{"gene":"NGB","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2007,"finding":"NGB (NF2-associated GTP-binding protein) physically interacts with merlin (the NF2 tumor suppressor product) as demonstrated by co-immunoprecipitation. This interaction impairs merlin turnover, but merlin does not affect the GTPase or GTP-binding activity of NGB. The tumor suppressor function of NGB requires merlin and is linked to suppression of cyclin D1 expression.","method":"Co-immunoprecipitation, ectopic expression/loss-of-function, GTPase activity assay, cyclin D1 Western blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus GTPase assay and functional readouts (growth suppression, cyclin D1), single lab","pmids":["17210637"],"is_preprint":false},{"year":2007,"finding":"NGB (NF2-associated GTP-binding protein) functions as a tumor suppressor: ectopic expression inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwannoma cells. Its GTP-binding region is similar to R-ras and Rap2.","method":"Ectopic overexpression in schwannoma cells with growth, aggregation, and tumorigenicity assays; sequence/domain analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss/gain-of-function with multiple defined cellular phenotypes, single lab","pmids":["17210637"],"is_preprint":false},{"year":2013,"finding":"Neuroglobin (Ngb) promotes neuroprotection via Akt phosphorylation and activation of CREB, engaging a cell survival signaling pathway. In an Alzheimer's disease rat model, maintaining high Ngb levels correlated with increased p-Akt/Akt and p-CREB/CREB ratios and reduced cytochrome C/Apaf-1 immunocomplex formation (reduced apoptosis).","method":"Western blot (p-Akt, Akt, CREB, p-CREB), co-immunoprecipitation (cytochrome C/Apaf-1), immunohistochemistry, TUNEL assay in rat AD model","journal":"Gerontology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative in vivo measurements with pharmacological intervention, single lab, no direct manipulation of Ngb","pmids":["23428737"],"is_preprint":false},{"year":2013,"finding":"TAT PTD-Ngb fusion protein translocates into primary cortical neurons within 30 min and protects them against hypoxia-induced apoptosis by increasing Bcl-2 expression and decreasing caspase-3 and caspase-9 activities, implicating suppression of the mitochondrial apoptotic pathway.","method":"Fluorescent immunostaining, MTT cell viability assay, transmission electron microscopy, Western blot (Bcl-2), caspase activity assays in primary cortical neurons","journal":"Neurological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein delivery with multiple orthogonal readouts (viability, ultrastructure, caspase activity, Bcl-2), single lab","pmids":["23456442"],"is_preprint":false},{"year":2019,"finding":"Mn-TAT PTD-Ngb (a manganese porphyrin reconstituted Ngb fusion) exhibits enhanced ROS scavenging activity compared to TAT PTD-Ngb and protects against oxidative injury by restoring mitochondrial function, inhibiting mitochondria-dependent apoptosis, and activating the PI3K/Akt signaling pathway, which upregulates Nrf2, HO-1, SOD, and catalase.","method":"ROS scavenging assay, mitochondrial function assays, apoptosis assays, Western blot (PI3K/Akt, Nrf2, HO-1, SOD, CAT) in cell culture","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and cellular assays, single lab","pmids":["31882813"],"is_preprint":false},{"year":2020,"finding":"Mn-TAT PTD-Ngb suppresses LPS-induced inflammatory responses by blocking NF-κB nuclear translocation, attenuating MAPK phosphorylation, reducing ROS production, alleviating mitochondrial dysfunction, and suppressing NLRP3 inflammasome assembly, thereby reducing IL-1β and IL-18 production and improving Nrf2 levels.","method":"NF-κB nuclear translocation assay, MAPK Western blot, ROS assay, mitochondrial function assay, inflammasome assembly assay, cytokine ELISA in LPS-stimulated cells","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic readouts in defined inflammatory model, single lab","pmids":["32470548"],"is_preprint":false},{"year":2021,"finding":"Neuroglobin (Ngb) transcription is directly activated by CREB binding to the Ngb promoter. Polydatin activates AKT/CREB signaling, increasing CREB binding to the Ngb promoter (shown by luciferase reporter and ChIP), upregulating Ngb protein, and Ngb knockdown abrogates the neuroprotective effect of polydatin against H2O2-induced neuronal death.","method":"Luciferase reporter assay, ChIP assay, Western blot (AKT, CREB phosphorylation, Ngb), siRNA knockdown, cell viability assay, mitochondrial ROS measurement","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding (ChIP), reporter assay, and loss-of-function rescue, multiple orthogonal methods, single lab","pmids":["34751416"],"is_preprint":false},{"year":2019,"finding":"Intravitreal delivery of exogenous Neuroglobin (Ngb) protein in hypoxia-exposed rat retina restores Ngb levels reduced by 30% post-hypoxia and significantly decreases inflammatory chemokines (IL-6, TNFα, IL-1β, RANTES, MCP-1, VEGF) and microglial activation, demonstrating a direct anti-inflammatory role of Ngb in retinal hypoxia.","method":"Intravitreal protein injection, ELISA (chemokines), immunohistochemistry (microglial markers, Ngb), electroretinogram, histology in rat retinal hypoxia model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein replacement experiment with multiple functional readouts, single lab","pmids":["31827177"],"is_preprint":false}],"current_model":"Neuroglobin (NGB) is a neuroprotective globin protein that, upon hypoxic/ischemic stress, engages the PI3K/Akt/CREB signaling axis (with CREB directly binding the NGB promoter to upregulate its expression), suppresses mitochondria-dependent apoptosis (via Bcl-2 upregulation and caspase-3/9 inhibition), scavenges ROS, blocks NF-κB–mediated inflammation and NLRP3 inflammasome assembly, and activates Nrf2-driven antioxidant responses; a distinct GTP-binding protein also called NGB interacts with the NF2 tumor suppressor merlin to stabilize it and suppress cyclin D1–driven cell proliferation."},"narrative":{"mechanistic_narrative":"Neuroglobin (NGB) is a neuroprotective globin that defends neurons and retinal tissue against hypoxic, oxidative, and inflammatory injury [PMID:23456442, PMID:31827177]. Upon stress, exogenously delivered NGB suppresses the mitochondria-dependent apoptotic pathway, increasing Bcl-2 expression while reducing caspase-3 and caspase-9 activities, and protects primary cortical neurons from hypoxia-induced death [PMID:23456442]. NGB-mediated protection engages the PI3K/Akt/CREB signaling axis, and CREB in turn directly binds the Ngb promoter to upregulate Ngb transcription, establishing a feed-forward loop in which Ngb is both effector and transcriptional target of survival signaling [PMID:34751416]. A manganese-porphyrin-reconstituted NGB fusion enhances ROS scavenging and restores mitochondrial function while activating PI3K/Akt to drive an Nrf2/HO-1/SOD/catalase antioxidant program [PMID:31882813], and the same agent suppresses LPS-induced inflammation by blocking NF-κB nuclear translocation, attenuating MAPK signaling, and preventing NLRP3 inflammasome assembly to limit IL-1β and IL-18 production [PMID:32470548]. In retinal hypoxia, restoring NGB lowers inflammatory chemokines and microglial activation, confirming a direct anti-inflammatory role [PMID:31827177]. The available corpus also contains a distinct GTP-binding protein designated NGB (NF2-associated GTP-binding protein) that physically interacts with the NF2 tumor suppressor merlin to impair its turnover and acts as a tumor suppressor by inhibiting schwannoma growth and cyclin D1 expression [PMID:17210637]; this entity is mechanistically unrelated to the globin and reflects a shared symbol.","teleology":[{"year":2007,"claim":"Established that a GTP-binding protein named NGB binds the NF2 tumor suppressor merlin and functions in growth suppression, defining a tumor-suppressor role for this symbol-sharing entity.","evidence":"Reciprocal co-immunoprecipitation, GTPase assays, and gain/loss-of-function growth, aggregation, and tumorigenicity assays in schwannoma cells","pmids":["17210637"],"confidence":"Medium","gaps":["Single lab; relationship (if any) to the neuroprotective globin NGB is not addressed","Mechanism by which NGB stabilizes merlin not resolved beyond impaired turnover"]},{"year":2013,"claim":"Showed that NGB protein delivered directly into neurons suppresses the mitochondrial apoptotic pathway, moving NGB from a correlate of survival to a sufficient protective effector.","evidence":"TAT PTD-Ngb fusion delivery with viability, ultrastructure, caspase activity, and Bcl-2 Western blot in primary cortical neurons under hypoxia","pmids":["23456442"],"confidence":"Medium","gaps":["Single lab","Upstream signaling linking Ngb to Bcl-2/caspase changes not defined in this study"]},{"year":2013,"claim":"Correlated high Ngb levels with Akt/CREB activation and reduced apoptosis in vivo, implicating a survival signaling axis but without direct Ngb manipulation.","evidence":"Western blot, co-IP, immunohistochemistry, and TUNEL in an Alzheimer's disease rat model with pharmacological intervention","pmids":["23428737"],"confidence":"Low","gaps":["Correlative with no direct Ngb gain/loss-of-function","Cannot distinguish cause from consequence in the Akt/CREB association"]},{"year":2019,"claim":"Demonstrated that a ROS-scavenging-enhanced NGB fusion restores mitochondrial function and activates a PI3K/Akt-Nrf2 antioxidant program, linking NGB to redox defense.","evidence":"ROS scavenging, mitochondrial function and apoptosis assays, and PI3K/Akt/Nrf2/HO-1/SOD/CAT Western blots in cell culture (Mn-TAT PTD-Ngb)","pmids":["31882813"],"confidence":"Medium","gaps":["Uses an engineered Mn-porphyrin fusion rather than native Ngb","Single lab; in vivo relevance not established here"]},{"year":2019,"claim":"Established a direct anti-inflammatory role for NGB in tissue, distinct from its cell-autonomous antiapoptotic action.","evidence":"Intravitreal Ngb protein replacement with chemokine ELISA, microglial immunohistochemistry, ERG, and histology in rat retinal hypoxia","pmids":["31827177"],"confidence":"Medium","gaps":["Single lab","Molecular mechanism connecting Ngb to chemokine suppression not dissected in this model"]},{"year":2020,"claim":"Defined the molecular anti-inflammatory mechanism of NGB, tying it to NF-κB, MAPK, and NLRP3 inflammasome suppression.","evidence":"NF-κB translocation, MAPK Western blot, ROS, mitochondrial, inflammasome assembly, and cytokine ELISA in LPS-stimulated cells (Mn-TAT PTD-Ngb)","pmids":["32470548"],"confidence":"Medium","gaps":["Engineered fusion rather than native protein","Single lab; direct versus ROS-indirect contributions to inflammasome suppression not separated"]},{"year":2021,"claim":"Closed a regulatory loop by showing CREB directly binds the Ngb promoter to drive its transcription, making Ngb both target and effector of Akt/CREB survival signaling.","evidence":"Luciferase reporter, ChIP, AKT/CREB phosphorylation Western blots, siRNA knockdown rescue, and ROS/viability assays in neuronal cells (polydatin)","pmids":["34751416"],"confidence":"Medium","gaps":["Single lab","Whether other transcription factors co-regulate the Ngb promoter is not addressed"]},{"year":null,"claim":"The relationship between the neuroprotective globin NGB and the merlin-associated GTP-binding NGB, and whether the corpus describes one protein or two distinct entities sharing a symbol, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct structural or mechanistic link established between the two NGB entities","No endogenous, native-protein in vivo loss-of-function study of the globin clarifying its physiological role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[4]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7]}],"complexes":[],"partners":["NF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPG2","full_name":"Neuroglobin","aliases":["Nitrite reductase"],"length_aa":151,"mass_kda":16.9,"function":"Monomeric globin with a bis-histidyl six-coordinate heme-iron atom through which it can bind dioxygen, carbon monoxide and nitric oxide (PubMed:11473128, PubMed:12962627, PubMed:24699645). Could help transport oxygen and increase its availability to the metabolically active neuronal tissues, though its low quantity in tissues as well as its high affinity for dioxygen, which may limit its oxygen-releasing ability, argue against it (PubMed:11473128, PubMed:12860983, PubMed:12962627, PubMed:24699645). The ferrous/deoxygenated form exhibits a nitrite reductase activity and it could produce nitric oxide which in turn inhibits cellular respiration in response to hypoxia (PubMed:21296891). In its ferrous/deoxygenated state, it may also exhibit GDI (Guanine nucleotide Dissociation Inhibitor) activity toward heterotrimeric G-alpha proteins, thereby regulating signal transduction to facilitate neuroprotective responses in the wake of hypoxia and associated oxidative stress (PubMed:12860983, PubMed:18302932)","subcellular_location":"Cytoplasm, cytosol; Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9NPG2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NGB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NGB","total_profiled":1310},"omim":[{"mim_id":"605304","title":"NEUROGLOBIN; NGB","url":"https://www.omim.org/entry/605304"},{"mim_id":"104760","title":"AMYLOID BETA A4 PRECURSOR PROTEIN; APP","url":"https://www.omim.org/entry/104760"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":75.1}],"url":"https://www.proteinatlas.org/search/NGB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NPG2","domains":[{"cath_id":"1.10.490.10","chopping":"4-145","consensus_level":"high","plddt":96.1999,"start":4,"end":145}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPG2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPG2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPG2-F1-predicted_aligned_error_v6.png","plddt_mean":95.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NGB","jax_strain_url":"https://www.jax.org/strain/search?query=NGB"},"sequence":{"accession":"Q9NPG2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPG2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPG2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPG2"}},"corpus_meta":[{"pmid":"16205781","id":"PMC_16205781","title":"The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats.","date":"2005","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16205781","citation_count":129,"is_preprint":false},{"pmid":"15858839","id":"PMC_15858839","title":"Acute administration of SB-277011A, NGB 2904, or BP 897 inhibits cocaine cue-induced reinstatement of drug-seeking behavior in rats: role of dopamine D3 receptors.","date":"2005","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15858839","citation_count":119,"is_preprint":false},{"pmid":"17627675","id":"PMC_17627675","title":"Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction.","date":"2007","source":"CNS drug reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17627675","citation_count":90,"is_preprint":false},{"pmid":"9873609","id":"PMC_9873609","title":"NGB 2904 and NGB 2849: two highly selective dopamine D3 receptor antagonists.","date":"1998","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/9873609","citation_count":79,"is_preprint":false},{"pmid":"17272677","id":"PMC_17272677","title":"Effects of two novel D3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys.","date":"2007","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/17272677","citation_count":60,"is_preprint":false},{"pmid":"17985117","id":"PMC_17985117","title":"The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats.","date":"2007","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17985117","citation_count":59,"is_preprint":false},{"pmid":"17408730","id":"PMC_17408730","title":"The dopamine D3 receptor antagonist NGB 2904 increases spontaneous and amphetamine-stimulated locomotion.","date":"2007","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/17408730","citation_count":39,"is_preprint":false},{"pmid":"18329700","id":"PMC_18329700","title":"The effects of two highly selective dopamine D3 receptor antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity.","date":"2008","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/18329700","citation_count":38,"is_preprint":false},{"pmid":"23428737","id":"PMC_23428737","title":"Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in Alzheimer's disease rat model.","date":"2013","source":"Gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/23428737","citation_count":24,"is_preprint":false},{"pmid":"21339183","id":"PMC_21339183","title":"Different expression patterns of Ngb and EPOR in the cerebral cortex and hippocampus revealed distinctive therapeutic effects of intranasal delivery of Neuro-EPO for ischemic insults to the gerbil brain.","date":"2011","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/21339183","citation_count":23,"is_preprint":false},{"pmid":"17210637","id":"PMC_17210637","title":"Identification and characterization of putative tumor suppressor NGB, a GTP-binding protein that interacts with the neurofibromatosis 2 protein.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17210637","citation_count":21,"is_preprint":false},{"pmid":"23080171","id":"PMC_23080171","title":"Human carotid body HIF and NGB expression during human development and aging.","date":"2012","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/23080171","citation_count":15,"is_preprint":false},{"pmid":"28829495","id":"PMC_28829495","title":"The expression and mechanism of BDNF and NGB in perihematomal tissue in rats with intracerebral hemorrhage.","date":"2017","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28829495","citation_count":13,"is_preprint":false},{"pmid":"22410316","id":"PMC_22410316","title":"Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904.","date":"2012","source":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22410316","citation_count":13,"is_preprint":false},{"pmid":"31827177","id":"PMC_31827177","title":"Effects of Exogenous Neuroglobin (Ngb) on retinal inflammatory chemokines and microglia in a rat model of transient hypoxia.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31827177","citation_count":13,"is_preprint":false},{"pmid":"23456442","id":"PMC_23456442","title":"Neuroprotective effect of TAT PTD-Ngb fusion protein on primary cortical neurons against hypoxia-induced apoptosis.","date":"2013","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/23456442","citation_count":12,"is_preprint":false},{"pmid":"31882813","id":"PMC_31882813","title":"Mn-TAT PTD-Ngb attenuates oxidative injury by an enhanced ROS scavenging ability and the regulation of redox signaling pathway.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31882813","citation_count":11,"is_preprint":false},{"pmid":"34751416","id":"PMC_34751416","title":"Polydatin protects neuronal cells from hydrogen peroxide damage by activating CREB/Ngb signaling.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34751416","citation_count":10,"is_preprint":false},{"pmid":"36056962","id":"PMC_36056962","title":"A new source of bacterial myrosinase isolated from endophytic Bacillus sp. NGB-B10, and its relevance in biological control activity.","date":"2022","source":"World journal of microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36056962","citation_count":9,"is_preprint":false},{"pmid":"32470548","id":"PMC_32470548","title":"Mn-TAT PTD-Ngb ameliorates inflammation through the elimination of damaged mitochondria and the activation of Nrf2-antioxidant signaling pathway.","date":"2020","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32470548","citation_count":7,"is_preprint":false},{"pmid":"26646387","id":"PMC_26646387","title":"Pichia pastoris Production of Tat-NGB and Its Neuroprotection on Rat Pheochromocytoma Cells.","date":"2016","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26646387","citation_count":5,"is_preprint":false},{"pmid":"25131407","id":"PMC_25131407","title":"Suppression of NGB and NAB/ERabp1 in tomato modifies root responses to potato cyst nematode infestation.","date":"2014","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25131407","citation_count":4,"is_preprint":false},{"pmid":"35818200","id":"PMC_35818200","title":"Expression Pattern of Ngb in Astrocytes after Spinal Cord Injury and the Clinical Significance.","date":"2022","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/35818200","citation_count":3,"is_preprint":false},{"pmid":"24325104","id":"PMC_24325104","title":"[Effects of hypoxia preconditioning on serum NGB and S-100B in patients with intracranial aneurysm surgery].","date":"2013","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/24325104","citation_count":1,"is_preprint":false},{"pmid":"41641147","id":"PMC_41641147","title":"Electroacupuncture improves hypoxic stress and energy metabolism to alleviate vascular cognitive impairment through activation of the HIF-1α/p53/NGB signaling pathway in rats.","date":"2026","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41641147","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.05.25333018","title":"Lack of policy support for chronic conditions in UK sport: a scoping review of National Governing Bodies","date":"2025-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.05.25333018","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.20.608782","title":"Genomic loci for sclerotinia stem rot resistance and chlorophyll stability in  <i>Brassica napus</i>  : integrating GWAS with microbiome insights","date":"2024-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.20.608782","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16959,"output_tokens":2521,"usd":0.044346,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9235,"output_tokens":2806,"usd":0.058162,"stage2_stop_reason":"end_turn"},"total_usd":0.102508,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the human/mammalian gene NGB (Neuroglobin). Let me classify each paper:\n\n- Papers 1-8: About NGB 2904, a dopamine D3 receptor antagonist compound — NOT the NGB gene\n- Papers 9-18, 21, 23-25: About Neuroglobin (Ngb/NGB) protein — the mammalian gene\n- Paper 11: About a GTP-binding protein named NGB (NF2-associated GTP binding protein) — different gene, but could be the query\n- Paper 19: Bacillus NGB-B10 strain — NOT the gene\n- Paper 22: Plant NGB (tomato GTP-binding protein) — possible ortholog/collision\n- Papers 26-27: Unrelated (NGBs = National Governing Bodies, plant accessions)\n\nThe query gene is NGB. The corpus has papers about two different proteins called NGB: (1) Neuroglobin (Ngb) - a neuroprotective globin protein, and (2) NGB - an NF2-associated GTP-binding protein (paper 11). Given the preponderance of the corpus focuses on Neuroglobin, that is likely the primary query. Paper 11 describes a distinct GTP-binding protein. I'll include both as they represent different genes sharing the symbol, but weight Neuroglobin papers more heavily since they dominate the corpus.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"NGB (NF2-associated GTP-binding protein) physically interacts with merlin (the NF2 tumor suppressor product) as demonstrated by co-immunoprecipitation. This interaction impairs merlin turnover, but merlin does not affect the GTPase or GTP-binding activity of NGB. The tumor suppressor function of NGB requires merlin and is linked to suppression of cyclin D1 expression.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression/loss-of-function, GTPase activity assay, cyclin D1 Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus GTPase assay and functional readouts (growth suppression, cyclin D1), single lab\",\n      \"pmids\": [\"17210637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NGB (NF2-associated GTP-binding protein) functions as a tumor suppressor: ectopic expression inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwannoma cells. Its GTP-binding region is similar to R-ras and Rap2.\",\n      \"method\": \"Ectopic overexpression in schwannoma cells with growth, aggregation, and tumorigenicity assays; sequence/domain analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss/gain-of-function with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"17210637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Neuroglobin (Ngb) promotes neuroprotection via Akt phosphorylation and activation of CREB, engaging a cell survival signaling pathway. In an Alzheimer's disease rat model, maintaining high Ngb levels correlated with increased p-Akt/Akt and p-CREB/CREB ratios and reduced cytochrome C/Apaf-1 immunocomplex formation (reduced apoptosis).\",\n      \"method\": \"Western blot (p-Akt, Akt, CREB, p-CREB), co-immunoprecipitation (cytochrome C/Apaf-1), immunohistochemistry, TUNEL assay in rat AD model\",\n      \"journal\": \"Gerontology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative in vivo measurements with pharmacological intervention, single lab, no direct manipulation of Ngb\",\n      \"pmids\": [\"23428737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TAT PTD-Ngb fusion protein translocates into primary cortical neurons within 30 min and protects them against hypoxia-induced apoptosis by increasing Bcl-2 expression and decreasing caspase-3 and caspase-9 activities, implicating suppression of the mitochondrial apoptotic pathway.\",\n      \"method\": \"Fluorescent immunostaining, MTT cell viability assay, transmission electron microscopy, Western blot (Bcl-2), caspase activity assays in primary cortical neurons\",\n      \"journal\": \"Neurological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein delivery with multiple orthogonal readouts (viability, ultrastructure, caspase activity, Bcl-2), single lab\",\n      \"pmids\": [\"23456442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mn-TAT PTD-Ngb (a manganese porphyrin reconstituted Ngb fusion) exhibits enhanced ROS scavenging activity compared to TAT PTD-Ngb and protects against oxidative injury by restoring mitochondrial function, inhibiting mitochondria-dependent apoptosis, and activating the PI3K/Akt signaling pathway, which upregulates Nrf2, HO-1, SOD, and catalase.\",\n      \"method\": \"ROS scavenging assay, mitochondrial function assays, apoptosis assays, Western blot (PI3K/Akt, Nrf2, HO-1, SOD, CAT) in cell culture\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and cellular assays, single lab\",\n      \"pmids\": [\"31882813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mn-TAT PTD-Ngb suppresses LPS-induced inflammatory responses by blocking NF-κB nuclear translocation, attenuating MAPK phosphorylation, reducing ROS production, alleviating mitochondrial dysfunction, and suppressing NLRP3 inflammasome assembly, thereby reducing IL-1β and IL-18 production and improving Nrf2 levels.\",\n      \"method\": \"NF-κB nuclear translocation assay, MAPK Western blot, ROS assay, mitochondrial function assay, inflammasome assembly assay, cytokine ELISA in LPS-stimulated cells\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic readouts in defined inflammatory model, single lab\",\n      \"pmids\": [\"32470548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Neuroglobin (Ngb) transcription is directly activated by CREB binding to the Ngb promoter. Polydatin activates AKT/CREB signaling, increasing CREB binding to the Ngb promoter (shown by luciferase reporter and ChIP), upregulating Ngb protein, and Ngb knockdown abrogates the neuroprotective effect of polydatin against H2O2-induced neuronal death.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, Western blot (AKT, CREB phosphorylation, Ngb), siRNA knockdown, cell viability assay, mitochondrial ROS measurement\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding (ChIP), reporter assay, and loss-of-function rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34751416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Intravitreal delivery of exogenous Neuroglobin (Ngb) protein in hypoxia-exposed rat retina restores Ngb levels reduced by 30% post-hypoxia and significantly decreases inflammatory chemokines (IL-6, TNFα, IL-1β, RANTES, MCP-1, VEGF) and microglial activation, demonstrating a direct anti-inflammatory role of Ngb in retinal hypoxia.\",\n      \"method\": \"Intravitreal protein injection, ELISA (chemokines), immunohistochemistry (microglial markers, Ngb), electroretinogram, histology in rat retinal hypoxia model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein replacement experiment with multiple functional readouts, single lab\",\n      \"pmids\": [\"31827177\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Neuroglobin (NGB) is a neuroprotective globin protein that, upon hypoxic/ischemic stress, engages the PI3K/Akt/CREB signaling axis (with CREB directly binding the NGB promoter to upregulate its expression), suppresses mitochondria-dependent apoptosis (via Bcl-2 upregulation and caspase-3/9 inhibition), scavenges ROS, blocks NF-κB–mediated inflammation and NLRP3 inflammasome assembly, and activates Nrf2-driven antioxidant responses; a distinct GTP-binding protein also called NGB interacts with the NF2 tumor suppressor merlin to stabilize it and suppress cyclin D1–driven cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Neuroglobin (NGB) is a neuroprotective globin that defends neurons and retinal tissue against hypoxic, oxidative, and inflammatory injury [#3, #7]. Upon stress, exogenously delivered NGB suppresses the mitochondria-dependent apoptotic pathway, increasing Bcl-2 expression while reducing caspase-3 and caspase-9 activities, and protects primary cortical neurons from hypoxia-induced death [#3]. NGB-mediated protection engages the PI3K/Akt/CREB signaling axis, and CREB in turn directly binds the Ngb promoter to upregulate Ngb transcription, establishing a feed-forward loop in which Ngb is both effector and transcriptional target of survival signaling [#6]. A manganese-porphyrin-reconstituted NGB fusion enhances ROS scavenging and restores mitochondrial function while activating PI3K/Akt to drive an Nrf2/HO-1/SOD/catalase antioxidant program [#4], and the same agent suppresses LPS-induced inflammation by blocking NF-\\u03baB nuclear translocation, attenuating MAPK signaling, and preventing NLRP3 inflammasome assembly to limit IL-1\\u03b2 and IL-18 production [#5]. In retinal hypoxia, restoring NGB lowers inflammatory chemokines and microglial activation, confirming a direct anti-inflammatory role [#7]. The available corpus also contains a distinct GTP-binding protein designated NGB (NF2-associated GTP-binding protein) that physically interacts with the NF2 tumor suppressor merlin to impair its turnover and acts as a tumor suppressor by inhibiting schwannoma growth and cyclin D1 expression [#0, #1]; this entity is mechanistically unrelated to the globin and reflects a shared symbol.\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that a GTP-binding protein named NGB binds the NF2 tumor suppressor merlin and functions in growth suppression, defining a tumor-suppressor role for this symbol-sharing entity.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, GTPase assays, and gain/loss-of-function growth, aggregation, and tumorigenicity assays in schwannoma cells\",\n      \"pmids\": [\"17210637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; relationship (if any) to the neuroprotective globin NGB is not addressed\", \"Mechanism by which NGB stabilizes merlin not resolved beyond impaired turnover\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that NGB protein delivered directly into neurons suppresses the mitochondrial apoptotic pathway, moving NGB from a correlate of survival to a sufficient protective effector.\",\n      \"evidence\": \"TAT PTD-Ngb fusion delivery with viability, ultrastructure, caspase activity, and Bcl-2 Western blot in primary cortical neurons under hypoxia\",\n      \"pmids\": [\"23456442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Upstream signaling linking Ngb to Bcl-2/caspase changes not defined in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Correlated high Ngb levels with Akt/CREB activation and reduced apoptosis in vivo, implicating a survival signaling axis but without direct Ngb manipulation.\",\n      \"evidence\": \"Western blot, co-IP, immunohistochemistry, and TUNEL in an Alzheimer's disease rat model with pharmacological intervention\",\n      \"pmids\": [\"23428737\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative with no direct Ngb gain/loss-of-function\", \"Cannot distinguish cause from consequence in the Akt/CREB association\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that a ROS-scavenging-enhanced NGB fusion restores mitochondrial function and activates a PI3K/Akt-Nrf2 antioxidant program, linking NGB to redox defense.\",\n      \"evidence\": \"ROS scavenging, mitochondrial function and apoptosis assays, and PI3K/Akt/Nrf2/HO-1/SOD/CAT Western blots in cell culture (Mn-TAT PTD-Ngb)\",\n      \"pmids\": [\"31882813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Uses an engineered Mn-porphyrin fusion rather than native Ngb\", \"Single lab; in vivo relevance not established here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a direct anti-inflammatory role for NGB in tissue, distinct from its cell-autonomous antiapoptotic action.\",\n      \"evidence\": \"Intravitreal Ngb protein replacement with chemokine ELISA, microglial immunohistochemistry, ERG, and histology in rat retinal hypoxia\",\n      \"pmids\": [\"31827177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular mechanism connecting Ngb to chemokine suppression not dissected in this model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the molecular anti-inflammatory mechanism of NGB, tying it to NF-\\u03baB, MAPK, and NLRP3 inflammasome suppression.\",\n      \"evidence\": \"NF-\\u03baB translocation, MAPK Western blot, ROS, mitochondrial, inflammasome assembly, and cytokine ELISA in LPS-stimulated cells (Mn-TAT PTD-Ngb)\",\n      \"pmids\": [\"32470548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Engineered fusion rather than native protein\", \"Single lab; direct versus ROS-indirect contributions to inflammasome suppression not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Closed a regulatory loop by showing CREB directly binds the Ngb promoter to drive its transcription, making Ngb both target and effector of Akt/CREB survival signaling.\",\n      \"evidence\": \"Luciferase reporter, ChIP, AKT/CREB phosphorylation Western blots, siRNA knockdown rescue, and ROS/viability assays in neuronal cells (polydatin)\",\n      \"pmids\": [\"34751416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether other transcription factors co-regulate the Ngb promoter is not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between the neuroprotective globin NGB and the merlin-associated GTP-binding NGB, and whether the corpus describes one protein or two distinct entities sharing a symbol, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct structural or mechanistic link established between the two NGB entities\", \"No endogenous, native-protein in vivo loss-of-function study of the globin clarifying its physiological role\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}