metabolism, immunity, and liver damage
- Results support new diagnostic and therapeutic strategies
iPSC-Derived Astrocytes and Neurons Replicate Brain Gene Expression, Epigenetic, Cell Morphology and Connectivity Alterations Found in Autism.
Mostafavi Abdolmaleky H, Alam R, Nohesara S, Deth RC, Zhou JR
Cells derived from autism patients show gene expression and epigenetic changes similar to those seen in autistic brains, including altered levels of NURR1 and inflammation-related genes, which may help develop personalized treatments.
- NURR1 is reduced in autism-derived astrocytes
- Inflammation genes like IL6 and TGFB2 are overactive
- Epigenetic changes match those in real autistic brain tissue
- Neurons show poor growth and connectivity
- These lab-grown cells mirror real brain changes
The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis.
Woo MS, Bal LC, Winschel I, Manca E, Walkenhorst M, Sevgili B, Sonner JK, Di Liberto G, Mayer C, Binkle-Ladisch L, Rothammer N, Unger L, Raich L, Hadjilaou A, Noli B, Manai AL, Vieira V, Meurs N, Wagner I, Pless O, Cocco C, Stephens SB, Glatzel M, Merkler D, Friese MA
NR4A2 and its target VGF drive brain cell death during inflammation by forcing neurons to rely on glycolysis, a metabolic shift that worsens neurodegeneration. Blocking VGF protects neurons in mouse models of MS, suggesting a potential treatment path.
- NR4A2 triggers harmful metabolic changes in neurons
- VGF secretion increases cell death during inflammation
- High VGF levels found in MS patients' brains and blood
- Deleting VGF protects neurons in MS mouse models
- Targeting this pathway may slow neurodegeneration
The Nurr1 ligand indole acetic acid hydrazide loaded onto ZnFe2O4 nanoparticles suppresses proinflammatory gene expressions in SimA9 microglial cells.
Qasim R, Thiab TA, Alhindi T, Al-Hunaiti A, Imraish A
A compound called IAAH, delivered using special nanoparticles, activates the Nurr1 protein in brain immune cells, reducing the production of harmful inflammatory signals. This approach may help calm chronic brain inflammation linked to neurological disorders.
- IAAH activates Nurr1 to reduce brain inflammation
- Nanoparticles improve delivery and effectiveness
- Targets key inflammatory genes like IL-6 and TNF-α
- Potential for treating neuroinflammatory conditions
- Uses a targeted delivery system to boost therapy
Gangliosides in neural stem cell fate determination and nerve cell specification--preparation and administration.
Itokazu Y, Ariga T, Fuchigami T, Li D
Gangliosides GD3 and GM1 play critical roles in maintaining neural stem cells and guiding their development into nerve cells, with GM1 specifically promoting the formation of dopamine-producing neurons through epigenetic regulation. Administering these molecules can restore stem cell function and improve neuronal outcomes in mouse models.
- GD3 supports neural stem cell survival and self-renewal
- GM1 boosts neuron development and dopamine gene activation
- GM1 works by modifying gene expression through epigenetic changes
- Gangliosides act on membranes in the cell's nucleus, mitochondria, and surface
- Direct administration of GD3/GM1 improves brain cell function in mice
Transcription Factor-Mediated Generation of Dopaminergic Neurons from Human iPSCs-A Comparison of Methods.
McDonald KO, Lyons NMA, Gray LKC, Xu JB, Schoderboeck L, Hughes SM, Basak I
This study developed a faster and more efficient method to create human dopaminergic neurons from skin cells using transcription factors and small molecules, producing over 85% dopaminergic neurons in just three weeks. The approach avoids viral integration by using a safe genetic location, improving safety and consistency.
- Creates dopaminergic neurons in three weeks, not months
- Over 85% of neurons are dopaminergic
- Uses safer genetic methods without viral integration
- Combines transcription factors and small molecules for best results
- May help study and treat NR4A2-related disorders
Impact of food additives on neurodevelopmental processes in zebrafish (Danio rerio): Exploring circadian clock genes and dopamine system.
Christy LD, Vignesh K, Nellore J, Tippabathani J
Food additives like aspartame and tartrazine disrupt brain development in zebrafish, affecting genes linked to the circadian clock and dopamine signaling, leading to abnormal movement, heart rate, and brain changes. These effects occur at levels below current safety limits and suggest potential risks to human neurodevelopment, especially during pregnancy.
- Additives alter dopamine and circadian genes in zebrafish
- Exposure causes movement and heart rate changes
- Effects seen at safe levels, raising concern for early development
- Zebrafish findings may reflect human neurodevelopment risks
- Supports re-evaluating food additive safety during pregnancy
NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies.
Gabaldon-Albero A, Mayo S, Martinez F
NR4A2 gene variants cause a serious neurological condition affecting development, movement, language, and epilepsy, with symptoms appearing from infancy to young adulthood. The review supports testing NR4A2 as a top priority in genetic testing for children with unexplained developmental delay and epilepsy.
- NR4A2 variants cause developmental delay and intellectual disability
- Epilepsy occurs in 42% of patients, often drug-resistant
- Language and movement problems are common and underdiagnosed
- NR4A2 should be tested early in developmental and epileptic encephalopathy
- New therapies targeting NR4A2 are being explored
Expression of G2019S LRRK2 in Rat Primary Astrocytes Mediates Neurotoxicity and Alters the Dopamine Synthesis Pathway in N27 Cells via Astrocytic Proinflammatory Cytokines and Neurotrophic Factors.
Ho DH, Kim H, Nam D, Seo MK, Park SW, Son I
Mutant LRRK2 in astrocytes harms brain cells by triggering inflammation and disrupting dopamine production, which may worsen Parkinson's disease. This effect happens through toxic signals released by astrocytes carrying the G2019S mutation.
- G2019S-LRRK2 in astrocytes causes inflammation and reduces survival signals
- Astrocytes with the mutation release harmful factors that damage dopamine-producing neurons
- Dopamine production and transport are impaired in nearby neurons
- This mechanism may accelerate Parkinson’s disease progression
- Targeting astrocyte inflammation could be a new treatment strategy
Nurr1 overexpression in the primary motor cortex alleviates motor dysfunction induced by intracerebral hemorrhage in the striatum in mice.
Kinoshita K, Motomura K, Ushida K, Hirata Y, Konno A, Hirai H, Kotani S, Hitora-Imamura N, Kurauchi Y, Seki T, Katsuki H
Overexpressing the Nurr1 protein in brain cells that control movement helps protect nerve pathways after a stroke-like brain bleed in mice, reducing motor problems. This effect happens by strengthening nerve fibers in the brain's motor circuit, not by reducing brain inflammation or cell death.
- Nurr1 overexpression improves motor recovery after brain bleeds in mice
- It protects nerve fibers in the motor pathway without reducing brain inflammation
- Nurr1 boosts protective signaling in motor brain cells
- Nurr1 ligands also activate the same protective brain pathways
- This suggests targeting Nurr1 could help treat motor symptoms in NR4A2-related conditions
Corrigendum to "Nurr1: A vital participant in the TLR4-NF-κB signal pathway stimulated by a-synuclein in BV-2 cells" [Neuropharmacol. (2019) 144 388-399] doi:10.1016/j.neuropharm.2018.04.008.
Shao QH, Yan WF, Zhang Z, Ma KL, Peng SY, Cao YL, Yuan YH, Chen NH
Nurr1 reduces inflammation in brain cells exposed to alpha-synuclein, a protein linked to neurodegeneration, suggesting it may protect against brain damage in NR4A2-related disorders.
- Nurr1 dampens harmful brain inflammation
- Alpha-synuclein triggers inflammation via NF-κB
- Nurr1 blocks this inflammatory pathway
- This may protect neurons in NR4A2-related conditions
Differentiation of neural stem cells from human olfactory mucosa into dopaminergic neuron-like cells.
Ertem T, Uysal O
Human olfactory mucosa neural stem cells can be turned into dopamine-producing cells in the lab, offering a potential source for cell-based treatments in Parkinson's disease and similar conditions.
- Olfactory stem cells can become dopamine-making neurons
- Cells express key genes like NURR1 and TH after differentiation
- These cells are easy to collect and grow in culture
- They show promise for treating Parkinson's disease
- Results support future cell replacement therapies
Nur77 Mediates Anaphylaxis by Regulating miR-21a.
Jo H, Jeoung J, Shim K, Jeoung D
Nur77, a gene related to NR4A2, plays a key role in triggering anaphylaxis by controlling immune responses through a feedback loop with miR-21a. Blocking Nur77 or boosting miR-21a reduces allergic reactions in cell and animal models, suggesting potential new treatments for severe allergies.
- Nur77 drives anaphylaxis in immune cells
- miR-21a suppresses Nur77 and reduces allergic reactions
- Targeting Nur77 or miR-21a may treat severe allergies
- Nur77 activity is controlled by c-JUN in allergic responses
Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1.
Chen N, Zhou H, He B, Peng S, Ding F, Liu QH, Ma Z, Liu W, Xu B
Melatonin helps protect neural stem cells from manganese damage by activating the Nurr1 protein, which restores normal cell division and prevents developmental delays. This suggests melatonin could be a potential therapy for neurodevelopmental issues linked to manganese exposure.
- Melatonin protects brain cell development from manganese damage
- It works by activating the Nurr1 protein
- Nurr1 helps restart cell division blocked by manganese
- Blocking Nurr1 reduces melatonin's protective effect
- Findings may lead to treatments for NR4A2-related disorders
Relapse to cocaine seeking is regulated by medial habenula NR4A2/NURR1 in mice.
Childs JE, Morabito S, Das S, Santelli C, Pham V, Kusche K, Vera VA, Reese F, Campbell RR, Matheos DP, Swarup V, Wood MA
NR4A2 in the medial habenula controls relapse to cocaine seeking in mice, suggesting this gene plays a key role in addiction-related behaviors. Manipulating NR4A2 disrupts the brain's reward circuitry involved in relapse, highlighting a potential target for treating substance use disorders.
- NR4A2 in the medial habenula drives relapse to cocaine use
- Blocking NR4A2 prevents reinstatement of drug-seeking behavior
- NR4A2 regulates genes linked to addiction and brain plasticity
- This pathway involves GABA and glutamate signaling networks
- Findings may inform treatments for addiction and relapse
Vascular Endothelial Cell-Derived Exosomal Sphingosylphosphorylcholine Attenuates Myocardial Ischemia-Reperfusion Injury through NR4A2-Mediated Mitophagy.
Yu Y, Li Z, Cai Y, Guo J, Lin Y, Zhao J
Exosomes from blood vessel cells deliver a molecule called SPC that protects heart muscle cells after a heart attack by boosting a cleanup process called mitophagy through the NR4A2 pathway. This suggests SPC could be a potential treatment to reduce heart damage.
- SPC in exosomes protects heart cells after injury
- NR4A2 activation boosts mitophagy in heart cells
- Exosome delivery reduces heart damage in mice
- SPC may be a therapeutic target for heart attacks
Investigating the Effect of an Anti-Inflammatory Drug in Determining NURR1 Expression and Thus Exploring the Progression of Parkinson's Disease.
Zheng X, Zhao Z, Zhao L
Ibuprofen improved motor function and boosted NURR1 levels in early-stage Parkinson's disease in mice, but had no benefit in advanced disease. NURR1 appears to play a key role in protecting brain cells and mediating ibuprofen’s effects.
- Ibuprofen helped early Parkinson's mice recover motor function
- NURR1 levels rose with ibuprofen in early disease only
- No benefit from ibuprofen in advanced Parkinson's mice
- NURR1 has protective effects in brain cells
- Timing of treatment matters for potential benefit
Promoting collateral formation in type 2 diabetes mellitus using ultra-small nanodots with autophagy activation and ROS scavenging.
Wang Y, Li F, Mao L, Liu Y, Chen S, Liu J, Huang K, Chen Q, Wu J, Lu L, Zheng Y, Shen W, Ying T, Dai Y, Shen Y
MoS2 nanodots improve blood vessel growth in diabetic mice by activating a protective cellular process called autophagy and reducing harmful oxidative stress. This effect is driven by a specific molecular pathway involving NR4A2, which helps repair damaged blood vessels.
- MoS2 nanodots boost blood vessel formation in diabetic mice
- They activate autophagy via the cAMP/PKA-NR4A2 pathway
- They reduce oxidative stress by scavenging harmful free radicals
- The dual action enhances endothelial cell repair under high glucose
- NR4A2 is a key player in protecting blood vessels in diabetes
Preconditioning exercise reduces brain damage of ischemic stroke in rats via PI3K-AKT pathway by bioinformatic analysis.
Li K, Gao ZK, Guo YS, Shen XY, Han Y, Yuan M, Bi X
Preconditioning exercise in rats reduces brain damage from stroke by activating the PI3K-AKT pathway, which helps protect brain cells and improve recovery. This protective effect involves key genes like NR4A2 and others that regulate cell survival and blood vessel growth.
- Exercise before stroke reduces brain damage in rats
- The PI3K-AKT pathway is central to protection
- NR4A2 is among key genes involved in cell survival
- Exercise boosts blood vessel formation in the brain
- Reduced cell death helps preserve brain function
The nuclear receptor Nurr1 is preferentially expressed in human pro-inflammatory macrophages and limits their inflammatory profile.
Solís-Barbosa MA, Santana E, Muñoz-Torres JR, Segovia-Gamboa NC, Patiño-Martínez E, Meraz-Ríos MA, Samaniego R, Sánchez-Mateos P, Sánchez-Torres C
Nurr1 is highly active in human pro-inflammatory macrophages and acts as a natural brake to reduce the production of multiple inflammatory signals, including TNF, IL-6, and reactive oxygen species. This suggests that boosting Nurr1 activity could help calm harmful inflammation in conditions like autoimmune diseases.
- Nurr1 is mainly found in pro-inflammatory human macrophages
- Activating Nurr1 reduces key inflammatory molecules
- Nurr1 limits NF-κB activity, a major driver of inflammation
- High Nurr1 levels correlate with inflammation in skin disease
- Nurr1 may be a therapeutic target to control excessive inflammation