title: Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function.
abstract: Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.
authors.affiliation: Second Hospital of HeBei Medical University, Shijiazhuang 050000, PR China. Electronic address: biwei@hb2h.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Bi
authors.affiliation: Second Hospital of HeBei Medical University, Shijiazhuang 050000, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Chemistry and Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Second Hospital of HeBei Medical University, Shijiazhuang 050000, PR China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Hou
authors.affiliation: Second Hospital of HeBei Medical University, Shijiazhuang 050000, PR China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Bammert
authors.affiliation: Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jockusch
authors.affiliation: Marquette General Heart and Vascular Institute, Marquette General Hospital, Marquette, MI 49855, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Legalley
authors.affiliation: Department of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane WA 99202, USA. Electronic address: mike.gibson@wsu.edu.
authors.forename: K
authors.initials: K
authors.lastname: Michael Gibson
authors.affiliation: Department of Chemistry and Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA. Electronic address: lanrong@mtu.edu.
authors.forename: Lanrong
authors.initials: L
authors.lastname: Bi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D001241:Aspirin / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D007421:Intestine, Small / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D003497:Cyclic N-Oxides; D007211:Indoles; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D001241:Aspirin
keywords: Anti-inflammation activity; Indole-TEMPO conjugates; Ischemia/reperfusion injury; Mitochondrial function; Oxidative damage