Molecular Characterization of Hypothalamic-Pituitary-Ovarian Axis Regulation in the Manchurian Zokor (Myospalax psilurus) During Seasonal Estrus.
Nai R, Li X, Shan D, Bao S, Wang F, Lin Y, Zhang Y, Hu B, Xie Y, Man D
This study identifies NR4A2 as a differentially expressed gene in the pituitary gland of rodents during seasonal breeding cycles. The research focuses on reproductive adaptation in subterranean mammals and does not investigate human neurodevelopment or clinical outcomes related to NR4A2 variants.
- NR4A2 expression changes in rodent pituitary glands during seasonal estrus.
- Study examines reproductive biology, not human neurological development.
- No data on NR4A2-related syndromes or potential treatments for humans.
RNA Sequencing and Metabolomic Analyses Reveal Differences in Muscle Characteristics and Metabolic Profiles Between Purebred and Crossbred Huainan Pigs.
Wang J, Li Y, Zhang M, Chen J, Lu Q, Zhang H, Yan X, Pan C, Zhang X, Xing B
This study in pigs found that crossbreeding Huainan pigs with commercial breeds changes muscle gene activity and metabolism, leading to improved lean meat production. The genes NR4A2 and NR4A1 were more active in crossbred pigs, but these findings are in animals, not humans, and do not relate to NR4A2-related syndrome in children.
- NR4A2 gene was more active in crossbred pigs
- Crossbreeding improved lean meat yield in pigs
- Changes in muscle metabolism and gene activity were found
- No direct link to human NR4A2-related syndrome
- Findings are in pig models, not human patients
Development of a diagnostic model for MASLD and identification of daidzein as the potential drug using bioinformatics analysis and experiments.
Wang T, Zhang H, Wang K, Liu C, Kong N, Zhou L, Qu L
This study identified a 17-gene signature that accurately predicts metabolic dysfunction-associated steatotic liver disease (MASLD), with NR4A2 among the key genes. It found that daidzein, a natural compound, reduces fat buildup in liver cells by targeting ENO3 and the PPAR pathway, suggesting a potential treatment for MASLD.
- NR4A2 is part of a 17-gene signature that predicts MASLD
- Daidzein reduces fat accumulation in liver cells
- Daidzein works by targeting ENO3 and PPAR signaling
- The findings are based on human data and lab experiments
- The model shows strong accuracy across multiple datasets
Tanshinone IIA ameliorates pancreatic injury in type 2 diabetic mice by modulating inflammation and endoplasmic reticulum stress via the IL-6/JAK2/STAT3 pathway.
Li Y, Wang D, Liu Y, Liu C, Chen M, Li J, Wu Z, Wu N
This study investigates how a plant-derived compound protects pancreatic cells in diabetic mice, identifying NR4A2 as one of several molecular targets involved in reducing inflammation and cell stress. The research focuses entirely on metabolic disease mechanisms in animal models and does not address neurological development or symptoms associated with NR4A2 syndromes.
- The study uses diabetic mice, not human patients or NR4A2-specific models.
- NR4A2 appears as an incidental target in pancreatic tissue, not the brain.
- Findings relate to diabetes management, not neurodevelopmental outcomes.
- No clinical data or relevance to NR4A2-related neurological conditions is presented.
Dual Targeting of Orphan Nuclear Receptors NR4A1 and NR4A2 for Nonhormonal Endometriosis Therapy.
Tsui WNT, Park Y, Upadhyay S, Kim DM, Zhang L, Wright G, Hailemariam A, Oany AR, Han SJ, Safe S
This study found that blocking both NR4A1 and NR4A2 proteins with a new drug candidate (DIM-3,5-Cl2) effectively reduces endometriosis growth in mice without harmful side effects, offering a potential non-hormonal treatment option. The drug works by turning off key pathways involved in cell survival, migration, and tissue scarring, which are common in endometriosis.
- NR4A1 and NR4A2 drive endometriosis progression
- A new drug blocks both proteins and shrinks lesions in mice
- Treatment works without harming healthy cells
- Drug reduces key disease processes like cell migration and scarring
- Offers a non-hormonal alternative to current therapies
Regulation of NR4A2 Gene Expression and Its Importance in Neurodegenerative and Psychiatric Diseases.
Ruiz-Sánchez E, Rojas C, Yescas Gómez P, Martínez-Rodríguez N, Ruiz-Chow ÁA, Nava-Ruiz C, Ibáñéz-Cervantes G, Arciniega-Martínez IM, Reséndiz-Albor AA, Rojas P
This review summarizes current knowledge on how NR4A2 gene expression is regulated and its role in various neurodegenerative and psychiatric diseases. It highlights epigenetic mechanisms like DNA methylation and microRNAs as potential therapeutic targets and biomarkers.
- NR4A2 regulates essential biological processes including neuronal development and cellular stress responses.
- Reduced NR4A2 expression links to Parkinson's, Alzheimer's, schizophrenia, and cognitive impairment.
- The paper details epigenetic controls such as DNA methylation and histone deacetylation.
- Regulatory mechanisms are proposed as future biomarkers or therapeutic targets for CNS pathologies.
Nurr1 attenuates hepatic stellate cell activation by inhibiting EMT and cell cycle progression via interaction with Smad3.
Liu D, Xiong X, Chen P
Nurr1 reduces the activation of liver cells involved in scarring by blocking processes that drive cell growth and transformation, partly by interacting with a key signaling protein called Smad3.
- Nurr1 reduces liver scarring by blocking cell activation
- It stops cells from changing into scar-forming types
- Nurr1 interferes with Smad3 signaling to slow cell growth
- This may help treat liver fibrosis in diseases like cirrhosis
Nr4a2, A Key Factor Controlling the Development and Functional Maintenance of Forebrain Car3 Neurons.
Tao YC, Zhao L, Zhang Q, Liu XY, Liu WT, Li ZX, Hu L, Zhang L, Chen JY, Ding YQ, Song NN
This study identifies a specific group of forebrain neurons that rely on the NR4A2 protein for their development and ongoing function. Removing this protein in mice causes these neurons to lose their identity and leads to behavioral changes such as hyperactivity.
- NR4A2 controls the development and maintenance of forebrain Car3 neurons.
- Deleting NR4A2 alters neuron identity but does not change their core genetic profile.
- Mice lacking NR4A2 in these neurons show increased activity and reduced anxiety.
- This research focuses on mouse models, not human patients or treatments.
Comprehensive Analysis of N6-Methyladenosine Methylation in Transverse Aortic Constriction-Induced Cardiac Fibrosis Based on MeRIP-Seq Analysis.
Liu S, Zhao P, He Y, Wang J, Song B, Yu C
This study maps RNA methylation changes in mouse hearts subjected to pressure overload, identifying Nr4a2 as a hub gene within the fibrotic process. It suggests that m6A modifications regulate cardiac fibrosis but does not provide evidence for treating NR4A2-related syndromes in humans. The findings are limited to molecular mechanisms in a cardiovascular disease model.
- The study uses mouse models of cardiac pressure overload, not human patients with NR4A2 syndrome.
- Nr4a2 is identified as a hub gene in a network regulating cardiac fibrosis via m6A methylation.
- No clinical data, patient phenotypes, or therapeutic interventions for NR4A2 conditions are presented.
- The research focuses on molecular biology of heart disease rather than neurological or developmental aspects.
A spatial single-cell atlas of the claustro-insular region uncovers key regulators of neuronal identity and excitability.
Fodoulian L, Boillat M, Moulinier M, Carleton A, Rodriguez I
This study maps brain cell types in mice and shows that reducing NR4A2 levels changes the identity and electrical activity of specific neurons in the claustrum. The findings describe basic molecular mechanisms in animal models without offering clinical insights or treatment options for humans.
- Researchers created a detailed map of mouse brain cells in the claustro-insular region using single-cell sequencing.
- Reducing NR4A2 levels alters the molecular identity and firing activity of claustrum neurons in mice.
- The study identifies NR4A2 as a key regulator of neuronal identity in this specific brain area.
- No human data, clinical trials, or therapeutic strategies are presented in this research.
Hypoxia-associated genes and metabolic abnormalities in peripheral blood mononuclear cells of type 1 diabetes mellitus patients.
Ma WB, Wang XY, Zuo YY
This study found that people with type 1 diabetes have abnormal gene activity and metabolism in immune cells, with NR4A2 and other key genes linked to inflammation, immune response, and metabolic changes. These findings may help explain how diabetes affects the body beyond blood sugar control.
- NR4A2 is a hub gene linked to immune and metabolic changes in type 1 diabetes
- Immune cell gene activity shows strong links to inflammation and hypoxia
- Metabolic changes involve glucose, leucine, and phenylalanine levels
- These patterns may reflect broader disease mechanisms beyond insulin deficiency
Identification and Validation of Inverse Agonists for Nuclear Receptor Subfamily 4 Group A Member 2.
Tian L, Lin Y, Cheng C, Yang H, Qiu X, Li S, Jia C, Le W
Researchers identified a compound called K-strophanthoside that suppresses the activity of the NR4A2 protein in laboratory settings. This molecule binds directly to the protein and reduces its transcriptional function, acting as an inverse agonist.
- K-strophanthoside is a new chemical tool that inhibits NR4A2 activity.
- The compound binds to specific amino acids in the NR4A2 ligand-binding domain.
- It mimics the effects of reducing NR4A2 levels in cell studies.
- This work provides a potential target for disorders involving excessive NR4A2 function.
Saikosaponin A, a bioactive compound from Bupleuri radix, protects dopaminergic neurons and correlates with NURR1 expression in 6-hydroxydopamine-injected hemi-Parkinsonian mouse model.
Huh E, Choi Y, Kim JH, Lee S, Oh MS
Saikosaponin A protects dopaminergic neurons and increases NURR1 expression in a mouse model of Parkinson's disease. This preclinical study suggests a potential mechanism for neuroprotection but does not involve human patients or NR4A2-specific genetic variants.
- Saikosaponin A reduces neuronal damage in mice with Parkinson-like symptoms.
- The compound correlates with increased NURR1 expression in dopaminergic neurons.
- This is a preclinical animal study, not human clinical evidence.
- NR4A2 variants are not specifically studied or targeted in this research.
Evaluating SH-SY5Y cells as a dopaminergic neuronal model: morphological, transcriptomic, and proteomic insights.
Işlek Camadan EE, Sarihan M, Kasap M, Akpinar G, Koçyiğit E
This study evaluates the stability and maturity of SH-SY5Y neuroblastoma cells as a model for Parkinson's disease research. The differentiated cells show transient expression of dopaminergic markers and require continuous external stimuli to maintain their state, suggesting they do not fully replicate mature neurons.
- SH-SY5Y cells differentiate into neuron-like forms using a specific chemical protocol.
- Dopaminergic markers like Nurr1 appear but show asynchronous and transient expression patterns.
- Cells require continuous external stimuli to maintain their differentiated state.
- The model lacks the stability and functional maturity of true mature neurons.
Distinct endothelial gene responses to acute exercise in skeletal muscle.
Addington AK, Wall RM, Wei X, Frate SD, Olsen ML, Drake JC, Craige SM
This study identifies Nr4a2 as one of the early genes activated in endothelial cells (blood vessel lining) during acute exercise in mice. It characterizes how these specific cells respond to physical stress by altering gene expression related to blood flow and metabolism, distinct from the response in muscle fibers themselves.
- Nr4a2 activates in mouse endothelial cells immediately after acute exercise.
- Endothelial cells show a unique gene signature compared to skeletal muscle fibers.
- The study uses specialized mouse technology to isolate blood vessel cell responses.
- Findings highlight roles in angiogenesis, oxidative stress, and vascular remodeling.
- Results provide insight into how blood vessels adapt to physiological stress.
Computational association in parkinson's disease SNPs with brain structural and functional alterations.
Subramaniyan S, Kuriakose BB, Nattan V, Alhazmi AH, Wong LS, Muthusamy K
This study uses computer modeling to predict how Parkinson's disease-related genetic variants affect protein structure and drug binding. It identifies specific mutations in the NURR1 gene that may alter its function and suggests potential FDA-approved drugs might bind to these altered proteins.
- The research relies entirely on computational simulations, not human or animal experiments.
- It analyzes nine Parkinson's genes, including NURR1, for harmful genetic variants.
- Molecular docking predicts how specific drugs interact with mutant proteins in silico.
- No clinical data or patient outcomes are reported in this study.
Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression.
Chawla A, Cakmakci D, Fiori LM, Zang W, Maitra M, Yang J, Żurawek D, Frosi G, Rahimian R, Mitsuhashi H, Davoli MA, Denniston R, Chen GG, Yerko V, Mash D, Girdhar K, Akbarian S, Mechawar N, Suderman M, Li Y, Nagy C, Turecki G
This study links major depression to specific genetic changes in brain cells, identifying NR4A2 as a key transcription factor active in neurons affected by the disorder. It demonstrates that depression-associated DNA variants disrupt NR4A2 binding sites, potentially altering synaptic communication in deep-layer excitatory neurons.
- NR4A2 binds to regulatory regions in neurons linked to major depression risk.
- Depression genetic variants disrupt these NR4A2 binding sites in human brain tissue.
- The study uses single-nucleus profiling of over 200,000 cells from human donors.
- Microglia also show altered chromatin accessibility related to immune regulation in depression.
Carboxylic Acid Bioisosteres Boost Nurr1 Agonist Selectivity.
Stiller T, Gege C, Saeb W, Vietor J, López-García Ú, Busch R, Kohlhof H, Vitt D, Merk D
Researchers modified a drug candidate to selectively activate the Nurr1 protein without affecting other enzymes, demonstrating that this selective activation promotes neuroprotective gene expression in dopaminergic cells. This work provides a more specific tool for studying Nurr1 biology but does not involve human trials or direct treatment of NR4A2-related syndromes.
- The study creates a selective Nurr1 agonist by removing unwanted DHODH inhibition from vidofludimus.
- The new compound shows over 100-fold selectivity for Nurr1 compared to the original drug.
- Treatment of dopaminergic cells induces genes linked to neuroprotection and neuronal health.
- This is preclinical chemistry work with no human clinical data or patient outcomes.
Conspecifics confer survival advantage in the face of night-light polluted environment: Evidence from melatonin secretion, sleep, mood and cognitive performance in Indian house crows.
Buniyaadi A, Bhardwaj SK, Kumar V
Living with other crows helps Indian house crows cope better with nighttime light pollution, improving mood and brain function without changing melatonin or sleep. This social support may be a key survival strategy in noisy, disrupted environments.
- Group living reduces depression-like behavior in crows under light pollution
- Social interaction boosts problem-solving and cognitive performance
- No change in melatonin or sleep patterns despite improved mood
- Brain gene changes suggest enhanced neural plasticity and reduced inflammation
- Social support may be an evolutionary survival mechanism
Neuroprotective role of Nigella Sativa seed oil in mitigating bisphenol a-induced neurodegeneration.
Hatipoglu D, Burak Ates M, Senturk G, Koca O, Bulut A, Donmez N
Nigella Sativa seed oil reduces brain and nerve damage caused by bisphenol A (BPA) in rats by boosting protective genes like NR4A2, reducing inflammation and cell death, and improving antioxidant levels. This suggests NSO may help protect the nervous system from environmental toxins.
- NSO boosts NR4A2, a gene linked to brain health
- NSO reduces brain and nerve damage from BPA
- NSO lowers inflammation and cell death markers
- NSO increases antioxidants like glutathione
- Findings suggest NSO could protect against toxin-induced neurodegeneration
NR4A2 attenuates early brain injury after intracerebral hemorrhage by promoting M2 microglial polarization via TLR4/TRAF6/NF-κB pathway inhibition.
Hu D, Huang C, Tang L, Lei J, Wang J, Hu W, Chen M, Song S, Lu L, Xu P
This study shows that NR4A2 protects brain tissue in rats after bleeding by reducing inflammation and strengthening the blood-brain barrier. The protein works by shifting immune cells to a healing state and blocking specific inflammatory signals.
- NR4A2 levels drop significantly in rat brains following hemorrhage.
- Boosting NR4A2 reduces bleeding volume and improves neurological outcomes.
- The protein promotes anti-inflammatory M2 microglial polarization.
- NR4A2 blocks the TLR4/TRAF6/NF-κB inflammatory pathway.
- Blocking this pathway negates the protective effects of NR4A2.
Berberine mitigates colitis-associated neuroinflammation and anxiety through modulation of the AMPK/NURR1 pathway.
Habiba ES, Fathelbab MH, AbdElaziz MM, El-Sayed NS, Mady MM, Khamis GM
Berberine reduces anxiety and gut inflammation in rats with colitis by activating the AMPK/NURR1 pathway. This preclinical study demonstrates that modulating NURR1 can alleviate neuroinflammation associated with intestinal disease.
- Study uses a rat model of colitis, not humans or NR4A2 patients.
- Berberine lowers anxiety-like behaviors and gut inflammation in treated rats.
- Mechanism involves upregulating AMPK and NURR1 expression in colon tissue.
- Results are preclinical; no clinical trials or human data are presented.
Nurr1 modulators - a patent review (2019-present).
Egner M, Merk D
This review catalogs recent patents for small molecules that activate the Nurr1 protein, which is relevant to NR4A2-related syndromes. It highlights ongoing efforts to develop drugs for neurodegenerative diseases and cancer but notes significant gaps in experimental validation for many of these compounds.
- Patents cover synthetic and natural ligands targeting Nurr1 modulation.
- Proposed uses focus on neurodegeneration and cancer treatment.
- Many claimed ligands lack sufficient experimental validation.
- Some patent claims are overly broad without supporting data.
Exploring the genetic characteristics of overweight-related osteoarthritis using machine learning.
Jiang Z, Xu C, Shi W, Lin Z, Li H, Zhang H, Li Z
This study identifies NR4A2 as one of six genes associated with osteoarthritis in overweight patients using machine learning analysis of human tissue data. The research focuses on joint health and inflammation rather than the neurological or developmental aspects of NR4A2-related syndromes.
- NR4A2 appears in a diagnostic model for osteoarthritis linked to body weight.
- The study analyzes gene expression in human cartilage and meniscus tissue.
- It connects NR4A2 to DNA replication, inflammation, and epigenetic changes.
- No findings relate to dopaminergic neurons or NR4A2 syndrome phenotypes.
Comparative transcriptomic analyses of macrophages infected with Toxoplasma gondii strains of different virulence provide molecular insights into the response of macrophage in phagocytosis and polarization to infection.
Zhu S, Liu J, Xu K, Xu F, Jiang Y, Dai L, Pei T, Zhu Y, Liu D, Zhang X, Xu J, Yang J, Pan Z, Tao J, Hou Z
The study found that different strains of Toxoplasma gondii alter macrophage function in distinct ways, with one strain (YZ-1) strongly boosting immune activity by increasing the expression of key genes like Nr4a2 and Il6, enhancing macrophage phagocytosis and promoting an inflammatory M1 state. These findings highlight Nr4a2 as a central player in macrophage responses during infection.
- Nr4a2 is upregulated during Toxoplasma infection and linked to immune activation
- The YZ-1 strain boosts macrophage phagocytosis and M1 polarization
- Il6 and Nr4a2 are central genes in the macrophage response network
- Different Toxoplasma strains affect macrophages in unique ways
- These findings may reveal new targets for treating toxoplasmosis
Structural and mechanistic profiling of Nurr1 modulation by vidofludimus enables structure-guided ligand design.
López-García Ú, Vietor J, Marschner JA, Heering J, Morozov V, Wein T, Merk D
Researchers identified the specific binding site and mechanism by which vidofludimus activates the NR4A2 protein, allowing them to design a more potent version of this drug. This structural insight provides a foundation for creating better synthetic activators of NR4A2 in the future.
- Vidofludimus binds to an allosteric pocket on the NR4A2 protein.
- Activation involves dimer dissociation and coregulator release.
- Structure-guided design created a more potent NR4A2 agonist.
- The study focuses on molecular mechanics, not clinical outcomes.
Chromatin accessibility and transcriptomic profiles of sheep pituitary function associated with fecundity.
Li S, Zhao B, Chen P, Cai Y, Xu H, Yan C, Wang F, Zhang Y
This study found that changes in chromatin structure and gene activity in sheep pituitary glands are linked to fertility differences. It identified NR4A2 and other key genes that may control hormone release involved in reproduction.
- NR4A2 is a potential regulator of pituitary hormone secretion in sheep
- Chromatin changes affect genes tied to reproductive hormone control
- Key genes like CMKLR1 and TAFA1 may influence fertility
- Findings could help improve reproductive efficiency in sheep
Expression of HDAC3-Y298H Point Mutant in Medial Habenula Cholinergic Neurons Has No Effect on Cocaine-Induced Behaviors.
Alizo Vera V, Childs JE, Kim J, Matheos DP, Wood MA
Changing a specific HDAC3 enzyme in brain cells linked to addiction did not affect cocaine-related behaviors in mice, suggesting HDAC3 may not play a key role in these processes in the medial habenula.
- HDAC3 mutation in addiction-related brain cells had no effect on cocaine behaviors
- Results contradict earlier expectations about HDAC3's role in addiction
- Findings suggest other pathways may be more important in addiction relapse
- No impact on cocaine-seeking or reward-related behaviors in mice
Alpha-Synuclein drives NURR1 and NLRP3 Inflammasome dysregulation in Parkinson's disease: From pathogenesis to potential therapeutic strategies.
Abdelaziz AM
This review explains how alpha-synuclein aggregates disrupt NURR1 function and trigger inflammatory responses in Parkinson's disease. It highlights the molecular mechanisms linking protein misfolding, neuroinflammation, and dopaminergic neuron loss.
- Alpha-synuclein aggregates damage neurons by disrupting mitochondria and lysosomes.
- These aggregates activate the NLRP3 inflammasome, driving harmful neuroinflammation.
- Reduced NURR1 activity increases vulnerability to oxidative stress and toxicity.
- The paper is a review of mechanisms, not a clinical study or trial.
Expression of Prooncogenic Nuclear Receptor 4A (NR4A)-Regulated Genes β1-Integrin and G9a Inhibited by Dual NR4A1/2 Ligands.
Zhang L, Gatlin V, Gupta S, Salinas ML, Romero S, Cai JJ, Chapkin RS, Safe S
Dual inhibitors of NR4A1 and NR4A2 reduce the expression of specific genes in colon cancer cells by blocking these receptors from binding to DNA. This study demonstrates that chemical compounds can simultaneously target both NR4A1 and NR4A2 proteins to alter gene activity in a cellular model.
- Compounds block NR4A1 and NR4A2 from activating target genes in cancer cells.
- The study uses colon cancer cell lines, not human patients or animal models.
- No evidence is provided regarding neurological development or dopaminergic function.
- The findings do not translate to current treatment options for NR4A2 syndrome.
Correction: Molecular basis of ligand-dependent Nurr1-RXRα activation.
Yu X, Shang J, Kojetin DJ
This paper details the molecular mechanism by which Nurr1 and RXRα proteins interact to activate gene expression when bound to specific ligands. It provides structural insights into how these transcription factors function together at the cellular level.
- The study focuses on the molecular basis of ligand-dependent activation of Nurr1-RXRα complexes.
- It describes protein-protein interactions without testing treatments in humans or animal models.
- No clinical data, patient outcomes, or therapeutic trials are reported.