PMID- 30247915 OWN - NLM STAT- MEDLINE DCOM- 20181212 LR - 20200930 IS - 1530-6992 (Electronic) IS - 1530-6984 (Linking) VI - 18 IP - 10 DP - 2018 Oct 10 TI - Peroxidase-Mimicking Nanoassembly Mitigates Lipopolysaccharide-Induced Endotoxemia and Cognitive Damage in the Brain by Impeding Inflammatory Signaling in Macrophages. PG - 6417-6426 LID - 10.1021/acs.nanolett.8b02785 [doi] AB - Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (H(2)O(2)), a potentially toxic reactive oxygen species (ROS), is excessively produced by pro-inflammatory immune cells during the initial phases of sepsis and plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation. In the present study, we constructed a peroxide scavenger mannosylated polymeric albumin manganese dioxide (mSPAM) nanoassembly to catalyze the decomposition of H(2)O(2) responsible for the hyper-activation of pro-inflammatory immune cells. In a detailed manner, we investigated the role of mSPAM nanoassembly in modulating the expression and secretion of pro-inflammatory markers elevated in bacterial lipopolysaccharide (LPS)-mediated endotoxemia during sepsis. Through a facile one-step solution-phase approach, hydrophilic bovine serum albumin reduced manganese dioxide (BM) nanoparticles were synthesized and subsequently self-assembled with cationic mannosylated disulfide cross-linked polyethylenimine (mSP) to formulate mSPAM nanoassembly. In particular, we observed that the highly stable mSPAM nanoassembly suppressed HIF1alpha expression by scavenging H(2)O(2) in LPS-induced macrophage cells. Initial investigation revealed that a significant reduction of free radicals by the treatment of mSPAM nanoassembly has reduced the infiltration of neutrophils and other leukocytes in a local endotoxemia animal model. Furthermore, therapeutic studies in a systemic endotoxemia model demonstrated that mSPAM treatment reduced TNF-alpha and IL-6 inflammatory cytokines in serum, in turn circumventing organ damage done by the inflammatory macrophages. Interestingly, we also observed that the reduction of these inflammatory cytokines by mSPAM nanoassembly further prevented IBA-1 immuno-positive microglial cell activation in the brain and consequently improved the cognitive function of the animals. Altogether, the administration of mSPAM nanoassembly scavenged H(2)O(2) and suppressed HIF1alpha expression in LPS-stimulated macrophages and thereby inhibited the progression of local and systemic inflammation as well as neuroinflammation in an LPS-induced endotoxemia model. This mSPAM nanoassembly system could serve as a potent anti-inflammatory agent, and we further anticipate its successful application in treating various inflammation-related diseases. FAU - Rajendrakumar, Santhosh Kalash AU - Rajendrakumar SK AD - Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University , Chonnam National University Medical School , Gwangju 61469 , Republic of Korea. FAU - Revuri, Vishnu AU - Revuri V AD - Department of Green Bioengineering , Korea National University of Transportation , Chungju 27469 , Republic of Korea. FAU - Samidurai, Manikandan AU - Samidurai M AD - Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University , Chonnam National University Medical School , Gwangju 61469 , Republic of Korea. AD - NeuroMedical Convergence Lab, Biomedical Research Institute , Chonnam National University Hospital , Jebong-ro, Gwangju 501-757 , Republic of Korea. FAU - Mohapatra, Adityanarayan AU - Mohapatra A AD - Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University , Chonnam National University Medical School , Gwangju 61469 , Republic of Korea. FAU - Lee, Jae Hyuk AU - Lee JH AD - Department of Pathology , Chonnam National University Hwasun Hospital, Chonnam National University Medical School , Hwasun 58128 , Republic of Korea. FAU - Ganesan, Palanivel AU - Ganesan P AD - Nanotechnology Research Center, Department of Biotechnology and Applied Life Science, College of Biomedical and Health Science , Konkuk University GLOCAL Campus , Chungju 380-701 , Republic of Korea. FAU - Jo, Jihoon AU - Jo J AD - NeuroMedical Convergence Lab, Biomedical Research Institute , Chonnam National University Hospital , Jebong-ro, Gwangju 501-757 , Republic of Korea. FAU - Lee, Yong-Kyu AU - Lee YK AUID- ORCID: 0000-0001-8336-3592 AD - Department of Green Bioengineering , Korea National University of Transportation , Chungju 27469 , Republic of Korea. FAU - Park, In-Kyu AU - Park IK AUID- ORCID: 0000-0003-1616-9153 AD - Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University , Chonnam National University Medical School , Gwangju 61469 , Republic of Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180927 PL - United States TA - Nano Lett JT - Nano letters JID - 101088070 RN - 0 (Albumins) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Lipopolysaccharides) RN - 0 (Manganese Compounds) RN - 0 (Oxides) RN - 0 (Peroxides) RN - 0 (Reactive Oxygen Species) RN - 0 (Tumor Necrosis Factor-alpha) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 1.11.1.7 (Peroxidase) RN - TF219GU161 (manganese dioxide) SB - IM MH - Albumins/chemistry/pharmacology MH - Animals MH - Brain/drug effects/metabolism/pathology MH - Cognitive Dysfunction/chemically induced/*drug therapy/genetics/pathology MH - Endotoxemia/chemically induced/*drug therapy/genetics MH - Gene Expression Regulation/drug effects MH - Humans MH - Hydrogen Peroxide/toxicity MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics MH - Inflammation/chemically induced/*drug therapy/genetics/pathology MH - Lipopolysaccharides/toxicity MH - Macrophages/drug effects/pathology MH - Manganese Compounds/chemistry/pharmacology MH - Mice MH - Nanocomposites/*administration & dosage/chemistry MH - Oxidative Stress/drug effects MH - Oxides/chemistry/pharmacology MH - Peroxidase/chemistry/genetics MH - Peroxides/chemistry/pharmacology MH - Reactive Oxygen Species/toxicity MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/genetics OTO - NOTNLM OT - Endotoxemia OT - bovine serum albumin OT - inflammation OT - lipopolysaccharide OT - manganese dioxide EDAT- 2018/09/25 06:00 MHDA- 2018/12/13 06:00 CRDT- 2018/09/25 06:00 PHST- 2018/09/25 06:00 [pubmed] PHST- 2018/12/13 06:00 [medline] PHST- 2018/09/25 06:00 [entrez] AID - 10.1021/acs.nanolett.8b02785 [doi] PST - ppublish SO - Nano Lett. 2018 Oct 10;18(10):6417-6426. doi: 10.1021/acs.nanolett.8b02785. Epub 2018 Sep 27.