{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPlatelet basic protein (PPBP) is a precursor stored in platelet α‐granules that, upon proteolytic processing, generates several bioactive peptides—including connective tissue–activating peptide III (CTAP‐III), neutrophil‐activating peptide‐2 (NAP‐2/CXCL7) and β‐thromboglobulin—that mediate diverse immune and inflammatory responses. PPBP‐derived peptides exhibit potent antibacterial activity and rapid bactericidal effects against a range of pathogens, thereby contributing to innate host defense."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, these peptides modulate neutrophil behavior by promoting cell adhesion and transmigration through their interactions with CXCR receptors; in some settings, limited proteolysis of an inactive precursor can generate a chemokine with enhanced neutrophil‐stimulating capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Structural studies have shown that proteolytic cleavage of the high molecular weight precursor yields the lower–molecular weight β‐thromboglobulin fragment, underscoring the importance of post‐translational processing in regulating PPBP bioactivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond platelets, PPBP and its processed peptides are expressed by other cell types such as monocytes and mast cells, especially under inflammatory conditions. Glucocorticoids and anti‐inflammatory cytokines can down‐regulate PPBP expression in monocytes, suggesting a role in controlling inflammatory mediator production"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In the skin, activated mast cells efficiently convert CTAP‐III into the potent chemoattractant NAP‐2, thereby influencing leukocyte recruitment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the bone marrow microenvironment, stromal stimulation of monocytes leads to CXCL7 expression, which in turn can negatively regulate megakaryocyte colony formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, NAP‐2 has been implicated in atherogenesis by affecting endothelial function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", while reduced serum levels of CXCL7 and related chemokines have been observed in advanced myelodysplastic syndromes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Chemotaxis studies in mesenchymal stem cells further reflect the role of PPBP‐derived molecules in tissue repair and regenerative processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant PPBP expression and processing have been linked to a wide range of pathological conditions. Thermal inflammatory injury leads to enhanced release of β‐thromboglobulin from platelets"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and altered levels of β‐thromboglobulin and platelet factor 4 serve as prognostic indicators in infections such as SARS"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and in autoinflammatory disorders like familial Mediterranean fever."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Elevated CXCL7 signaling via CXCR2 is associated with aggressive tumor relapse in metastatic colorectal cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while in Alzheimer’s disease, differential expression of platelet basic protein has been detected, highlighting its potential as a peripheral biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In cholangiocarcinoma, CXCL7 overexpression correlates with tumor invasion and poor patient prognosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", and distinct chemokine heterodimerization involving CXCL7 may further fine‐tune its biological activities"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " PPBP‐derived peptides are also being explored as diagnostic markers in non–small cell lung cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "and renal cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", while a panel that includes PPBP has demonstrated efficacy for detecting growth hormone deficiency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Interestingly, CXCL7 deficiency in knockout mouse models produces ossification pathologies resembling human conditions such as OPLL"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and transcript alterations in PF4 and β‐thromboglobulin mRNAs are emerging as biomarkers in thrombotic disorders like deep vein thrombosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "and recurrent pregnancy loss."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " In systemic mastocytosis, increased CXCL7 levels correlate with disease severity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", and in postmenopausal women, PPBP is being evaluated as a part of a synergistic biomarker strategy for coronary heart disease risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " Finally, in neuroinflammatory conditions such as neuromyelitis optica, CXCL7 aggravates astrocyte injury and demyelination"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": ", while elevated β‐thromboglobulin levels have been documented in rheumatoid arthritis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Moreover, PPBP‐derived peptides modulate fibroblast proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "and are subject to regulated proteolysis that influences their downstream functions, including effects on coagulation and tissue remodeling.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J Krijgsveld, S A Zaat, J Meeldijk, et al. 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