{"gene":"ADM","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":1994,"finding":"rat proADM22-41 (prodepin), a product of the ADM gene distinct from adrenomedullin itself, produces systemic vasodilation and increases cardiac output when injected intravenously in rats, but this activity is species-specific (no effect in rabbit, piglet, cat, or dog).","method":"In vivo hemodynamic measurements (systemic arterial pressure, systemic vascular resistance, cardiac output) following bolus i.v. injection in multiple anesthetized species","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vivo functional assay with defined peptide product, single lab, no mechanistic receptor identification","pmids":["8196484"],"is_preprint":false},{"year":1995,"finding":"proADM153-185 (termed 'adrenotensin'), another product of the ADM gene, produces concentration-dependent vasoconstriction in cat pulmonary arterial rings, opposite to the vasodilatory effect of ADM itself, indicating the ADM gene locus encodes peptides with divergent vascular activities.","method":"Isolated organ bath contractility assay on cat pulmonary artery rings with and without U46619 precontraction","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional in vitro vascular assay with defined gene product, single lab, single method","pmids":["7637545"],"is_preprint":false},{"year":1997,"finding":"Pharmacologically distinct, specific ADM-binding sites (separate from CGRP-binding sites) are present in rat uterus; ADM attenuates galanin-induced uterine contractions and this effect is blocked by CGRP(8-37), establishing that ADM acts through CGRP(8-37)-sensitive receptors in this tissue. Binding site density increases 10-fold in pregnancy.","method":"Radioligand binding assays with 125I-ADM and 125I-CGRP, competition binding, isolated organ bath contractility assay, mRNA detection by RT-PCR","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (radioligand binding, functional contractility, receptor pharmacology with antagonist), single lab","pmids":["9165042"],"is_preprint":false},{"year":1998,"finding":"ADM inhibits angiotensin-II-stimulated aldosterone secretion from human adrenocortical zona glomerulosa cells via ADM(22-52)-sensitive receptors; the six-membered ring structure AND the C-terminal amino-acid sequence (but not the N-terminal sequence) are both required for ADM's antimineralocorticoid effect; the C-terminal sequence is needed for receptor binding while the ring structure is needed for receptor activation.","method":"Autoradiographic radioligand binding with 125I-ADM(1-52) and competition by ADM fragments; aldosterone secretion assay from dispersed human adrenocortical cells treated with ADM fragments and antagonist ADM(22-52)","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — systematic structure-activity study with multiple ADM fragments, receptor binding plus functional aldosterone assay, single lab but multiple orthogonal methods","pmids":["9877221"],"is_preprint":false},{"year":2000,"finding":"ADM plays a major role in LPS-induced hypotension in rats, acting through ADM(22-52)-sensitive receptors; the ADM receptor antagonist ADM(22-52) counteracted and reversed LPS-induced blood pressure lowering, whereas the selective CGRP1 receptor antagonist CGRP(8-37) was ineffective.","method":"In vivo rat model of LPS-induced endotoxemia; blood pressure measurements with pharmacological antagonists ADM(22-52) and CGRP(8-37)","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo pharmacological antagonism with defined receptor-selective antagonists, single lab, single method","pmids":["11210719"],"is_preprint":false},{"year":2002,"finding":"Human adrenal zona glomerulosa (ZG) cells express ADM, its precursor pADM mRNA, and ADM receptors of both L1-R and CRLR/RAMP2,3 subtypes; through activation of these receptors, ADM (10^-8 M) inhibits angiotensin-II- and K+-stimulated aldosterone secretion, increases cell proliferation, and decreases apoptosis; all effects are reversed by ADM receptor antagonist ADM(22-52), establishing an autocrine/paracrine ADM system in human adrenal cortex.","method":"RT-PCR for pADM, L1-R, CRLR, RAMPs 1-3; immunocytochemistry and RIA for ADM protein; aldosterone secretion assay; proliferation and apoptosis assays in cultured ZG cells","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RT-PCR, protein detection, functional secretion and cell viability assays, receptor antagonist reversal), single lab","pmids":["11786920"],"is_preprint":false},{"year":2003,"finding":"In human thymic arteries, ADM-induced vasodilation is mediated by two distinct mechanisms: (1) an endothelial ADM receptor signals through nitric oxide–guanylyl cyclase (responses attenuated by endothelial denudation and by NOS/guanylyl cyclase inhibitors), and (2) a smooth muscle CGRP receptor signals through cAMP/PKA. Both CGRP and ADM responses (but not PAMP responses) are attenuated by the CGRP1 receptor antagonist CGRP(8-37).","method":"Isolated human thymic artery vascular reactivity assay; endothelial denudation; pharmacological inhibitors of NOS (L-NAME), guanylyl cyclase (ODQ), adenylyl cyclase (SQ-22536), PKA (Rp-cAMPS), and CGRP(8-37) receptor antagonist","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — functional vascular assay with systematic pharmacological dissection using multiple pathway inhibitors plus receptor antagonist; single lab but multiple orthogonal interventions","pmids":["12529288"],"is_preprint":false},{"year":2003,"finding":"Calcified vascular smooth muscle cells (VSMCs) upregulate both ADM mRNA (by 78%) and RAMP2 mRNA (by 56%), and release more ADM protein; RAMP2 mRNA levels positively correlate with ADM mRNA levels in calcified VSMCs, suggesting coordinated upregulation of ADM and its receptor component during vascular calcification.","method":"Competitive quantitative RT-PCR for ADM mRNA and RAMP2 mRNA; RIA for ADM protein; in vitro calcification model of rat VSMCs with β-glycerophosphate; calcium content, alkaline phosphatase activity, and 45Ca2+ uptake measurements","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — quantitative mRNA and protein measurements in a defined cell model, single lab, no direct functional perturbation of ADM","pmids":["12668214"],"is_preprint":false},{"year":2009,"finding":"A SNP (rs11042725) in the upstream flanking region of the ADM gene significantly alters ADM promoter activity in reporter gene assays, and this variant is associated with response to the antidepressant paroxetine (OR=0.075, P<0.001) but not to fluoxetine or citalopram, suggesting ADM expression level modulates paroxetine efficacy.","method":"Luciferase reporter gene assay for ADM promoter SNP functional effect; microarray and quantitative PCR for ADM expression after paroxetine treatment; pharmacogenetic association analysis","journal":"The pharmacogenomics journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter gene assay directly demonstrates functional effect of SNP on ADM expression, single lab; association finding is correlational","pmids":["19636336"],"is_preprint":false},{"year":2016,"finding":"ADM protects rat Leydig cells from LPS-induced inflammation and apoptosis; ADM pretreatment reduces ROS, pro-inflammatory cytokines (IL-1β, IL-6, NO, PGE2), and apoptosis markers (Bax, caspase-3, PARP), while promoting Bcl-2 and mitochondrial membrane potential; these effects are associated with increased p-Akt levels, placing ADM's protective signaling upstream of the PI3K/Akt pathway.","method":"Cell culture with LPS-induced cytotoxicity model; TUNEL assay; DNA fragmentation; Western blot and RT-PCR for Bcl-2, Bax, caspase-3, PARP, and p-Akt; ROS/MDA/GSH/LDH and cytokine measurements","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal readouts (apoptosis, inflammation, signaling pathway), single lab, no direct ADM receptor blocking experiment to confirm mechanism","pmids":["27212810"],"is_preprint":false},{"year":2021,"finding":"Under hypoxia, ADM expression in trophoblast cells is upregulated in an HIF-1α-dependent manner; treatment with ADM agonists reduces HIF-1α activity and enhances trophoblast invasion by altering MMP2, MMP9, and Rac1 expression; ADM also increases HLA-G expression under normoxia, while ADM2 or combined ADM/ADM2 treatment under hypoxia attenuates HLA-G expression.","method":"Trophoblast cell (HTR-8/SVneo) culture under hypoxia; siRNA knockdown; YC-1 HIF-1α inhibitor; invasion assay; RT-PCR and protein expression analysis of HIF-1α, MMP2, MMP9, Rac1, HLA-G, ADM, ADM2","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic (siRNA) and pharmacological (YC-1) perturbation with functional invasion readout, single lab, moderate mechanistic depth","pmids":["32997116"],"is_preprint":false},{"year":2022,"finding":"ADM knockdown in glioma cells enhances the suppressive effect of temozolomide (TMZ) on cell viability and promotes apoptosis; miR-1297 directly targets the ADM transcript (confirmed experimentally) and inhibits ADM expression; miR-1297 overexpression phenocopies ADM knockdown under TMZ treatment, and ADM knockdown partially rescues miR-1297 inhibition effects; mechanistically, ADM modulates Bax/Bcl-2 ratio, Akt phosphorylation, and Erk1/2 phosphorylation.","method":"CCK-8 cell viability; Annexin V apoptosis assay; JC-1 mitochondrial membrane potential; nude mouse tumor assay; immunoblotting for Akt, Erk1/2 phosphorylation and apoptosis proteins; bioinformatics prediction + experimental validation of miR-1297 targeting ADM","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function (ADM knockdown, miR-1297 OE) with defined cellular phenotypes and partial pathway placement; single lab","pmids":["36183123"],"is_preprint":false},{"year":2022,"finding":"Overexpression of ADM in human dental pulp stem cells (DPSCs) promotes cell cycle progression (increased G2/M ratio), reduces senescence markers (p53, P21WAF1, P16INK4A), and decreases ROS accumulation; mechanistically, ADM overexpression suppresses miR-152, which normally directly targets CCNA2 (Cyclin A2) to induce senescence; restoration of miR-152 reverses ADM's anti-senescence effects, and CCNA2 overexpression rescues the miR-152-induced senescence, placing ADM upstream of the miR-152/CCNA2 axis.","method":"Lentiviral ADM overexpression; transcriptome/microRNA profiling; luciferase reporter assay (miR-152 targeting CCNA2 3'-UTR implied); transfection of miR-152 mimic, pCDH-CCNA2, CCNA2 siRNA; senescence assays; flow cytometry for cell cycle; immunoblotting for p53, P21, P16","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (OE, KD, rescue experiments), pathway placement via epistasis (miR-152/CCNA2), single lab","pmids":["36310381"],"is_preprint":false}],"current_model":"Adrenomedullin (ADM) is a multifunctional secreted peptide encoded by the ADM gene that acts through CGRP(8-37)-sensitive receptors (CRLR/RAMP complexes and L1-R) to produce vasodilation via endothelial nitric oxide–guanylyl cyclase and smooth muscle cAMP/PKA signaling; the ADM gene also encodes divergent vasoactive products (prodepin/proADM22-41 and adrenotensin/proADM153-185); within target tissues including adrenal zona glomerulosa, uterus, and Leydig cells, ADM suppresses aldosterone secretion, modulates contractility, and promotes cell survival via PI3K/Akt signaling; in stem cells, ADM inhibits senescence through suppression of the miR-152/CCNA2 axis; and in glioma cells, ADM modulates chemosensitivity through Akt/Erk1/2 and Bax/Bcl-2 pathways, with miR-1297 identified as an upstream regulator targeting ADM mRNA."},"narrative":{"mechanistic_narrative":"Adrenomedullin (ADM) is a secreted multifunctional peptide that signals through CGRP(8-37)- and ADM(22-52)-sensitive receptors to regulate vascular tone, endocrine secretion, and cell survival across multiple tissues [PMID:9877221, PMID:12529288]. In the vasculature, ADM produces vasodilation through two parallel mechanisms in a single vessel: an endothelial receptor coupled to the nitric oxide–guanylyl cyclase axis and a smooth-muscle CGRP receptor coupled to cAMP/PKA, with responses blocked by CGRP(8-37) [PMID:12529288]; ADM also drives LPS-induced hypotension in vivo through ADM(22-52)-sensitive rather than CGRP1 receptors [PMID:11210719]. The ADM gene locus additionally encodes peptides with divergent vascular activity, including the vasodilatory prodepin (proADM22-41) and the vasoconstrictor adrenotensin (proADM153-185) [PMID:8196484, PMID:7637545]. In the human adrenal zona glomerulosa, ADM and its receptors (L1-R and CRLR/RAMP) form an autocrine/paracrine system in which ADM inhibits angiotensin-II- and K+-stimulated aldosterone secretion while promoting proliferation and suppressing apoptosis, with the antimineralocorticoid effect requiring both the C-terminal sequence (for binding) and the six-membered ring (for activation) [PMID:9877221, PMID:11786920]. ADM functions broadly as a cytoprotective and pro-survival factor: it protects Leydig cells from LPS-induced inflammation and apoptosis via PI3K/Akt signaling [PMID:27212810], modulates glioma chemosensitivity through Akt/Erk1/2 and Bax/Bcl-2 pathways under control of miR-1297 [PMID:36183123], and inhibits stem-cell senescence by suppressing the miR-152/CCNA2 axis [PMID:36310381]. ADM expression is induced under hypoxia in an HIF-1α-dependent manner and enhances trophoblast invasion [PMID:32997116].","teleology":[{"year":1994,"claim":"Established that the ADM gene locus produces bioactive peptides beyond adrenomedullin itself, showing the prodepin fragment is a vasoactive product in its own right.","evidence":"In vivo hemodynamic measurement after i.v. injection of proADM22-41 across multiple anesthetized species","pmids":["8196484"],"confidence":"Medium","gaps":["No receptor identified for prodepin","Activity species-specific, mechanism of the difference unknown"]},{"year":1995,"claim":"Demonstrated that the same gene encodes a peptide with opposite vascular action, defining the locus as a source of functionally divergent products.","evidence":"Isolated cat pulmonary artery ring contractility assay with adrenotensin (proADM153-185)","pmids":["7637545"],"confidence":"Medium","gaps":["No receptor characterized for adrenotensin","Single vessel/species tested"]},{"year":1997,"claim":"Resolved which receptor class mediates ADM tissue effects by identifying CGRP(8-37)-sensitive binding sites distinct from CGRP receptors and showing functional modulation of uterine contraction.","evidence":"Radioligand competition binding and organ-bath contractility in rat uterus with CGRP(8-37) antagonism","pmids":["9165042"],"confidence":"Medium","gaps":["Molecular identity of the binding site not defined","Functional consequence of pregnancy-associated 10-fold density increase not established"]},{"year":1998,"claim":"Mapped the structural determinants of ADM action by separating receptor binding (C-terminal sequence) from receptor activation (ring structure) in the aldosterone-suppressing response.","evidence":"Structure-activity study with ADM fragments, radioligand binding, and aldosterone secretion assay in human adrenocortical cells, antagonized by ADM(22-52)","pmids":["9877221"],"confidence":"High","gaps":["Receptor subtype not molecularly resolved","Downstream signaling pathway for aldosterone inhibition not defined"]},{"year":2000,"claim":"Distinguished the ADM-specific receptor from the CGRP1 receptor in vivo by showing ADM(22-52), but not CGRP(8-37), reverses endotoxic hypotension.","evidence":"Rat LPS endotoxemia model with selective ADM(22-52) and CGRP(8-37) antagonists","pmids":["11210719"],"confidence":"Medium","gaps":["Cellular source of ADM during endotoxemia not identified","Downstream vasodilatory mediator not defined in this model"]},{"year":2002,"claim":"Defined an autocrine/paracrine ADM system in human adrenal cortex coupling receptor expression to aldosterone suppression, proliferation, and anti-apoptosis.","evidence":"RT-PCR for pADM/L1-R/CRLR/RAMPs, protein detection, and functional secretion/proliferation/apoptosis assays with ADM(22-52) reversal in cultured ZG cells","pmids":["11786920"],"confidence":"Medium","gaps":["Signaling pathways linking ADM to proliferation/apoptosis not delineated","Relative roles of L1-R vs CRLR/RAMP not separated"]},{"year":2003,"claim":"Dissected the dual vasodilatory mechanism of ADM, separating an endothelial NO–guanylyl cyclase arm from a smooth-muscle cAMP/PKA arm in a single vessel.","evidence":"Human thymic artery reactivity with endothelial denudation and inhibitors of NOS, guanylyl cyclase, adenylyl cyclase, PKA, plus CGRP(8-37)","pmids":["12529288"],"confidence":"High","gaps":["Molecular receptor identity at each cell type not defined","Relative in vivo contribution of the two arms not quantified"]},{"year":2003,"claim":"Linked ADM and its receptor component to a pathological vascular state by showing coordinated upregulation of ADM and RAMP2 during VSMC calcification.","evidence":"Quantitative RT-PCR for ADM and RAMP2 mRNA and RIA for ADM protein in a β-glycerophosphate VSMC calcification model","pmids":["12668214"],"confidence":"Medium","gaps":["No direct functional perturbation of ADM in calcification","Causal direction between calcification and ADM induction unresolved"]},{"year":2009,"claim":"Provided functional genetic evidence that an upstream ADM SNP alters promoter activity and correlates with paroxetine response.","evidence":"Luciferase reporter assay of rs11042725 plus expression analysis and pharmacogenetic association","pmids":["19636336"],"confidence":"Medium","gaps":["Association is correlational, no mechanistic link to antidepressant action","Drug-specificity (paroxetine only) unexplained"]},{"year":2016,"claim":"Placed ADM's cytoprotective action upstream of PI3K/Akt by showing it reduces inflammation and apoptosis in LPS-challenged Leydig cells.","evidence":"LPS cytotoxicity model with TUNEL, immunoblot for Bax/Bcl-2/caspase-3/PARP/p-Akt, ROS and cytokine measurements","pmids":["27212810"],"confidence":"Medium","gaps":["No ADM receptor-blocking experiment to confirm mechanism","Whether Akt activation is necessary not tested"]},{"year":2021,"claim":"Connected ADM to hypoxic signaling and trophoblast biology, showing HIF-1α-dependent induction and ADM-driven invasion via MMP/Rac1.","evidence":"HTR-8/SVneo hypoxia culture with siRNA, HIF-1α inhibitor YC-1, invasion assay, and expression analysis","pmids":["32997116"],"confidence":"Medium","gaps":["Receptor mediating trophoblast effects not identified","Opposing ADM/ADM2 effects on HLA-G mechanistically unresolved"]},{"year":2022,"claim":"Established ADM as a determinant of glioma chemosensitivity under miR-1297 control, modulating Akt/Erk1/2 and Bax/Bcl-2.","evidence":"ADM knockdown and miR-1297 overexpression with viability/apoptosis assays, xenografts, immunoblotting, and validated miR-1297–ADM targeting","pmids":["36183123"],"confidence":"Medium","gaps":["Receptor and ligand requirement for the survival effect not tested","Whether Akt/Erk1/2 changes are causal not established"]},{"year":2022,"claim":"Defined an anti-senescence role for ADM in stem cells by epistatic placement upstream of the miR-152/CCNA2 axis.","evidence":"Lentiviral ADM overexpression in DPSCs with miR-152 mimic/CCNA2 rescue, cell-cycle and senescence assays","pmids":["36310381"],"confidence":"Medium","gaps":["Mechanism by which ADM suppresses miR-152 unknown","Receptor dependence of the anti-senescence effect not tested"]},{"year":null,"claim":"The molecular identities of the distinct ADM receptors operating across tissues and how a single peptide selects between vasodilatory, endocrine, and pro-survival signaling outputs remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified receptor-to-pathway map across vascular, adrenal, and tumor contexts","Mechanism of ADM coupling to miRNA networks unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,5,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,11]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35318","full_name":"Pro-adrenomedullin","aliases":[],"length_aa":185,"mass_kda":20.4,"function":"Adrenomedullin/ADM and proadrenomedullin N-20 terminal peptide/PAMP are peptide hormones that act as potent hypotensive and vasodilatator agents (PubMed:8387282, PubMed:9620797). Numerous actions have been reported most related to the physiologic control of fluid and electrolyte homeostasis. In the kidney, ADM is diuretic and natriuretic, and both ADM and PAMP inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptides at physiologically relevant doses inhibit basal ACTH secretion. Both peptides appear to act in brain and pituitary gland to facilitate the loss of plasma volume, actions which complement their hypotensive effects in blood vessels Peptide hormone that act as potent hypotensive and vasodilatator agents (PubMed:8387282). ADM function is mediated by the CALCRL-RAMP2 and CALCRL-RAMP3 receptor complexes with ADM showing the highest potency for the CALCRL-RAMP2 complex (PubMed:32296767, PubMed:9620797) Peptide hormone that act as potent hypotensive and vasodilatator agents by inhibiting catecholamine secretion from sympathetic nerve endings and adrenal chromaffin cells (PubMed:10588445, PubMed:9578982). Acts as a ligand for MRGPRX2 receptor in mast cells (PubMed:15823563) Peptide hormone that act as potent hypotensive and vasodilatator agents by inhibiting catecholamine secretion from sympathetic nerve endings and adrenal chromaffin cells (PubMed:10588445, PubMed:9578982). Acts as a ligand for MRGPRX2 receptor in mast cells (PubMed:15823563, PubMed:34789875)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P35318/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADM","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADM","total_profiled":1310},"omim":[{"mim_id":"618773","title":"LYMPHATIC MALFORMATION 8; LMPHM8","url":"https://www.omim.org/entry/618773"},{"mim_id":"616412","title":"THIOREDOXIN DOMAIN-CONTAINING PROTEIN 5; TXNDC5","url":"https://www.omim.org/entry/616412"},{"mim_id":"611775","title":"KAWASAKI DISEASE","url":"https://www.omim.org/entry/611775"},{"mim_id":"610658","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 29; TRIM29","url":"https://www.omim.org/entry/610658"},{"mim_id":"608682","title":"ADRENOMEDULLIN 2; ADM2","url":"https://www.omim.org/entry/608682"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":339.7}],"url":"https://www.proteinatlas.org/search/ADM"},"hgnc":{"alias_symbol":["AM"],"prev_symbol":[]},"alphafold":{"accession":"P35318","domains":[{"cath_id":"1.20.5","chopping":"1-47","consensus_level":"medium","plddt":74.7789,"start":1,"end":47}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35318","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35318-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35318-F1-predicted_aligned_error_v6.png","plddt_mean":61.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADM","jax_strain_url":"https://www.jax.org/strain/search?query=ADM"},"sequence":{"accession":"P35318","fasta_url":"https://rest.uniprot.org/uniprotkb/P35318.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35318/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35318"}},"corpus_meta":[{"pmid":"2569930","id":"PMC_2569930","title":"Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells.","date":"1989","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/2569930","citation_count":386,"is_preprint":false},{"pmid":"8476431","id":"PMC_8476431","title":"Apoptosis of lung cancer cells caused by some anti-cancer agents (MMC, CPT-11, ADM) is inhibited by bcl-2.","date":"1993","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8476431","citation_count":169,"is_preprint":false},{"pmid":"23994249","id":"PMC_23994249","title":"Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway.","date":"2013","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/23994249","citation_count":161,"is_preprint":false},{"pmid":"23563091","id":"PMC_23563091","title":"Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23563091","citation_count":147,"is_preprint":false},{"pmid":"28514653","id":"PMC_28514653","title":"The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28514653","citation_count":104,"is_preprint":false},{"pmid":"9165042","id":"PMC_9165042","title":"Expression of adrenomedullin (ADM) and its binding sites in the rat uterus: increased number of binding sites and ADM messenger ribonucleic acid in 20-day pregnant rats compared with nonpregnant rats.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9165042","citation_count":70,"is_preprint":false},{"pmid":"29137246","id":"PMC_29137246","title":"Apigenin sensitizes BEL-7402/ADM cells to doxorubicin through inhibiting miR-101/Nrf2 pathway.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29137246","citation_count":57,"is_preprint":false},{"pmid":"26984633","id":"PMC_26984633","title":"Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26984633","citation_count":54,"is_preprint":false},{"pmid":"25714665","id":"PMC_25714665","title":"Involvement of miR-133a and miR-326 in ADM resistance of HepG2 through modulating expression of ABCC1.","date":"2015","source":"Journal of drug targeting","url":"https://pubmed.ncbi.nlm.nih.gov/25714665","citation_count":50,"is_preprint":false},{"pmid":"23178914","id":"PMC_23178914","title":"miR-137 restoration sensitizes multidrug-resistant MCF-7/ADM cells to anticancer agents by targeting YB-1.","date":"2012","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/23178914","citation_count":50,"is_preprint":false},{"pmid":"11069027","id":"PMC_11069027","title":"Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells.","date":"2000","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/11069027","citation_count":49,"is_preprint":false},{"pmid":"27212810","id":"PMC_27212810","title":"Protective Effect of Adrenomedullin on Rat Leydig Cells from Lipopolysaccharide-Induced Inflammation and Apoptosis via the PI3K/Akt Signaling Pathway ADM on Rat Leydig Cells from Inflammation and Apoptosis.","date":"2016","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/27212810","citation_count":47,"is_preprint":false},{"pmid":"1353119","id":"PMC_1353119","title":"Establishment and characterization of doxorubicin-resistant human 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resistance.","date":"2017","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29164556","citation_count":10,"is_preprint":false},{"pmid":"20645795","id":"PMC_20645795","title":"Tegillarca granosa extract Haishengsu inhibits the expression of P-glycoprotein and induces apoptosis in drug-resistant K562/ADM cells.","date":"2010","source":"Pharmaceutical biology","url":"https://pubmed.ncbi.nlm.nih.gov/20645795","citation_count":10,"is_preprint":false},{"pmid":"36746773","id":"PMC_36746773","title":"Reconstruction of Abdominal Wall Defect with Composite Scaffold of 3D Printed ADM/PLA in a Rat Model.","date":"2023","source":"Macromolecular bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/36746773","citation_count":10,"is_preprint":false},{"pmid":"34447462","id":"PMC_34447462","title":"MicroRNA-18a-5p regulates the Warburg effect by targeting hypoxia-inducible factor 1α in the K562/ADM cell line.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34447462","citation_count":10,"is_preprint":false},{"pmid":"8196484","id":"PMC_8196484","title":"Prodepin: a new product of the adrenomedullin (ADM) gene has systemic vasodilator activity.","date":"1994","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8196484","citation_count":10,"is_preprint":false},{"pmid":"36310381","id":"PMC_36310381","title":"Overexpression of adrenomedullin (ADM) alleviates the senescence of human dental pulp stem cells by regulating the miR-152/CCNA2 pathway.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/36310381","citation_count":9,"is_preprint":false},{"pmid":"29928376","id":"PMC_29928376","title":"Solanine reverses multidrug resistance in human myelogenous leukemia K562/ADM cells by downregulating MRP1 expression.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29928376","citation_count":9,"is_preprint":false},{"pmid":"14646556","id":"PMC_14646556","title":"Adriamycin (ADM) induced apoptosis in transitional cell cancer (TCC) cell lines accompanied by p21 WAF1/CIP1 induction.","date":"1997","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/14646556","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54069,"output_tokens":4487,"usd":0.114756,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11805,"output_tokens":4003,"usd":0.07955,"stage2_stop_reason":"end_turn"},"total_usd":0.194306,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human gene ADM (adrenomedullin). Many papers use \"ADM\" as an abbreviation for adriamycin/doxorubicin (a chemotherapy drug), or refer to \"ADM\" as acellular dermal matrix, or to unrelated genes in C. elegans or Streptomyces. I need to focus only on papers about the human adrenomedullin gene/protein.\n\nRelevant papers about human ADM (adrenomedullin):\n- PMID:9165042 - ADM binding sites in rat uterus\n- PMID:11786920 - ADM receptors in adrenal zona glomerulosa\n- PMID:7637545 - Adrenotensin, product of ADM gene\n- PMID:12529288 - Responses to ADM in human thymic arteries\n- PMID:9877221 - ADM inhibitory effect on aldosterone\n- PMID:11210719 - ADM in endotoxin-induced hypotension\n- PMID:8196484 - Prodepin, product of ADM gene\n- PMID:12668214 - ADM mRNA in calcified VSMCs\n- PMID:27212810 - ADM protective effect on Leydig cells via PI3K/Akt\n- PMID:36183123 - miR-1297 targets ADM in glioma\n- PMID:32997116 - ADM and ADM2 in trophoblast migration\n- PMID:36310381 - ADM overexpression alleviates DPSC senescence via miR-152/CCNA2\n- PMID:18081029 - ADM upregulation in schizophrenia (expression only, not mechanistic)\n- PMID:19636336 - ADM SNP and paroxetine response (functional SNP)\n- PMID:25948679 - ADM and kidney disease (association, not direct mechanism)\n- PMID:24147025 - ADM SNP and hypertension (association)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"rat proADM22-41 (prodepin), a product of the ADM gene distinct from adrenomedullin itself, produces systemic vasodilation and increases cardiac output when injected intravenously in rats, but this activity is species-specific (no effect in rabbit, piglet, cat, or dog).\",\n      \"method\": \"In vivo hemodynamic measurements (systemic arterial pressure, systemic vascular resistance, cardiac output) following bolus i.v. injection in multiple anesthetized species\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vivo functional assay with defined peptide product, single lab, no mechanistic receptor identification\",\n      \"pmids\": [\"8196484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"proADM153-185 (termed 'adrenotensin'), another product of the ADM gene, produces concentration-dependent vasoconstriction in cat pulmonary arterial rings, opposite to the vasodilatory effect of ADM itself, indicating the ADM gene locus encodes peptides with divergent vascular activities.\",\n      \"method\": \"Isolated organ bath contractility assay on cat pulmonary artery rings with and without U46619 precontraction\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional in vitro vascular assay with defined gene product, single lab, single method\",\n      \"pmids\": [\"7637545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Pharmacologically distinct, specific ADM-binding sites (separate from CGRP-binding sites) are present in rat uterus; ADM attenuates galanin-induced uterine contractions and this effect is blocked by CGRP(8-37), establishing that ADM acts through CGRP(8-37)-sensitive receptors in this tissue. Binding site density increases 10-fold in pregnancy.\",\n      \"method\": \"Radioligand binding assays with 125I-ADM and 125I-CGRP, competition binding, isolated organ bath contractility assay, mRNA detection by RT-PCR\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (radioligand binding, functional contractility, receptor pharmacology with antagonist), single lab\",\n      \"pmids\": [\"9165042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ADM inhibits angiotensin-II-stimulated aldosterone secretion from human adrenocortical zona glomerulosa cells via ADM(22-52)-sensitive receptors; the six-membered ring structure AND the C-terminal amino-acid sequence (but not the N-terminal sequence) are both required for ADM's antimineralocorticoid effect; the C-terminal sequence is needed for receptor binding while the ring structure is needed for receptor activation.\",\n      \"method\": \"Autoradiographic radioligand binding with 125I-ADM(1-52) and competition by ADM fragments; aldosterone secretion assay from dispersed human adrenocortical cells treated with ADM fragments and antagonist ADM(22-52)\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — systematic structure-activity study with multiple ADM fragments, receptor binding plus functional aldosterone assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9877221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ADM plays a major role in LPS-induced hypotension in rats, acting through ADM(22-52)-sensitive receptors; the ADM receptor antagonist ADM(22-52) counteracted and reversed LPS-induced blood pressure lowering, whereas the selective CGRP1 receptor antagonist CGRP(8-37) was ineffective.\",\n      \"method\": \"In vivo rat model of LPS-induced endotoxemia; blood pressure measurements with pharmacological antagonists ADM(22-52) and CGRP(8-37)\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo pharmacological antagonism with defined receptor-selective antagonists, single lab, single method\",\n      \"pmids\": [\"11210719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human adrenal zona glomerulosa (ZG) cells express ADM, its precursor pADM mRNA, and ADM receptors of both L1-R and CRLR/RAMP2,3 subtypes; through activation of these receptors, ADM (10^-8 M) inhibits angiotensin-II- and K+-stimulated aldosterone secretion, increases cell proliferation, and decreases apoptosis; all effects are reversed by ADM receptor antagonist ADM(22-52), establishing an autocrine/paracrine ADM system in human adrenal cortex.\",\n      \"method\": \"RT-PCR for pADM, L1-R, CRLR, RAMPs 1-3; immunocytochemistry and RIA for ADM protein; aldosterone secretion assay; proliferation and apoptosis assays in cultured ZG cells\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RT-PCR, protein detection, functional secretion and cell viability assays, receptor antagonist reversal), single lab\",\n      \"pmids\": [\"11786920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In human thymic arteries, ADM-induced vasodilation is mediated by two distinct mechanisms: (1) an endothelial ADM receptor signals through nitric oxide–guanylyl cyclase (responses attenuated by endothelial denudation and by NOS/guanylyl cyclase inhibitors), and (2) a smooth muscle CGRP receptor signals through cAMP/PKA. Both CGRP and ADM responses (but not PAMP responses) are attenuated by the CGRP1 receptor antagonist CGRP(8-37).\",\n      \"method\": \"Isolated human thymic artery vascular reactivity assay; endothelial denudation; pharmacological inhibitors of NOS (L-NAME), guanylyl cyclase (ODQ), adenylyl cyclase (SQ-22536), PKA (Rp-cAMPS), and CGRP(8-37) receptor antagonist\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional vascular assay with systematic pharmacological dissection using multiple pathway inhibitors plus receptor antagonist; single lab but multiple orthogonal interventions\",\n      \"pmids\": [\"12529288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Calcified vascular smooth muscle cells (VSMCs) upregulate both ADM mRNA (by 78%) and RAMP2 mRNA (by 56%), and release more ADM protein; RAMP2 mRNA levels positively correlate with ADM mRNA levels in calcified VSMCs, suggesting coordinated upregulation of ADM and its receptor component during vascular calcification.\",\n      \"method\": \"Competitive quantitative RT-PCR for ADM mRNA and RAMP2 mRNA; RIA for ADM protein; in vitro calcification model of rat VSMCs with β-glycerophosphate; calcium content, alkaline phosphatase activity, and 45Ca2+ uptake measurements\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — quantitative mRNA and protein measurements in a defined cell model, single lab, no direct functional perturbation of ADM\",\n      \"pmids\": [\"12668214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A SNP (rs11042725) in the upstream flanking region of the ADM gene significantly alters ADM promoter activity in reporter gene assays, and this variant is associated with response to the antidepressant paroxetine (OR=0.075, P<0.001) but not to fluoxetine or citalopram, suggesting ADM expression level modulates paroxetine efficacy.\",\n      \"method\": \"Luciferase reporter gene assay for ADM promoter SNP functional effect; microarray and quantitative PCR for ADM expression after paroxetine treatment; pharmacogenetic association analysis\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter gene assay directly demonstrates functional effect of SNP on ADM expression, single lab; association finding is correlational\",\n      \"pmids\": [\"19636336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADM protects rat Leydig cells from LPS-induced inflammation and apoptosis; ADM pretreatment reduces ROS, pro-inflammatory cytokines (IL-1β, IL-6, NO, PGE2), and apoptosis markers (Bax, caspase-3, PARP), while promoting Bcl-2 and mitochondrial membrane potential; these effects are associated with increased p-Akt levels, placing ADM's protective signaling upstream of the PI3K/Akt pathway.\",\n      \"method\": \"Cell culture with LPS-induced cytotoxicity model; TUNEL assay; DNA fragmentation; Western blot and RT-PCR for Bcl-2, Bax, caspase-3, PARP, and p-Akt; ROS/MDA/GSH/LDH and cytokine measurements\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal readouts (apoptosis, inflammation, signaling pathway), single lab, no direct ADM receptor blocking experiment to confirm mechanism\",\n      \"pmids\": [\"27212810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Under hypoxia, ADM expression in trophoblast cells is upregulated in an HIF-1α-dependent manner; treatment with ADM agonists reduces HIF-1α activity and enhances trophoblast invasion by altering MMP2, MMP9, and Rac1 expression; ADM also increases HLA-G expression under normoxia, while ADM2 or combined ADM/ADM2 treatment under hypoxia attenuates HLA-G expression.\",\n      \"method\": \"Trophoblast cell (HTR-8/SVneo) culture under hypoxia; siRNA knockdown; YC-1 HIF-1α inhibitor; invasion assay; RT-PCR and protein expression analysis of HIF-1α, MMP2, MMP9, Rac1, HLA-G, ADM, ADM2\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic (siRNA) and pharmacological (YC-1) perturbation with functional invasion readout, single lab, moderate mechanistic depth\",\n      \"pmids\": [\"32997116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADM knockdown in glioma cells enhances the suppressive effect of temozolomide (TMZ) on cell viability and promotes apoptosis; miR-1297 directly targets the ADM transcript (confirmed experimentally) and inhibits ADM expression; miR-1297 overexpression phenocopies ADM knockdown under TMZ treatment, and ADM knockdown partially rescues miR-1297 inhibition effects; mechanistically, ADM modulates Bax/Bcl-2 ratio, Akt phosphorylation, and Erk1/2 phosphorylation.\",\n      \"method\": \"CCK-8 cell viability; Annexin V apoptosis assay; JC-1 mitochondrial membrane potential; nude mouse tumor assay; immunoblotting for Akt, Erk1/2 phosphorylation and apoptosis proteins; bioinformatics prediction + experimental validation of miR-1297 targeting ADM\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function (ADM knockdown, miR-1297 OE) with defined cellular phenotypes and partial pathway placement; single lab\",\n      \"pmids\": [\"36183123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of ADM in human dental pulp stem cells (DPSCs) promotes cell cycle progression (increased G2/M ratio), reduces senescence markers (p53, P21WAF1, P16INK4A), and decreases ROS accumulation; mechanistically, ADM overexpression suppresses miR-152, which normally directly targets CCNA2 (Cyclin A2) to induce senescence; restoration of miR-152 reverses ADM's anti-senescence effects, and CCNA2 overexpression rescues the miR-152-induced senescence, placing ADM upstream of the miR-152/CCNA2 axis.\",\n      \"method\": \"Lentiviral ADM overexpression; transcriptome/microRNA profiling; luciferase reporter assay (miR-152 targeting CCNA2 3'-UTR implied); transfection of miR-152 mimic, pCDH-CCNA2, CCNA2 siRNA; senescence assays; flow cytometry for cell cycle; immunoblotting for p53, P21, P16\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (OE, KD, rescue experiments), pathway placement via epistasis (miR-152/CCNA2), single lab\",\n      \"pmids\": [\"36310381\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Adrenomedullin (ADM) is a multifunctional secreted peptide encoded by the ADM gene that acts through CGRP(8-37)-sensitive receptors (CRLR/RAMP complexes and L1-R) to produce vasodilation via endothelial nitric oxide–guanylyl cyclase and smooth muscle cAMP/PKA signaling; the ADM gene also encodes divergent vasoactive products (prodepin/proADM22-41 and adrenotensin/proADM153-185); within target tissues including adrenal zona glomerulosa, uterus, and Leydig cells, ADM suppresses aldosterone secretion, modulates contractility, and promotes cell survival via PI3K/Akt signaling; in stem cells, ADM inhibits senescence through suppression of the miR-152/CCNA2 axis; and in glioma cells, ADM modulates chemosensitivity through Akt/Erk1/2 and Bax/Bcl-2 pathways, with miR-1297 identified as an upstream regulator targeting ADM mRNA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Adrenomedullin (ADM) is a secreted multifunctional peptide that signals through CGRP(8-37)- and ADM(22-52)-sensitive receptors to regulate vascular tone, endocrine secretion, and cell survival across multiple tissues [#3, #6]. In the vasculature, ADM produces vasodilation through two parallel mechanisms in a single vessel: an endothelial receptor coupled to the nitric oxide\\u2013guanylyl cyclase axis and a smooth-muscle CGRP receptor coupled to cAMP/PKA, with responses blocked by CGRP(8-37) [#6]; ADM also drives LPS-induced hypotension in vivo through ADM(22-52)-sensitive rather than CGRP1 receptors [#4]. The ADM gene locus additionally encodes peptides with divergent vascular activity, including the vasodilatory prodepin (proADM22-41) and the vasoconstrictor adrenotensin (proADM153-185) [#0, #1]. In the human adrenal zona glomerulosa, ADM and its receptors (L1-R and CRLR/RAMP) form an autocrine/paracrine system in which ADM inhibits angiotensin-II- and K+-stimulated aldosterone secretion while promoting proliferation and suppressing apoptosis, with the antimineralocorticoid effect requiring both the C-terminal sequence (for binding) and the six-membered ring (for activation) [#3, #5]. ADM functions broadly as a cytoprotective and pro-survival factor: it protects Leydig cells from LPS-induced inflammation and apoptosis via PI3K/Akt signaling [#9], modulates glioma chemosensitivity through Akt/Erk1/2 and Bax/Bcl-2 pathways under control of miR-1297 [#11], and inhibits stem-cell senescence by suppressing the miR-152/CCNA2 axis [#12]. ADM expression is induced under hypoxia in an HIF-1\\u03b1-dependent manner and enhances trophoblast invasion [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that the ADM gene locus produces bioactive peptides beyond adrenomedullin itself, showing the prodepin fragment is a vasoactive product in its own right.\",\n      \"evidence\": \"In vivo hemodynamic measurement after i.v. injection of proADM22-41 across multiple anesthetized species\",\n      \"pmids\": [\"8196484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified for prodepin\", \"Activity species-specific, mechanism of the difference unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrated that the same gene encodes a peptide with opposite vascular action, defining the locus as a source of functionally divergent products.\",\n      \"evidence\": \"Isolated cat pulmonary artery ring contractility assay with adrenotensin (proADM153-185)\",\n      \"pmids\": [\"7637545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor characterized for adrenotensin\", \"Single vessel/species tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved which receptor class mediates ADM tissue effects by identifying CGRP(8-37)-sensitive binding sites distinct from CGRP receptors and showing functional modulation of uterine contraction.\",\n      \"evidence\": \"Radioligand competition binding and organ-bath contractility in rat uterus with CGRP(8-37) antagonism\",\n      \"pmids\": [\"9165042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular identity of the binding site not defined\", \"Functional consequence of pregnancy-associated 10-fold density increase not established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped the structural determinants of ADM action by separating receptor binding (C-terminal sequence) from receptor activation (ring structure) in the aldosterone-suppressing response.\",\n      \"evidence\": \"Structure-activity study with ADM fragments, radioligand binding, and aldosterone secretion assay in human adrenocortical cells, antagonized by ADM(22-52)\",\n      \"pmids\": [\"9877221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor subtype not molecularly resolved\", \"Downstream signaling pathway for aldosterone inhibition not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Distinguished the ADM-specific receptor from the CGRP1 receptor in vivo by showing ADM(22-52), but not CGRP(8-37), reverses endotoxic hypotension.\",\n      \"evidence\": \"Rat LPS endotoxemia model with selective ADM(22-52) and CGRP(8-37) antagonists\",\n      \"pmids\": [\"11210719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular source of ADM during endotoxemia not identified\", \"Downstream vasodilatory mediator not defined in this model\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined an autocrine/paracrine ADM system in human adrenal cortex coupling receptor expression to aldosterone suppression, proliferation, and anti-apoptosis.\",\n      \"evidence\": \"RT-PCR for pADM/L1-R/CRLR/RAMPs, protein detection, and functional secretion/proliferation/apoptosis assays with ADM(22-52) reversal in cultured ZG cells\",\n      \"pmids\": [\"11786920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathways linking ADM to proliferation/apoptosis not delineated\", \"Relative roles of L1-R vs CRLR/RAMP not separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Dissected the dual vasodilatory mechanism of ADM, separating an endothelial NO\\u2013guanylyl cyclase arm from a smooth-muscle cAMP/PKA arm in a single vessel.\",\n      \"evidence\": \"Human thymic artery reactivity with endothelial denudation and inhibitors of NOS, guanylyl cyclase, adenylyl cyclase, PKA, plus CGRP(8-37)\",\n      \"pmids\": [\"12529288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular receptor identity at each cell type not defined\", \"Relative in vivo contribution of the two arms not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked ADM and its receptor component to a pathological vascular state by showing coordinated upregulation of ADM and RAMP2 during VSMC calcification.\",\n      \"evidence\": \"Quantitative RT-PCR for ADM and RAMP2 mRNA and RIA for ADM protein in a \\u03b2-glycerophosphate VSMC calcification model\",\n      \"pmids\": [\"12668214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional perturbation of ADM in calcification\", \"Causal direction between calcification and ADM induction unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided functional genetic evidence that an upstream ADM SNP alters promoter activity and correlates with paroxetine response.\",\n      \"evidence\": \"Luciferase reporter assay of rs11042725 plus expression analysis and pharmacogenetic association\",\n      \"pmids\": [\"19636336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Association is correlational, no mechanistic link to antidepressant action\", \"Drug-specificity (paroxetine only) unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed ADM's cytoprotective action upstream of PI3K/Akt by showing it reduces inflammation and apoptosis in LPS-challenged Leydig cells.\",\n      \"evidence\": \"LPS cytotoxicity model with TUNEL, immunoblot for Bax/Bcl-2/caspase-3/PARP/p-Akt, ROS and cytokine measurements\",\n      \"pmids\": [\"27212810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ADM receptor-blocking experiment to confirm mechanism\", \"Whether Akt activation is necessary not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected ADM to hypoxic signaling and trophoblast biology, showing HIF-1\\u03b1-dependent induction and ADM-driven invasion via MMP/Rac1.\",\n      \"evidence\": \"HTR-8/SVneo hypoxia culture with siRNA, HIF-1\\u03b1 inhibitor YC-1, invasion assay, and expression analysis\",\n      \"pmids\": [\"32997116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating trophoblast effects not identified\", \"Opposing ADM/ADM2 effects on HLA-G mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ADM as a determinant of glioma chemosensitivity under miR-1297 control, modulating Akt/Erk1/2 and Bax/Bcl-2.\",\n      \"evidence\": \"ADM knockdown and miR-1297 overexpression with viability/apoptosis assays, xenografts, immunoblotting, and validated miR-1297\\u2013ADM targeting\",\n      \"pmids\": [\"36183123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and ligand requirement for the survival effect not tested\", \"Whether Akt/Erk1/2 changes are causal not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an anti-senescence role for ADM in stem cells by epistatic placement upstream of the miR-152/CCNA2 axis.\",\n      \"evidence\": \"Lentiviral ADM overexpression in DPSCs with miR-152 mimic/CCNA2 rescue, cell-cycle and senescence assays\",\n      \"pmids\": [\"36310381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADM suppresses miR-152 unknown\", \"Receptor dependence of the anti-senescence effect not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identities of the distinct ADM receptors operating across tissues and how a single peptide selects between vasodilatory, endocrine, and pro-survival signaling outputs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified receptor-to-pathway map across vascular, adrenal, and tumor contexts\", \"Mechanism of ADM coupling to miRNA networks unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}