{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPregnancy zone protein (PZP) is a member of the alpha‐macroglobulin family that functions in proteinase inhibition and proteostasis. PZP covalently binds proteinases and, like its well‐studied relative alpha‐2‐macroglobulin, facilitates the clearance of proteinase–inhibitor complexes via receptors such as the low‐density lipoprotein receptor-related protein (LRP), albeit with distinct binding affinities and receptor interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role as a broad‐spectrum protease inhibitor, PZP exhibits potent chaperone activity. It forms stable complexes with misfolded proteins—including early aggregates and monomeric forms of amyloid beta—thereby efficiently inhibiting their progression to insoluble fibrils. This function is thought to be critical in maintaining extracellular proteostasis, as evidenced by its dramatic up-regulation during pregnancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMultiple studies implicate PZP in Alzheimer’s disease (AD). Quantitative proteomic analyses have revealed that increased serum levels of PZP precede the clinical diagnosis of AD, with immunohistochemical studies further identifying robust PZP deposition within senile plaques and activated glial cells in the AD brain. These findings suggest that altered PZP expression may serve as an early biomarker for AD and link the protein to amyloid pathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant regulation of PZP is also associated with tumorigenesis. In hepatocellular carcinoma, for example, the gene encoding PZP is frequently hypermethylated and downregulated; experimental restoration of its expression in cancer cell lines markedly inhibits proliferation, invasion, and migration. Similar observations in the context of breast cancer predisposition suggest that PZP’s protease inhibitor function may also contribute to its tumor-suppressive properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDuring pregnancy, PZP plays a central immunomodulatory role. It is markedly upregulated in the maternal circulation and is expressed by extravillous trophoblasts, where it collaborates with placental factors such as Glycodelin A to suppress Th1-mediated immune responses. Notably, reduced placental PZP expression has been observed in disorders such as preeclampsia and HELLP syndrome, underscoring its importance in sustaining normal placental function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent investigations have also linked PZP to cellular senescence. Proteomic profiling of senescent cells has demonstrated a dramatic increase in the secretion of PZP, a feature of the senescence-associated secretory phenotype. Functional studies indicate that secreted PZP can promote senescence in recipient cells, suggesting that it may act as a positive regulator of cellular aging processes, particularly under conditions of DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G A Chiabrando, M A Vides, M C Sánchez "}, {"type": "b", "children": [{"type": "t", "text": "Differential binding properties of human pregnancy zone protein- and alpha2-macroglobulin-proteinase complexes to low-density lipoprotein receptor-related protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/abbi.2001.2659"}], "href": "https://doi.org/10.1006/abbi.2001.2659"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11811950"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11811950"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jordan H Cater, Janet R Kumita, Rafaa Zeineddine Abdallah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1817298116"}], "href": "https://doi.org/10.1073/pnas.1817298116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30850528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30850528"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Linda Ijsselstijn, Lennard J M Dekker, Christoph Stingl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum levels of pregnancy zone protein are elevated in presymptomatic Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteome Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/pr200270z"}], "href": "https://doi.org/10.1021/pr200270z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21879768"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21879768"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Diana A T Nijholt, Linda Ijsselstijn, Marcel M van der Weiden, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Genetic ablation of pregnancy zone protein promotes breast cancer progression by activating TGF-β/SMAD signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-020-05958-y"}], "href": "https://doi.org/10.1007/s10549-020-05958-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33057846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33057846"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Minhua Wu, Hui Lan, Zhongwei Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypermethylation of the PZP gene is associated with hepatocellular carcinoma cell proliferation, invasion and migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Open Bio (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/2211-5463.13093"}], "href": "https://doi.org/10.1002/2211-5463.13093"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33471436"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33471436"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sanja Löb, Aurelia Vattai, Christina Kuhn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pregnancy Zone Protein (PZP) is significantly upregulated in the decidua of recurrent and spontaneous miscarriage and negatively correlated to Glycodelin A (GdA)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Reprod Immunol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jri.2020.103267"}], "href": "https://doi.org/10.1016/j.jri.2020.103267"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33388716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33388716"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sanja Löb, Aurelia Vattai, Christina Kuhn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Pregnancy Zone Protein (PZP) is significantly downregulated in the placenta of preeclampsia and HELLP syndrome patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Reprod Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jri.2022.103663"}], "href": "https://doi.org/10.1016/j.jri.2022.103663"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35843132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35843132"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ziqi Hu, Mingzhu Zhang, Jiankun Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-Level Secretion of Pregnancy Zone Protein Is a Novel Biomarker of DNA Damage-Induced Senescence and Promotes Spontaneous Senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteome Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.jproteome.3c00403"}], "href": "https://doi.org/10.1021/acs.jproteome.3c00403"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37831546"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37831546"}]}]}]}