{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:44:22Z","timestamp":1793065462403,"version":"4.5.0"},"reference-count":56,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Fundacao de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo (FAPESP)","doi-asserted-by":"publisher","award":["2017\/21052-0"],"award-info":[{"award-number":["2017\/21052-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Fundacao de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo (FAPESP)","doi-asserted-by":"publisher","award":["SNSF 310030_188525"],"award-info":[{"award-number":["SNSF 310030_188525"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Fundacao de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo (FAPESP)","doi-asserted-by":"publisher","award":["2018\/18418-5"],"award-info":[{"award-number":["2018\/18418-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swiss National Research Foundation","award":["2017\/21052-0"],"award-info":[{"award-number":["2017\/21052-0"]}]},{"name":"Swiss National Research Foundation","award":["SNSF 310030_188525"],"award-info":[{"award-number":["SNSF 310030_188525"]}]},{"name":"Swiss National Research Foundation","award":["2018\/18418-5"],"award-info":[{"award-number":["2018\/18418-5"]}]},{"name":"Leading House to the Latin American Region (Switzerland)","award":["2017\/21052-0"],"award-info":[{"award-number":["2017\/21052-0"]}]},{"name":"Leading House to the Latin American Region (Switzerland)","award":["SNSF 310030_188525"],"award-info":[{"award-number":["SNSF 310030_188525"]}]},{"name":"Leading House to the Latin American Region (Switzerland)","award":["2018\/18418-5"],"award-info":[{"award-number":["2018\/18418-5"]}]},{"name":"FAPESP","award":["2017\/21052-0"],"award-info":[{"award-number":["2017\/21052-0"]}]},{"name":"FAPESP","award":["SNSF 310030_188525"],"award-info":[{"award-number":["SNSF 310030_188525"]}]},{"name":"FAPESP","award":["2018\/18418-5"],"award-info":[{"award-number":["2018\/18418-5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Prior studies demonstrate the activation of poly-(ADP-ribose) polymerase 1 (PARP1) in various pathophysiological conditions, including sepsis. We have assessed the effect of olaparib, a clinically used PARP1 inhibitor, on the responses of human peripheral blood leukocytes (PBMCs) obtained from healthy volunteers in response to challenging with live bacteria, bacterial lipopolysaccharide (LPS), or oxidative stress (hydrogen peroxide, H2O2). The viability of PBMCs exposed to olaparib or to the earlier generation PARP inhibitor PJ-34 (0.1\u20131000 \u00b5M) was monitored using Annexin V and 7-aminoactinomycin D. To evaluate the effects of olaparib on the expression of PARP1 and its effects on protein PARylation, PBMCs were stimulated with Staphylococcus aureus with or without olaparib (1\u201310 \u03bcM). Changes in cellular levels of nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP), as well as changes in mitochondrial membrane potential (MMP), were measured in PBMCs exposed to H2O2. Bacterial killing was evaluated in PBMCs and polymorphonuclear leukocytes (PMNs) incubated with S. aureus. Cytokine production was measured in supernatants using a cytometric bead array. Reactive oxygen species (ROS), nitric oxide (NO) production, and phagocytic activity of monocytes and neutrophils were measured in whole blood. For ROS and NO production, samples were incubated with heat-killed S. aureus; phagocytic activity was assessed using killed Escherichia coli conjugated to FITC. Olaparib (0.1\u2013100 \u00b5M) did not adversely affect lymphocyte viability. Olaparib also did not interfere with PARP1 expression but inhibits S. aureus-induced protein PARylation. In cells challenged with H2O2, olaparib prevented NAD+ and ATP depletion and attenuated mitochondrial membrane depolarization. LPS-induced production of TNF-\u03b1, MIP-1\u03b1, and IL-10 by PBMCs was also reduced by olaparib. Monocytes and neutrophils displayed significant increases in the production of ROS and NO after stimulation with S. aureus and phagocytic (E. coli) and microbicidal activity, and these responses were not suppressed by olaparib. We conclude that, at clinically relevant concentrations, olaparib exerts cytoprotective effects and modulates inflammatory cytokine production without exerting adverse effects on the cells\u2019 ability to phagocytose or eradicate pathogens. The current data support the concept of repurposing olaparib as a potential experimental therapy for septic shock.<\/jats:p>","DOI":"10.3390\/biom12060788","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T09:42:32Z","timestamp":1654335752000},"page":"788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effects of the PARP Inhibitor Olaparib on the Response of Human Peripheral Blood Leukocytes to Bacterial Challenge or Oxidative Stress"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6807-9881","authenticated-orcid":false,"given":"Sidneia Sousa","family":"Santos","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04023, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2874-520X","authenticated-orcid":false,"given":"Milena Karina Col\u00f3","family":"Brunialti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04023, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6935-290X","authenticated-orcid":false,"given":"Larissa de Oliveira Cavalcanti Peres","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04023, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-973X","authenticated-orcid":false,"given":"Ana Maria Alvim","family":"Liberatore","sequence":"additional","affiliation":[{"name":"Discipline of Operative Technique and Experimental Surgery, Department of Surgery, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04023, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan Hong Jun","family":"Koh","sequence":"additional","affiliation":[{"name":"Discipline of Operative Technique and Experimental Surgery, Department of Surgery, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04023, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Martins","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Garcia","family":"Soriano","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Research, Faculty of Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 05403, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3110-4235","authenticated-orcid":false,"given":"Csaba","family":"Szabo","sequence":"additional","affiliation":[{"name":"Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1149-4598","authenticated-orcid":false,"given":"Reinaldo","family":"Salom\u00e3o","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04023, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s41573-020-0076-6","article-title":"Poly(ADP-ribose) polymerase inhibition: Past, present and future","volume":"19","author":"Curtin","year":"2020","journal-title":"Nat. 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