{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProstaglandin E synthases (PTGES) comprise a family of terminal enzymes—including the membrane‐bound isoforms (mPGES‐1 and mPGES‐2) and the cytosolic form (cPGES)—that catalyze the isomerization of the cyclooxygenase (COX) product PGH₂ into the bioactive lipid mediator prostaglandin E₂ (PGE₂). This conversion is central to maintaining tissue homeostasis as well as to driving pathological processes. In various cell types, PTGES enzymes are coupled with both constitutive (COX‐1) and inducible (COX‐2) cyclooxygenases, and their intrinsic catalytic properties, cofactor requirements (e.g. glutathione dependence) and even their structural organization (e.g. trimer formation) have been characterized using recombinant expression systems and electron crystallography. Furthermore, studies in human fetal membranes and endothelial cells demonstrate that both constitutive and stimulus‐inducible forms contribute to an immediate as well as delayed PGE₂ generation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nExpression of PTGES is tightly regulated by a variety of inflammatory and stress‐related signals. Proinflammatory cytokines such as interleukin‐1β, as well as environmental triggers like cigarette smoke and hypoxia, stimulate PTGES gene transcription via pathways involving NF‐κB, HIF‐1α and other transcription factors. In diverse cell types—including synovial fibroblasts, chondrocytes, endothelial cells, and even specialized cells in hair follicles or aortic tissue—epigenetic mechanisms (e.g. histone methylation and DNA hypomethylation) and regulatory circuits mediated by nuclear receptors (for example, PPARγ) further modulate PTGES expression. Such regulation is pivotal not only to orchestrate acute inflammatory responses (as seen in rheumatoid arthritis, osteoarthritis and atherosclerosis) but also to influence cellular phenotypes in contexts ranging from tissue repair to airway reactivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "34"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOwing to its central role in PGE₂ production, PTGES has emerged as a promising therapeutic target in a spectrum of diseases including various human cancers (colon, prostate, hepatocellular carcinoma, head and neck and gliomas), as well as inflammatory disorders and vascular pathologies. Selective pharmacological inhibitors—including small molecules and natural products—as well as genetic knockdown strategies have been shown to diminish PTGES activity, lower PGE₂ synthesis and thereby reduce tumor cell proliferation, angiogenesis and inflammatory cell recruitment. Such interventions have demonstrated efficacy in preclinical models by impeding tumor growth and vascular remodeling, underscoring the therapeutic potential of specifically modulating PTGES activity while sparing upstream COX functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "45"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "W Uracz, D Uracz, R Olszanecki, et al. 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