{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nP‐glycoprotein (P‐gp), a well‐established ATP‐dependent efflux transporter encoded by the MDR1 gene, is fundamentally involved in drug disposition and multidrug resistance. Studies have demonstrated that herbal agents such as St John’s wort potently induce P‐gp activity, thereby lowering the plasma concentrations of numerous co‐administered drugs. Moreover, in cancer models, certain anti‐tumor agents benefit from P‐gp–mediated lysosomal targeting that enhances their cytotoxicity in multidrug‐resistant cells. Additional investigations indicate that P‐gp may also facilitate the glycosylation of ceramide by translocating glucosylceramide across the Golgi membrane, a process relevant for detoxifying pro‐apoptotic metabolites. Structural and dynamic analyses further reveal that ATP binding drives conformational flexibility in P‐gp, while its over‐expression in acute myeloid leukemia correlates with poor clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic polymorphisms in the MDR1 gene also appear to influence P‐gp function and consequently affect drug penetration, especially across the blood–brain barrier. Investigations into neuropsychiatric conditions and movement disorders such as tardive dyskinesia have revealed that specific P‐gp alleles may alter central nervous system drug exposure and thereby influence both therapeutic efficacy and adverse effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a distinct vein, another protein product known as PGP functions as a phosphoglycolate phosphatase—a key enzyme for metabolite repair and lipid metabolism. This enzymatic PGP is involved in controlling intracellular glycerol-3-phosphate levels and modulates signaling cascades, such as those triggered by epidermal growth factor. Genetic studies have further implicated variants in this PGP gene as potential modulators of human longevity through their influence on metabolic processes and the clearance of deleterious side-products."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditionally, the designation “PGP 9.5” refers to a ubiquitously expressed protein used as a sensitive neural marker. Immunohistochemical studies employing PGP 9.5 have highlighted altered nerve fiber density in the skin lesions of disorders such as hidradenitis suppurativa, suggesting a potential contribution of neural elements to the pathogenesis of inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shufeng Zhou, Eli Chan, Shen-Quan Pan, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes multidrug resistance by a novel mechanism involving the hijacking of lysosomal P-glycoprotein (Pgp)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.631283"}], "href": "https://doi.org/10.1074/jbc.M114.631283"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25720491"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25720491"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mariana G García, Laura D Alaniz, Rosalía I Cordo Russo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI3K/Akt inhibition modulates multidrug resistance and activates NF-kappaB in murine lymphoma cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.leukres.2008.06.010"}], "href": "https://doi.org/10.1016/j.leukres.2008.06.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18640717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18640717"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Julie Turzanski, Martin Grundy, Shilli Shang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "P-glycoprotein is implicated in the inhibition of ceramide-induced apoptosis in TF-1 acute myeloid leukemia cells by modulation of the glucosylceramide synthase pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Hematol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.exphem.2004.10.005"}], "href": "https://doi.org/10.1016/j.exphem.2004.10.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15661399"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15661399"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Liadys Mora Lagares, Yunierkis Pérez-Castillo, Marjana Novič "}, {"type": "b", "children": [{"type": "t", "text": "Exploring the dynamics of the ABCB1 membrane transporter P-glycoprotein in the presence of ATP and active/non-active compounds through molecular dynamics simulations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Toxicology (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tox.2024.153732"}], "href": "https://doi.org/10.1016/j.tox.2024.153732"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38272384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38272384"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Maciej Machaczka, Björn Engelbrekt Wahlin, Beata Piatkowska-Jakubas, et al. 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