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Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Sonal Agrawal, Julia Fox, Baskaran Thyagarajan, Jonathan H. Fox
Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 μM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective.
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BMP signaling-driven osteogenesis is critically dependent on Prdx-1 expression-mediated maintenance of chondrocyte prehypetrophy
Publication date: April 2018
Source:Free Radical Biology and Medicine, Volume 118
Author(s): Yogesh Kumar, Tathagata Biswas, Gatha Thacker, Jitendra Kumar Kanaujiya, Sandeep Kumar, Anukampa Shukla, Kainat Khan, Sabyasachi Sanyal, Naibedya Chattopadhyay, Amitabha Bandyopadhyay, Arun Kumar Trivedi
During endochondral ossification, cartilage template is eventually replaced by bone. This process involves several well characterized, stereotypic, molecular and cellular changes in the cartilage primordia. These steps involve transition from resting to proliferative and then pre-hypertrophic to finally hypertrophic cartilage. BMP signaling is necessary and sufficient for osteogenesis. However, the specific step(s) of endochondral ossification in which BMP signaling plays an essential role is not yet known. In this study we have identified Prdx1, a known scavenger of ROS, to be expressed in pre-hypertrophic chondrocytes in a BMP signaling-dependent manner. We demonstrate that BMP signaling inhibition increases ROS levels in osteogenic cells. Further, Prdx1 regulates osteogenesis in vivo by helping maintenance of Ihh expressing pre-hypertrophic cells, in turn regulating these cells’ transition into hypertrophy. Therefore, our data suggests that one of the key roles of BMP signaling in endochondral ossification is to maintain pre-hypertrophic state.
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An evolving understanding of the S-glutathionylation cycle in pathways of redox regulation
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Jie Zhang, Zhi-wei Ye, Shweta Singh, Danyelle M. Townsend, Kenneth D. Tew
By nature of the reversibility of the addition of glutathione to low pKa cysteine residues, the post-translational modification of S-glutathionylation sanctions a cycle that can create a conduit for cell signaling events linked with cellular exposure to oxidative or nitrosative stress. The modification can also avert proteolysis by protection from over-oxidation of those clusters of target proteins that are substrates. Altered functions are associated with S-glutathionylation of proteins within the mitochondria and endoplasmic reticulum compartments, and these impact energy production and protein folding pathways. The existence of human polymorphisms of enzymes involved in the cycle (particularly glutathione S-transferase P) create a scenario for inter-individual variance in response to oxidative stress and a number of human diseases with associated aberrant S-glutathionylation have now been identified.
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Short-term sleep deprivation with exposure to nocturnal light alters mitochondrial bioenergetics in Drosophila
Publication date: Available online 12 April 2018
Source:Free Radical Biology and Medicine
Author(s): Nathane Rosa Rodrigues, Giulianna Echeverria Macedo, Illana Kemmerich Martins, Karen Kich Gomes, Nélson Rodrigues de Carvalho, Thaís Posser, Jeferson Luis Franco
Many studies have shown the effects of sleep deprivation in several aspects of health and disease. However, little is known about how mitochondrial bioenergetics function is affected under this condition. To clarify this, we developed a simple model of short-term sleep deprivation, in which fruit-flies were submitted to a nocturnal light condition and then mitochondrial parameters were assessed by high resolution respirometry (HRR). Exposure of flies to constant light was able to alter sleep patterns, causing locomotor deficits, increasing ROS production and lipid peroxidation, affecting mitochondrial activity, antioxidant defense enzymes and caspase activity. HRR analysis showed that sleep deprivation affected mitochondrial bioenergetics capacity, decreasing respiration at oxidative phosphorylation (OXPHOS) and electron transport system (ETS). In addition, the expression of genes involved in the response to oxidative stress and apoptosis were increased. Thus, our results suggest a connection between sleep deprivation and oxidative stress, pointing to mitochondria as a possible target of this relationship.
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Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Yang Yang, Lan Luo, Xueting Cai, Yuan Fang, Jiaqi Wang, Gang Chen, Jie Yang, Qian Zhou, Xiaoyan Sun, Xiaolan Cheng, Huaijiang Yan, Wuguang Lu, Chunping Hu, Peng Cao
Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting toxicity associated with cancer chemotherapy. The efficacy of antioxidant administration in OIPN is debatable, as the promising preliminary results obtained with a number of antioxidants have not been confirmed in larger clinical trials. Besides its antioxidant activity, the transcription factor, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2) plays a crucial role in the maintenance of mitochondrial homeostasis, and mitochondrial dysfunction is a key contributor to OIPN. Here, we have investigated the protective properties of Nrf2 in OIPN. Nrf2 -/- mice displayed severe mechanical allodynia and cold sensitivity and thus experienced increased peripheral nervous system injury compared to Nrf2 +/+ mice. Furthermore, Nrf2 knockout aggravated oxaliplatin-induced reactive oxygen species production, decreased the mitochondrial membrane potential, led to abnormal intracellular calcium levels, and induced cytochrome c-related apoptosis and overexpression of the TRP protein family. Sulforaphane-induced activation of the Nrf2 signaling pathway alleviated morphological alterations, mitochondrial dysfunction in dorsal root ganglion neurons, and nociceptive sensations in mice. Our findings reveal that Nrf2 may play a critical role in ameliorating OIPN, through protection of mitochondrial function by alleviating oxidative stress and inhibiting TRP protein family expression. This suggests that pharmacological or therapeutic activation of Nrf2 may be used to prevent or slow down the progression of OIPN.
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Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Kazumi Iwata, Kuniharu Matsuno, Ayumi Murata, Kai Zhu, Hitomi Fukui, Keiko Ikuta, Masato Katsuyama, Masakazu Ibi, Misaki Matsumoto, Makoto Ohigashi, Xiaopeng Wen, Jia Zhang, Wenhao Cui, Chihiro Yabe-Nishimura
Cardiac fibrosis is a common feature in failing heart and therapeutic strategy to halt the progression of fibrosis is highly needed. We here report on NOX1, a non-phagocytic isoform of superoxide-producing NADPH oxidase, which promotes cardiac fibrosis in a drug-induced myocardial injury model. A single-dose administration of doxorubicin (DOX) elicited cardiac dysfunction accompanied by increased production of reactive oxygen species and marked elevation of NOX1 mRNA in the heart. In mice deficient in Nox1 (Nox1 -/Y), cardiac functions were well retained and overall survival was significantly improved. However, increased level of serum creatine kinase was equivalent to that of wild-type mice (Nox1 +/Y). At 4 days after DOX treatment, severe cardiac fibrosis accompanied by increased hydroxyproline content and activation of matrix metalloproteinase-9 was demonstrated in Nox1 +/Y, but it was significantly attenuated in Nox1 -/Y. When H9c2 cardiomyocytes were exposed to their homogenate, a dose-dependent increase in NOX1 mRNA was observed. Up-regulation of NOX1 mRNA in H9c2 co-incubated with their homogenate was abolished in the presence of TAK242, a TLR4 inhibitor. When isolated cardiac fibroblasts were exposed to H9c2 homogenates, increased proliferation and up-regulation of collagen 3a1 mRNA were demonstrated. These changes were significantly attenuated in cardiac fibroblasts exposed to homogenates from H9c2 harboring disrupted Nox1. These findings suggest that up-regulation of NOX1 following cellular damage promotes cardiac dysfunction and fibrosis by aggravating the pro-fibrotic response of cardiac fibroblasts. Modulation of the NOX1/NADPH oxidase signaling pathway may be a novel therapeutic strategy for preventing heart failure after myocardial injury.
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Nitrite exerts antioxidant effects, inhibits the mTOR pathway and reverses hypertension-induced cardiac hypertrophy
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Danielle A. Guimaraes, Madla A. dos Passos, Elen Rizzi, Lucas C. Pinheiro, Jefferson H. Amaral, Raquel F. Gerlach, Michele M. Castro, Jose E. Tanus-Santos
Cardiac hypertrophy is a common consequence of chronic hypertension and leads to heart failure and premature death. The anion nitrite is now considered as a bioactive molecule able to exert beneficial cardiovascular effects. Previous results showed that nitrite attenuates hypertension-induced increases in reactive oxygen species (ROS) production in the vasculature. Whether antioxidant effects induced by nitrite block critical signaling pathways involved in cardiac hypertrophy induced by hypertension has not been determined yet. The Akt/mTOR signaling pathway is responsible to activate protein synthesis during cardiac remodeling and is activated by increased ROS production, which is commonly found in hypertension. Here, we investigated the effects of nitrite treatment on cardiac remodeling and activation of this hypertrophic signaling pathway in 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral nitrite at 1 or 15 mg/kg for four weeks. Nitrite treatment (15 mg/kg) reduced systolic blood pressure and decreased ROS production in the heart tissue from hypertensive rats. This nitrite dose also blunted hypertension-induced activation of mTOR pathway and cardiac hypertrophy. While the lower nitrite dose (1 mg/kg) did not affect blood pressure, it exerted antioxidant effects and tended to attenuate mTOR pathway activation and cardiac hypertrophy induced by hypertension. Our findings provide strong evidence that nitrite treatment decreases cardiac remodeling induced by hypertension as a result of its antioxidant effects and downregulation of mTOR signaling pathway. This study may help to establish nitrite as an effective therapy in hypertension-induced cardiac hypertrophic remodeling.
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Honokiol alleviates the degeneration of intervertebral disc via suppressing the activation of TXNIP-NLRP3 inflammasome signal pathway
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Pan Tang, Jia-Ming Gu, Zi-Ang Xie, Yu Gu, Zhi-Wei Jie, Kang-Mao Huang, Ji-Ying Wang, Shun-Wu Fan, Xue-Sheng Jiang, Zhi-Jun Hu
Intervertebral disc degeneration (IVDD) is a multifactorial disease and responsible for many spine related disorders, causes disability in the workforce and heavy social costs all over the world. Honokiol, a low molecular weight natural product, could penetrate into and distribute in IVDs to achieve therapeutic effect in a rat tail model. Therefore, the present study was undertaken to examine the antiinflammatory, antioxidation and IVD-protective effect of honokiol using nucleus pulposus cells and investigate its mechanisms to provide a new basis for future clinical treatment of IVDD. In the current study, we demonstrated that honokiol inhibits the H2O2-induced apoptosis (caspase-9, caspase-3, and bax), levels of oxidative stress mediators (ROS, MDA), expression of inflammatory mediators (Interleukin-6, COX-2, and iNOS), major matrix degrading proteases (MMP-3, MMP-13, ADAMTS5, and ADAMTS4) associated with nucleus pulposus degradation. Furthermore, we found nucleus pulposus protective ability of honokiol by up-regulating extra cellular matrix anabolic factors like type II collagen (Col II) and SOX9 in nucleus pulposus. We also found that honokiol suppressed the phosphorylation of NF-kB and JNK, and activation of TXNIP-NLRP3 inflammasome in H2O2-stimulated nucleus pulposus cells, thereby inhibiting the activation of downstream inflammatory mediators such as Interleukin-1β. Furthermore, honokiol showed a cartilage protective effect in the progression of IVDD in a rat model induced by puncture. Thus, our results demonstrate that honokiol inhibited the H2O2 induced apoptosis, oxidative stress, and inflammatory responses through the depression of TXNIP/NLRP3/caspase-1/ Interleukin − 1β signaling axis and the activation of NF-kB and JNK. Honokiol possess nucleus pulposus protective properties and may be of value in suppressing the pathogenesis of IVDD.
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Macrophage-derived superoxide production and antioxidant response following skeletal muscle injury
Publication date: 20 May 2018
Source:Free Radical Biology and Medicine, Volume 120
Author(s): Emmeran Le Moal, Gaëtan Juban, Anne Sophie Bernard, Tamas Varga, Clotilde Policar, Bénédicte Chazaud, Rémi Mounier
Macrophages are key players of immunity that display different functions according to their activation states. In a regenerative context, pro-inflammatory macrophages (Ly6Cpos) are involved in the mounting of the inflammatory response whereas anti-inflammatory macrophages (Ly6Cneg) dampen the inflammation and promote tissue repair. Reactive oxygen species (ROS) production is a hallmark of tissue injury and of subsequent inflammation as described in a bacterial challenge context. However, whether macrophages produce ROS following a sterile tissue injury is uncertain. In this study, we used complementary in vitro, ex vivo and in vivo experiments in mouse to show that macrophages do not release ROS following a sterile injury in skeletal muscle. Furthermore, expression profiles of genes involved in the response to oxidative stress in Ly6Cpos and Ly6Cneg macrophage subsets did not indicate any antioxidant response in this context. Finally, in vivo, pharmacological antioxidant supplementation with N-Acetyl-cysteine (NAC) following skeletal muscle injury did not alter macrophage phenotype during skeletal muscle regeneration. Overall, these results indicate that following a sterile injury, macrophage-derived ROS release is not involved in the regulation of the inflammatory response in the regenerating skeletal muscle.
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Redox biosensors in a context of multiparameter imaging
Publication date: Available online 6 April 2018
Source:Free Radical Biology and Medicine
Author(s): Alexander I. Kostyuk, Anastasiya S. Panova, Dmitry S. Bilan, Vsevolod V. Belousov
A wide variety of genetically encoded fluorescent biosensors are available to date. Some of them have already contributed significantly to our understanding of biological processes occurring at cellular and organismal levels. Using such an approach, outstanding success has been achieved in the field of redox biology. The probes allowed researchers to observe, for the first time, the dynamics of important redox parameters in vivo during embryogenesis, aging, the inflammatory response, the pathogenesis of various diseases, and many other processes. Given the differences in the readout and spectra of the probes, they can be used in multiparameter imaging in which several processes are monitored simultaneously in the cell. Intracellular processes form an extensive network of interactions. For example, redox changes are often accompanied by changes in many other biochemical reactions related to cellular metabolism and signaling. Therefore, multiparameter imaging can provide important information concerning the temporal and spatial relationship of various signaling and metabolic processes. In this review, we will describe the main types of genetically encoded biosensors, the most frequently used readout, and their use in multiplexed imaging mode.
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