{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProenkephalin (PENK) encodes a precursor for the endogenous enkephalin peptides that serve as natural opioids modulating nociception, cellular growth, apoptosis, and tumor suppression. In pancreatic neoplasia, for example, aberrant hypermethylation of the ppENK promoter is frequently observed and progressively increases with precursor lesion grade, thereby contributing to pancreatic carcinogenesis; similar epigenetic silencing has been linked to cigarette‐smoking–related pancreatic cancer and can be reversed by demethylating agents that restore ppENK expression and tumor‐suppressor functions. Moreover, PENK may directly influence tumor cell behavior by enhancing apoptosis and modulating cell migration in osteosarcoma cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neural and pain‐related contexts, PENK plays a central role in opioid neurotransmission and analgesia. Genetic deletion of the voltage‐gated sodium channel Nav1.7 leads to marked upregulation of PENK mRNA and increased production of met-enkephalin, an effect that underlies the analgesic phenotype seen in both mice and humans. Furthermore, genetic polymorphisms within PENK have been associated with vulnerability to opioid dependence and altered reward circuitry; imaging genetics studies indicate that such variations modulate key regions involved in error-related processing in substance use disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical neuronal roles, PENK is broadly expressed in non‐neuronal tissues where its gene product is processed and released to exert paracrine and endocrine functions. Robust quantitative assays have established that stable PENK fragments—such as PENK A 119–159 and the enkephalin-containing Peptide F—are present in circulation and cerebrospinal fluid. In peripheral tissues like the heart, skeletal muscle, and intestinal epithelium, PENK-derived enkephalins may mediate cardioprotection during ischemia or exercise and modulate immune cell activity. Alterations in circulating PENK levels are also apparent in conditions marked by stress or altered metabolic states, including exercise training adaptations and anorexia nervosa, highlighting its role in systemic homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_fs", "start_ref": "16", "end_ref": "18"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, circulating PENK has emerged as a promising biomarker with prognostic implications in diverse conditions. Elevated PENK levels have been correlated with greater injury severity and poorer outcomes in acute neurological insults such as intracerebral hemorrhage, traumatic brain injury, and ischemic stroke. In parallel, because PENK is freely filtered by the kidneys and correlates with glomerular filtration rate and albumin excretion, it is being evaluated as an early indicator of acute kidney injury and chronic kidney dysfunction—even within heart failure populations. Conformational studies of proenkephalin further reveal that its precise tertiary structure governs ordered proteolytic processing necessary for generating bioactive enkephalin peptides; notably, PENK-derived peptides have also been detected in the cerebrospinal fluid of moyamoya disease patients, suggesting additional neuromodulatory roles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Noriyoshi Fukushima, Norihiro Sato, Takashi Ueki, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients: in relation to cigarette smoking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pancreas (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/01.mpa.0000246665.68869.d4"}], "href": "https://doi.org/10.1097/01.mpa.0000246665.68869.d4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17198183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17198183"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xiaoling Xuei, Leah Flury-Wetherill, Laura Bierut, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The opioid system in alcohol and drug dependence: family-based association study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet B Neuropsychiatr Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.b.30531"}], "href": "https://doi.org/10.1002/ajmg.b.30531"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17503481"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17503481"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "N McTavish, L A Copeland, M K Saville, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-kappaB- and p53-regulated gene targets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.cdd.4402172"}], "href": "https://doi.org/10.1038/sj.cdd.4402172"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17599100"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17599100"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hao Zhang, Liang Chen, He-Qi Bu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of emodin on the demethylation of tumor-suppressor genes in pancreatic cancer PANC-1 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2015.3914"}], "href": "https://doi.org/10.3892/or.2015.3914"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25891176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25891176"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Hai-Ping Zhang, Zi-Liang Yu, Bing-Bing Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PENK inhibits osteosarcoma cell migration by activating the PI3K/Akt signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Orthop Surg Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13018-020-01679-6"}], "href": "https://doi.org/10.1186/s13018-020-01679-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32334633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32334633"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Gerene M Denning, Laynez W Ackermann, Thomas J Barna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proenkephalin expression and enkephalin release are widely observed in non-neuronal tissues."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2007.11.004"}], "href": "https://doi.org/10.1016/j.peptides.2007.11.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18082911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18082911"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Andrej Nikoshkov, Katarina Drakenberg, Xinyu Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Opioid neuropeptide genotypes in relation to heroin abuse: dopamine tone contributes to reversed mesolimbic proenkephalin expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0710902105"}], "href": "https://doi.org/10.1073/pnas.0710902105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18184800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18184800"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Andrea Ernst, Katharina Buerger, Oliver Hartmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Midregional Proenkephalin A and N-terminal Protachykinin A are decreased in the cerebrospinal fluid of patients with dementia disorders and acute neuroinflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroimmunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jneuroim.2010.02.004"}], "href": "https://doi.org/10.1016/j.jneuroim.2010.02.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20207019"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20207019"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Deike Weiss, Carmen Infante-Duarte, Harriet Salbach-Andrae, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Preproenkephalin expression in peripheral blood mononuclear cells of acutely underweight and recovered patients with anorexia nervosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuropsychobiology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000318571"}], "href": "https://doi.org/10.1159/000318571"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20628265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20628265"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Benjamin B Gelman, Joshua G Lisinicchia, Tianshen Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prefrontal dopaminergic and enkephalinergic synaptic accommodation in HIV-associated neurocognitive disorders and encephalitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroimmune Pharmacol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11481-012-9345-4"}], "href": "https://doi.org/10.1007/s11481-012-9345-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22391864"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22391864"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Didier Jutras-Aswad, Michelle M Jacobs, Georgia Yiannoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cannabis-dependence risk relates to synergism between neuroticism and proenkephalin SNPs associated with amygdala gene expression: case-control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0039243"}], "href": "https://doi.org/10.1371/journal.pone.0039243"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22745721"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22745721"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Scott J Moeller, Nicasia Beebe-Wang, Kristin E Schneider, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of an opioid (proenkephalin) polymorphism on neural response to errors in health and cocaine use disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Brain Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbr.2015.07.004"}], "href": "https://doi.org/10.1016/j.bbr.2015.07.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26164485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26164485"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "William J Kraemer, Maren S Fragala, Wendy R H Beijersbergen van Henegouwen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Responses of proenkephalin Peptide F to aerobic exercise stress in the plasma and white blood cell biocompartments."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2013.01.013"}], "href": "https://doi.org/10.1016/j.peptides.2013.01.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23395721"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23395721"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Antonio Malvasi, Carlo Cavallotti, Giuseppe Nicolardi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The opioid neuropeptides in uterine fibroid pseudocapsules: a putative association with cervical integrity in human reproduction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gynecol Endocrinol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/09513590.2013.824958"}], "href": "https://doi.org/10.3109/09513590.2013.824958"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23937196"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23937196"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "William H DuPont, William J Kraemer, Bradley C Nindl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The effects of different exercise training modalities on plasma proenkephalin Peptide F in women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2017.02.006"}], "href": "https://doi.org/10.1016/j.peptides.2017.02.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28263851"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28263851"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Xin-Gang Yang, Hai-Long An, Jian-Min Zhang "}, {"type": "b", "children": [{"type": "t", "text": "Neuropeptide proenkephalin A is associated with in-hospital mortality in patients with acute intracerebral hemorrhage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2014.06.005"}], "href": "https://doi.org/10.1016/j.peptides.2014.06.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24937654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24937654"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Jian-Bo Gao, Wei-Dong Tang, Xiao Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prognostic value of neuropeptide proenkephalin A in patients with severe traumatic brain injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2014.06.006"}], "href": "https://doi.org/10.1016/j.peptides.2014.06.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24937655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24937655"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Kornelis J J van Hateren, Gijs W D Landman, Jarinke F H Arnold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum Proenkephalin A Levels and Mortality After Long-Term Follow-Up in Patients with Type 2 Diabetes Mellitus (ZODIAC-32)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0133065"}], "href": "https://doi.org/10.1371/journal.pone.0133065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26218633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26218633"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Kinya Yokoyama, Mikio Maruwaka, Kazuhiro Yoshikawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevation of Proenkephalin 143-183 in Cerebrospinal Fluid in Moyamoya Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World Neurosurg (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.wneu.2017.09.204"}], "href": "https://doi.org/10.1016/j.wneu.2017.09.204"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29030229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29030229"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Lyanne M Kieneker, Oliver Hartmann, Andreas Bergmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proenkephalin and risk of developing chronic kidney disease: the Prevention of Renal and Vascular End-stage Disease study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomarkers (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/1354750X.2018.1443514"}], "href": "https://doi.org/10.1080/1354750X.2018.1443514"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29466891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29466891"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Johanna E Emmens, Jozine M Ter Maaten, Kevin Damman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Heart Fail (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCHEARTFAILURE.118.005544"}], "href": "https://doi.org/10.1161/CIRCHEARTFAILURE.118.005544"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31091993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31091993"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Philipp Gruber, Felix Fluri, Juliane Schweizer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proenkephalin A Adds No Incremental Prognostic Value After Acute Ischemic Stroke."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Appl Thromb Hemost (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1076029619895318"}], "href": "https://doi.org/10.1177/1076029619895318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31973568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31973568"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Weiya D Lu, Tong Liu, Sheng Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prohormone proenkephalin possesses differential conformational features of subdomains revealed by rapid H-D exchange mass spectrometry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/pro.2000"}], "href": "https://doi.org/10.1002/pro.2000"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22102294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22102294"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Michael S Minett, Vanessa Pereira, Shafaq Sikandar, et al. 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