tempo and Inflammation

Renal fibrosis is a common pathological symptom of chronic kidney disease (CKD). Many studies support that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are implicated in the pathogenesis of CKD. In our study, we investigated the benefits and underlying mechanisms of Mito-TEMPO on renal fibrosis in 5/6 nephrectomy mice.. Mice were randomly divided into five groups as follows: control group, CKD group, CKD + Mito-TEMPO (1 mg·kg. Impaired renal function and renal fibrosis were significantly improved by Mito-TEMPO treatment. Furthermore, inflammation cytokines, profibrotic factors, oxidative stress markers, mitochondrial dysfunction, and ER stress were all increased in the CKD group. However, these effects were significantly ameliorated in the Mito-TEMPO treatment group.. Mito-TEMPO ameliorates renal fibrosis by alleviating mitochondrial dysfunction and endoplasmic reticulum stress possibly through the Sirt3-SOD2 pathway, which sheds new light on prevention of renal fibrosis in chronic kidney disease.

Topics: Animals; Cyclic N-Oxides; Endoplasmic Reticulum Stress; Fibrosis; Inflammation; Kidney Diseases; Male; Mice; Mitochondria

Growing evidence suggests that inflammatory processes may be involved in depressive disorders. Inflammation is known to induce mitochondrial dysfunction in the nervous system. However, whether mitochondrial dysfunction is involved in the occurrence of inflammation-induced depressive-like behavior remains to be investigated. The present study aims to firstly, clarify whether mitochondrial dysfunction contributes to lipopolysaccharide (LPS)-induced depression-like behavior in mice and secondly, determine whether the anti-oxidant resveratrol alleviates inflammation-induced depressive-like behavior through the prevention of mitochondrial dysfunction in the hippocampus. We found that the administration of LPS led to mitochondrial oxidative stress and dysfunction as evidenced by increased mitochondrial superoxide production and decreased mitochondrial membrane potential and ATP production in the hippocampus. These effects were attenuated by intracerebroventricular (ICV) Injection of the mitochondria-targeted antioxidant Mito-TEMPO. LPS-treated mice displayed depressive-like behaviors as evidenced by reduced sucrose preference, increased immobility time and decreased struggling time in the forced swimming test. Both Mito-TEMPO and resveratrol could significantly improve the LPS-induced depressive-like behaviors. In contrast, ICV Injection of rotenone, the mitochondrial respiratory chain inhibitor, induced mitochondrial oxidative stress and dysfunction in the hippocampus, and resulted in depressive-like behaviors. Moreover, resveratrol alleviated the LPS-induced apoptosis of hippocampal cells. The antidepressant action of resveratrol was accomplished through the interruption of mitochondrial oxidative stress and the prevention of cell apoptosis in the hippocampus. These findings support the potential for resveratrol as a possible pharmacological agent for depression treatment in the future.

Topics: Animals; Antidepressive Agents; Antioxidants; Apoptosis; Cyclic N-Oxides; Depression; Disease Models, Animal; Food Preferences; Hippocampus; Inflammation; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred ICR; Mitochondria; Resveratrol; Rotenone; Stilbenes; Swimming; Uncoupling Agents

Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone. Mitochondrial reactive oxygen species (mtROS) have been proposed to regulate the activation of the inflammatory response by the innate immune system. However, the role of mtROS in modulating the response of human gingival fibroblasts (HGFs) to immune stimulation by lipopolysaccharides (LPS) has yet to be fully elucidated. Here, we showed that LPS from Porphyromonas gingivalis stimulated HGFs to increase mtROS production, which could be inhibited by treatment with a mitochondrial-targeted exogenous antioxidant (mito-TEMPO) or transfection with manganese superoxide dismutase (MnSOD). A time-course study revealed that an increase in the concentration of mtROS preceded the expression of inflammatory cytokines in HGFs. Mito-TEMPO treatment or MnSOD transfection also significantly prevented the LPS-induced increase of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. Furthermore, suppressing LPS-induced mtROS generation inhibited the activation of p38, c-Jun N-terminal kinase, and inhibitor of nuclear factor-κB kinase, as well as the nuclear localization of nuclear factor-κB. These results demonstrate that mtROS generation is a key signaling event in the LPS-induced pro-inflammatory response of HGFs.

Topics: Cyclic N-Oxides; Cytokines; Electrophoretic Mobility Shift Assay; Fibroblasts; Gingiva; Humans; I-kappa B Proteins; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mitochondria; Models, Biological; Reactive Oxygen Species; Superoxide Dismutase

The ultimate objective of nanoparticle-based therapy is to functionalize nanomedicines in a micro-disease environment without any side effects. Here, we reveal that our pH-responsive nitroxide radical-containing nanoparticles (RNP(pH)) disintegrate within the renal acidic lesion and act as scavengers of reactive oxygen species (ROS), leading to a relief of acute kidney injury (AKI). RNP(pH) was prepared using amphiphilic block copolymers possessing 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moieties via amine linkage as a side chain of the hydrophobic segment. The self-assembled RNP(pH) disintegrated at pH below 7.0 because of a protonation of the amino groups in the hydrophobic core of the nanoparticles, thereby resulting in an improvement in ROS scavenging activity. Using a renal ischemia-reperfusion AKI model in mice, the therapeutic effect of RNP(pH) on ROS damage was evaluated. Unlike the RNP without pH-triggered disintegration (RNP(Non-pH)), the RNP(pH) showed extremely high ROS scavenging activity and renal protective effects. It is interesting to note that the side effect of nitroxide radicals was markedly suppressed due to the compartmentalization of nitroxide radicals in the core of RNP(pH) in untargeted area. The morphology changes in RNP(pH) were confirmed by analyzing electron spin resonance spectra, and these findings provide the evidence of the real therapeutic effect of the environment-sensitive specific disintegration of nanoparticles in vivo.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cyclic N-Oxides; Cytokines; Free Radical Scavengers; Hydrogen-Ion Concentration; Inflammation; Kidney; Lipid Peroxidation; Mice; Molecular Conformation; Nanoparticles; Nitrogen Oxides; Particle Size; Protective Agents; Reactive Oxygen Species; Superoxides; Time Factors

Although both inflammation and oxidative stress contribute to the pathogenesis of many disease states, the interaction between the two is poorly understood. Cyclopentenone isoprostanes (IsoPs), highly reactive structural isomers of the bioactive cyclopentenone prostaglandins PGA2 and PGJ2, are formed non-enzymatically as products of oxidative stress in vivo. We have, for the first time, examined the effects of synthetic 15-A2- and 15-J2-IsoPs, two groups of endogenous cyclopentenone IsoPs, on the inflammatory response in RAW264.7 and primary murine macrophages. Cyclopentenone IsoPs potently inhibited lipopolysaccharide-stimulated IkappaB alpha degradation and subsequent NF-kappaB nuclear translocation and transcriptional activity. Expression of inducible nitric-oxide synthase and cyclooxygenase-2 were also inhibited by cyclopentenone IsoPs as was nitrite and prostaglandin production (IC50 approximately 360 and 210 nM, respectively). 15-J2-IsoPs potently activated peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptors, whereas 15-A2-IsoP did not, although the anti-inflammatory effects of both molecules were PPARgamma-independent. Interestingly 15-A2-IsoPs induced oxidative stress in RAW cells that was blocked by the antioxidant 4-hydroxy-TEMPO (TEMPOL) or the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone. TEMPOL also abrogated the inhibitory effect of 15-A2-IsoPs on lipopolysaccharide-induced NF-kappaB activation, inducible nitricoxide synthase expression, and nitrite production, suggesting that 15-A2-IsoPs inhibit the NF-kappaB pathway at least partially via a redox-dependent mechanism. 15-J2-IsoP, but not 15-A2-IsoP, also potently induced RAW cell apoptosis again via a PPAR gamma-independent mechanism. These findings suggest that cyclopentenone IsoPs may serve as negative feedback regulators of inflammation and have important implications for defining the role of oxidative stress in the inflammatory response.

Topics: Active Transport, Cell Nucleus; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Arachidonic Acid; Arachidonic Acids; Blotting, Northern; Blotting, Western; Bone Marrow Cells; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cell Line; Cell Nucleus; Cyclic N-Oxides; Cyclooxygenase 2; Cyclopentanes; F2-Isoprostanes; Genes, Reporter; Hydroxylamine; I-kappa B Proteins; Inflammation; Inhibitory Concentration 50; Isoprostanes; Lipopolysaccharides; Macrophages; Mice; Microscopy, Fluorescence; Models, Chemical; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; PPAR gamma; Prostaglandins; Protein Biosynthesis; Tetrazolium Salts; Thiazoles; Transcription, Genetic; Tumor Necrosis Factor-alpha