Development of a Brain-Penetrant Nurr1 Agonist Tool.
Vietor J, Stiller T, Gege C, Saeb W, López-García Ú, Kohlhof H, Vitt D, Merk D
Researchers developed a new drug-like molecule that activates the Nurr1 protein in the brain, which may help protect neurons and treat neurodegenerative diseases.
- A new brain-penetrant Nurr1 agonist was created to study its effects in the central nervous system.
- The molecule was designed to cross the blood-brain barrier and activate Nurr1 effectively.
- This compound could be used to test potential therapies for diseases linked to Nurr1 dysfunction.
Isoginkgetin stabilizes atherosclerotic plaques by targeting NR4A2 to modulate the PPAR signaling pathway and reprogram ceramide metabolism, thereby inhibiting vascular smooth muscle cell phenotypic transformation.
Wei D, Zhong Z, Li H, Qi J, Liu Y, Cao H, Ma Y, Li Z, Yang G, Jiang Y, Zhang Z
Isoginkgetin stabilizes atherosclerotic plaques by boosting NR4A2, which activates PPAR signaling and reduces harmful ceramide buildup, preventing vascular smooth muscle cells from changing into unstable, inflammatory forms.
- Isoginkgetin reduces plaque instability in atherosclerosis.
- It works by increasing NR4A2, which activates PPAR signaling.
- It lowers harmful ceramides by boosting their breakdown.
- It prevents vascular smooth muscle cells from becoming inflammatory.
- These effects suggest potential for treating atherosclerosis.
Genetic Variants and Clinical Characteristics of Young-Onset Parkinson's Disease in the Hakka Population of Western Fujian.
Pan LY, Guo F, Zheng C, Hu XH, Chen YG, Lin RR
This study found that genetic variants in genes like ATXN2, PRKN, VPS13C, and SNCA are linked to young-onset Parkinson's disease in the Hakka population of western Fujian, with some variants classified as likely pathogenic and others as uncertain significance. Many patients also carried risk variants in susceptibility genes, including NR4A2, suggesting a genetic predisposition even without clear pathogenic mutations.
- ATXN2 repeat expansions were found in two patients
- NR4A2 variants were among risk factors identified
- Several variants in PRKN and VPS13C were uncertain significance
- LRRK2 variants were common in this cohort
- Genetic testing improves diagnosis accuracy
Differential Expression Profiles of Orphan Nuclear Receptors (NR4A) and N-myc Downstream-Regulated Gene Family (NDRG) in Patients with Inflammatory Bowel Disease.
Fonseca-Camarillo G, Furuzawa-Carballeda J, Aguilar-León D, Barreto-Zuñiga R, Martínez-Benítez B, Yamamoto-Furusho JK
This study found that levels of NDRG and NR4A proteins differ between people with ulcerative colitis and Crohn's disease, and that these differences may affect how inflammation is controlled, suggesting potential new treatment targets for inflammatory bowel disease.
- NDRG and NR4A proteins are altered in the colon of people with ulcerative colitis.
- NR4A2 levels are lower in active disease and linked to higher inflammation markers.
- These changes may affect NF-κB signaling, a key driver of inflammation.
- The differences between ulcerative colitis and Crohn's disease suggest distinct disease mechanisms.
A53T α-Synuclein Expression is Associated with Altered Dopaminergic-Like Differentiation and Reduced DNA Topoisomerase IIβ Levels in an In Vitro Model of Parkinson's Disease.
Selim A, Avşar T, Neğiş Y, Işık S
Mutant A53T alpha-synuclein disrupts the development of dopamine-producing neurons in a lab model, reducing levels of key protective genes like NR4A2 and DNA topoisomerase IIβ, which may contribute to early brain changes seen in Parkinson’s disease.
- A53T alpha-synuclein impairs dopamine neuron development
- NR4A2 and topoisomerase IIβ levels drop in affected cells
- Reduced NR4A2 may weaken protective brain pathways
- Topo IIβ loss may link to early neurodevelopmental issues
- These changes mirror early Parkinson’s disease features
Identifying novel gene dysregulation associated with opioid overdose death: a meta-analysis of differential gene expression in human prefrontal cortex.
Carter JK, Quach BC, Willis C, Minto MS, Hancock DB, Montalvo-Ortiz J, Corradin O, Logan RW, Walss-Bass C, Maher BS, PGC-SUD Epigenetics Working Group, Johnson EO
Opioid overdose death is linked to widespread changes in gene activity in the brain's prefrontal cortex, including newly identified genes like NR4A2, which is involved in brain development and function. These changes affect key pathways related to neuron flexibility and signaling, particularly through the orexin and tyrosine kinase systems.
- NR4A2 is newly linked to opioid overdose in human brain tissue
- Gene changes affect brain plasticity and signaling pathways
- Findings may help explain neurological impacts of opioid overdose
- No strong genetic causes found for gene expression differences
- MEK/ERK/MAPK and orexin pathways are central to the changes
Multi-Target Antioxidant Potential of Tricin Against Parkinson's Disease- Linked Oxidative Stress.
Giri S, Chandra P
Tricin is a natural compound that shows strong potential to protect brain cells in Parkinson's disease by targeting multiple pathways involved in oxidative stress, including those linked to NURR1 and other key proteins. It effectively binds to and may regulate several disease-related targets, reducing harmful free radicals in lab tests.
- Tricin targets NURR1 and other Parkinson's-related proteins
- It reduces oxidative stress in lab tests
- Tricin may protect dopamine neurons by multiple mechanisms
- Binding strength suggests strong biological activity
- Natural compound with multitarget antioxidant effects
Therapeutic Effects of Cinnamaldehyde on Neuromuscular Function in Rat Parkinson's Model Induced by Rotenone.
Buyukakilli B, Balli E, Arslan M, Demirbag HO
Cinnamaldehyde improved motor function and protected brain cells in a rat model of Parkinson's disease by reducing oxidative stress and boosting dopamine levels. The treatment helped preserve nerve cells in brain regions critical for movement.
- Cinnamaldehyde reduced brain cell damage in Parkinson's rats
- It improved muscle function and nerve signaling
- It lowered oxidative stress and increased dopamine
- Effects seen in both brain and muscle tissues
- Suggests potential for protecting neurons in movement disorders
Towards a unified molecular mechanism for ligand-dependent activation of NR4A-RXR heterodimers.
Yu X, He Y, Kamenecka TM, Kojetin DJ
Some NR4A nuclear receptors team up with RXR to control gene activity, and certain drugs that activate RXR can turn on these pairs in unexpected ways. The study shows that for one such pair (Nur77-RXRγ), both classic drug action and a newly discovered mechanism involving the breakup of the protein pair contribute to activation, but only specific drugs reveal the full picture.
- NR4A-RXR pairs can be activated by RXR drugs through two mechanisms
- One mechanism involves the proteins splitting apart when a drug binds
- Only certain selective drugs reveal the split-protein mechanism
- This may apply to other NR4A-RXR pairs linked to brain and immune diseases
- Better drug testing requires diverse ligand sets to uncover true activation paths
Gestational and Lactational Atrazine Exposure Potentially Mediates Behavioral and Dopaminergic Alterations in Rat Offspring: Insights into Nurr1-Related ceRNA Regulation.
Ma Y, Sun T, Pan M, Zheng Z, Wei J, Yuan X, Wan J, Zhou Y, Sun Y
Exposure to the pesticide atrazine during pregnancy and breastfeeding harms brain development in rat offspring, disrupting dopamine systems and causing behavioral issues. The study identifies a specific molecular pathway involving Elavl4, miR-301a-5p, and Nurr1 that may explain how atrazine reduces Nurr1, a key protein linked to NR4A2-related disorders. Boosting Elavl4 reversed some of the damage in lab models, suggesting a potential therapeutic target.
- Atrazine exposure harms dopamine systems in offspring
- Nurr1 levels drop, linked to NR4A2-related syndromes
- Elavl4/miR-301a-5p/Nurr1 pathway is disrupted
- Boosting Elavl4 reduced Nurr1 loss in lab tests
- Findings suggest new treatment strategies
NR4A2-driven metabolic reprogramming in the heart: from adaptive response to maladaptive remodeling.
Stujanna EN, Yoshioka J
This study shows that NR4A2 controls metabolic changes in heart cells, helping the heart adapt under stress but contributing to heart damage when these changes become excessive. The findings suggest NR4A2 could be a target for treating heart conditions.
- NR4A2 regulates energy use in heart cells
- It helps the heart adapt to stress initially
- Overactive NR4A2 leads to heart damage
- Targeting NR4A2 may improve heart health
Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson's disease pathogenesis.
Darsono WHW, Hwang Y, Valencia E, Gunawan LT, Hyeon SJ, Ryu H, Stein TD, Chang MY, Wulansari N, Lee SH
DNAJC6, a protein linked to Parkinson's disease, is underactive in both neurons and astrocytes in sporadic Parkinson's, contributing to brain cell damage and inflammation. Restoring DNAJC6 in brain cells improved symptoms and pathology in a mouse model, suggesting a potential treatment strategy.
- DNAJC6 is reduced in Parkinson's patients' brains
- Low DNAJC6 harms astrocytes and worsens brain cell damage
- Fixing DNAJC6 in mice improved Parkinson's symptoms
- Both neurons and astrocytes are affected by DNAJC6 loss
- Targeting DNAJC6 may slow or stop disease progression
Downregulated transcription in chromosomal domains of midbrain dopamine neurons linked to schizophrenia.
Singh S, Iskhakova M, Lambert TY, Valada A, Shokrian N, Evans V, Bendl J, Auluck PK, Marenco S, Wang M, Zhang B, Hoffman GE, Girdhar K, Roussos P, Akbarian S
In people with schizophrenia, the genes in midbrain dopamine neurons are less active, especially those in tightly organized chromosomal regions that control brain cell connections. This reduced activity affects key genes linked to brain development and function, including NR4A2 (NURR1), and may explain some of the disorder’s core symptoms.
- Schizophrenia reduces gene activity in dopamine neurons
- Affected genes are in organized chromosomal regions
- NR4A2 (NURR1) and other key genes are downregulated
- This disruption impacts brain connectivity and development
- Changes are specific to dopamine neurons, not general
Cytokine armored CAR T cells for cancer immunotherapy.
Sek K, Yap KM, Hong WX, Darcy PK
This study develops enhanced CAR T cells that produce specific cytokines to boost cancer immunotherapy, using engineered receptors or tumor-responsive promoters to improve effectiveness and safety. The approach aims to make CAR T cells more durable and better at recruiting the body’s own immune system to fight tumors.
- CAR T cells engineered to produce IL-15 or IL-9 for better survival and function
- Tumor-targeted cytokine release via IL-36γ or IL-12 boosts immune response
- NR4A2 promoter used to limit cytokine release to tumor sites only
- Reduces harmful side effects by avoiding systemic cytokine exposure
- Improves CAR T cell persistence and anti-tumor activity in models
Valsartan promotes neuroprotection in Parkinson's disease via epigenetic modulation and activation of the ASCL1/Nurr1 pathway.
Gowied HG, El-Mezayen NS, Afify EA
Valsartan improved motor function and protected dopamine-producing neurons in a rat model of Parkinson's disease by boosting the Nurr1 pathway and altering gene regulation through epigenetic changes. These effects suggest valsartan may slow or reverse neurodegeneration, not just ease symptoms.
- Valsartan improved movement and neuron health in Parkinson's rats
- It boosted Nurr1 and related genes linked to dopamine neuron survival
- Valsartan changed gene activity via epigenetic mechanisms
- Blocking Nurr1 reduced but did not eliminate valsartan’s benefits
- Results suggest valsartan could be a disease-modifying treatment
Aberrant immune regulation and enrichment of stem-like CD8+ T cells in the pancreatic lymph node during type 1 diabetes development.
Peters LD, Seay HR, Smith J, Posgai AL, Berkowitz R, Wasserfall CH, Atkinson MA, Bacher R, Brusko MA, Brusko TM
In type 1 diabetes, CD8+ T cells in the pancreatic lymph nodes show abnormal immune behavior, including a buildup of stem-like cells that are prone to becoming destructive, and reduced levels of NR4A2, a gene linked to immune exhaustion. These cells are more active and less regulated, with signs of inflammation and potential for attacking insulin-producing cells. The findings suggest that boosting NR4A2 or targeting related pathways could help restore immune balance.
- NR4A2 levels are reduced in CD8+ T cells in T1D
- Stem-like CD8+ T cells are enriched in pancreatic lymph nodes
- These cells show signs of being overactive and not properly exhausted
- IL-15 signaling may drive this abnormal immune state
- T cells in the pancreas show stronger attack-ready traits than in lymph nodes
miR-19a-3p and miR-19b-3p repress Nurr1 and Nur77 to promote microglial inflammation after spinal cord injury.
Sahebdel F, Zia A, Quintá HR, Stucky A, Morse LR, Olson JK, Battaglino RA
miR-19a-3p and miR-19b-3p reduce levels of the Nurr1 and Nur77 proteins in microglia, worsening inflammation and neuropathic pain after spinal cord injury. Blocking these miRNAs may reduce inflammation and pain, offering a potential treatment strategy.
- miR-19a/b reduce Nurr1 and Nur77 in microglia
- Higher miR-19a/b levels link to pain after spinal injury
- These miRNAs drive harmful brain inflammation
- Blocking them may reduce pain and inflammation
- Nurr1 and Nur77 are key protective proteins
Janus kinase 2 regulates Nurr1 protein stability in dopaminergic neurons of the aging midbrain.
Jang Y, Kim YH, Jeon J, Cha Y, Lopes C, Jung JH, Oh E, Park Y, Ko C, Hyeon B, Leblanc P, Kim KS
JAK2 stabilizes the Nurr1 protein in dopamine-producing brain cells, helping protect them from aging-related damage. This stabilization happens without changing Nurr1's gene activity and may explain how some neurons survive longer in older brains.
- JAK2 boosts Nurr1 protein stability in aging brain cells
- JAK2 protects dopamine neurons from oxidative stress
- This effect happens without altering Nurr1 gene expression
- The mechanism is independent of common signaling pathways
- Targeting JAK2 could help maintain Nurr1 in NR4A2-related conditions
Momordicine I, a triterpene from bitter melon (Momordica charantia L.), ameliorates alcohol-associated liver disease: research on the possible liver benefits.
Hou Y, Wang SY, Xu ZY, Xin G, Zhao GY, Sun HM
Momordicine I, a compound from bitter melon, protects the liver in alcohol-related disease by boosting Nurr1, a protein linked to NR4A2. It reduces fat buildup, improves energy production in liver cells, and blocks harmful inflammation. Without Nurr1, the benefits of Momordicine I disappear.
- Momordicine I boosts Nurr1, which is linked to NR4A2
- It reduces liver fat and improves mitochondrial function
- It blocks inflammation and cell death in liver cells
- Nurr1 is essential for Momordicine I's protective effects
- These findings suggest a potential treatment for alcohol-related liver disease
The genetic architecture of Parkinson's disease in Mexico: a systematic review.
Arias-Carrión O, Romero-Gutiérrez E, Castellanos-Juárez FX, Sandoval-Carrillo AA, Salas-Pacheco JM
This review identifies NR4A2 as one of eight genes consistently linked to Parkinson's disease in Mexican populations, with specific NR4A2 haplotypes showing protective or risk-increasing effects. The findings highlight NR4A2's role in dopaminergic signaling and mitochondrial health, suggesting potential therapeutic relevance.
- NR4A2 haplotypes are linked to Parkinson's risk in Mexicans
- Protective NR4A2 variants may improve dopamine function
- NR4A2 fits into key Parkinson's pathways like mitochondrial health
- Genetic risk varies by ancestry and needs more study
- Findings support targeting NR4A2 for future therapies
Generating graftable dopaminergic neurons by NR4A2 activation and exploring associated lncRNA signatures.
Malekmohammad L, Esfahani NMJ, Momeni Z, Esmaeili F, Khademizadeh M, Farhadieh ME, Karimi F, Keimasi M, Soleimani-Delfan A
Activating the NR4A2 gene helps create dopaminergic neurons from stem cells that can survive and function when transplanted into a Parkinson’s disease model, with increased levels of key lncRNAs linked to neuron health. These findings suggest a potential path for cell-based therapies in NR4A2-related disorders.
- NR4A2 activation produces transplantable dopaminergic neurons
- Neat1, Hotair, and Uchl1os lncRNAs increase after transplantation
- Transplanted neurons boost dopamine levels in PD models
- LncRNA patterns may support neuron survival and function
- Results support NR4A2 as a target for future therapies
Mechanistic insights into the role of nuclear receptor related-1 protein in Parkinson's disease.
Sharma V, Singh TG
Nurr1 is a critical protein for the health and survival of dopamine-producing brain cells, and its dysfunction contributes to Parkinson's disease by increasing inflammation, weakening antioxidant defenses, and impairing mitochondrial function. Restoring Nurr1 activity may protect neurons and slow disease progression, making it a promising target for new treatments.
- Nurr1 protects dopamine neurons from damage
- Low Nurr1 levels increase brain inflammation
- Nurr1 helps maintain energy and antioxidant systems
- Boosting Nurr1 could treat Parkinson's disease
- Nurr1 is a key target for future therapies
De novo identification of potent ingredients for proteasome activation in MT101-5 using an AI-driven approach.
Kim S, Han M, Kim SW, Choi JG, Park SC, Choi SI, Son M, Lee D
Diterpenes from MT101-5 boost the proteasome by activating Nurr1, helping clear toxic alpha-synuclein and protecting dopamine neurons in a mouse model of Parkinson’s disease.
- Nurr1 activation enhances proteasome function
- Diterpenes reduce alpha-synuclein clumps
- Improved motor function and neuron survival in mice
- MT101-5 ingredients show promise for Parkinson’s treatment
Forward Programming Identifies Inducers of Blood-Brain Barrier Properties in Human Pluripotent Stem Cell-Derived Endothelial Cells.
Tamhankar S, Ding Y, Hashjin FY, Boutom SM, Daneman R, Palecek SP, Shusta EV
Researchers identified specific genes that can turn stem cell-derived blood vessel cells into brain barrier cells with strong protective properties. These engineered cells show improved barrier function and are useful for studying brain diseases and testing drugs.
- NR4A2 helps create brain barrier-like cells from stem cells
- Combining NR4A2 with other genes boosts barrier strength
- These cells can model brain diseases and test treatments
- The method may help develop therapies for brain disorders
Structure-activity landscape of Nurr1 (NR4A2) modulators: medicinal chemistry strategies for neurodegenerative disease intervention.
Jaidka S, Kumar A, Singh TG, Bhatia R, Singh RK
Nurr1 is a key protein for dopamine neuron health, and drugs that activate it may help treat Parkinson's and other neurodegenerative diseases. While several compounds show promise in lab studies, none yet reliably target Nurr1 without affecting similar proteins, cross the blood-brain barrier, or consistently work in living organisms.
- Nurr1 supports dopamine neuron survival and function
- Activating Nurr1 may protect against Parkinson’s and Alzheimer’s
- Many experimental drugs also activate related proteins, causing confusion
- Current compounds lack brain penetration and consistent in vivo results
- Designing selective, brain-penetrant Nurr1 drugs remains a major challenge
The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.
Kaur S, Mannan A, Singh TG
Nurr1 (NR4A2) helps protect dopamine-producing brain cells by boosting mitochondrial health and reducing oxidative stress, which are key issues in Parkinson's and Alzheimer's diseases. This makes Nurr1 a promising target for therapies aimed at slowing or stopping neurodegeneration.
- Nurr1 supports brain cell survival by improving mitochondria
- It reduces oxidative damage linked to Parkinson's and Alzheimer's
- Nurr1's activity can be boosted through post-translational changes
- Targeting Nurr1 may help treat neurodegenerative diseases
- Mitochondrial dysfunction is a major factor in brain cell loss
Epigenome-wide analysis identifies DNA methylation signatures associated with the infant pupillary light reflex, a candidate intermediate phenotype for autism.
Fish LA, Gliga T, Gui A, Ali JB, Mason L, Johnson MH, Charman T, Falck-Ytter T, Jones EJH, Kandaswamy R, Happé F, Wong CCY
DNA methylation patterns in early infancy are linked to variations in the pupillary light reflex, a simple neural response that may signal early differences in brain development related to autism. The study found that methylation changes in genes like NR4A2 are associated with how quickly and how much the pupil constricts in response to light.
- DNA methylation affects pupillary light reflex timing and strength
- NR4A2 and other autism-linked genes are involved
- Changes appear as early as 9 months
- Pupillary reflex may be an early sign of neurodevelopmental differences
- Findings focus on male infants with family history of autism
Renalase stimulates aldosterone production via PMCA4b/cAMP in NCI-H295R cells.
Fu R, Huang M, Liu T, Chen Y, Li X, Jiang W
Renalase increases aldosterone production in adrenal cells by activating a signaling pathway involving PMCA4b and cAMP, which turns on the NR4A2 gene. This process does not affect cell growth but may contribute to conditions where too much aldosterone is made.
- Renalase boosts aldosterone production in adrenal cells
- It works through PMCA4b and cAMP signaling
- NR4A2 gene activity increases as a result
- No effect on cell growth, but may drive disease
- Could be a target for treating aldosterone-related disorders
Single-Cell Transcriptomics and Integrated Bioinformatic Analysis Reveal Critical Biomarkers and Immune Infiltration Characteristics in Osteoarthritis.
Gao T, Yang C, Bi Y, Zou P, Wan M, Lan S, Song Y, Xu Y
This study identifies NR4A2 and other genes as key players in osteoarthritis, linking them to inflammation and immune activity in joint cartilage. The research suggests bexarotene may target NR4A2 and related proteins, pointing to a potential treatment for osteoarthritis.
- NR4A2 is a strong biomarker and drug target in osteoarthritis
- NR4A2 correlates with immune activity in joint tissue
- Bexarotene shows promise in binding NR4A2 and related proteins
- The findings reveal new pathways driving joint degeneration
- These insights could lead to targeted therapies for osteoarthritis
Exploring the Mechanism of Shexiang Baoxin Pill in the Treatment of Ischemic Stroke: A Study Integrating Network Pharmacology, Machine Learning, Molecular Docking, and Molecular Dynamics Simulation.
Fu J, Wang Y, Li X, Dong X
Shexiang Baoxin Pill may help treat ischemic stroke by reducing inflammation and immune system overactivity through multiple active ingredients that bind to key proteins like TNF and JUN, which are involved in brain injury after stroke.
- SBP targets inflammation and immune pathways linked to stroke
- Bufalin and bufotalin bind stably to TNF and JUN proteins
- NR4A2 is one of six key targets identified in stroke
- The effect involves multiple compounds and targets working together
- Findings suggest a potential protective role in brain blood vessel damage