Home Publication date: Available online 9 December 2019 Source: Free Radical Biology and Medicine Author(s): Michael O. Isei, Collins Kamunde AbstractHigh energy demand for continuous mechanical work and large number of mitochondria predispose the heart to excessive reactive oxygen species (ROS) production that may precipitate oxidative stress and heart failure. While mitochondria have been proposed as a unifying cellular target and driver of adverse effects induced by diverse stressful states, there is limited understanding of how heart mitochondrial ROS homeostasis is affected by combinations of stress factors. Thus, we probed the effect of Cu and thermal stress on ROS (as hydrogen peroxide, H2O2) emission and elucidated the effects of Cu on ROS production sites in rainbow trout heart mitochondria using the Amplex UltraRed-horseradish peroxidase detection system optimized for our model. Mitochondria oxidizing malate-glutamate or succinate were incubated at 4, 11 (control) and 23 °C and exposed to a range (1–100 μM) of Cu concentrations. We found that the rates and patterns of H2O2 emission depended on substrate type, Cu concentration and temperature. In mitochondria oxidizing malate-glutamate, Cu increased the rate of H2O2 emission with a spike at 1 μM while temperature had no effect. In contrast, both temperature and Cu increased the rate of H2O2 emission in mitochondria oxidizing succinate with a prominent spike at 25 μM Cu. The rates of H2O2 emission at the three temperatures during the spike imposed by 25 μM Cu were of the order 11 > 23 > 4 °C. Interestingly, 5 μM Cu supressed H2O2 emission in mitochondria oxidizing succinate or malate-glutamate suggesting a common mechanism of action independent of substrate type. In the absence of Cu, the site-specific capacities of H2O2 emission were: complex III outer ubiquinone binding site (site IIIQo) > complex II flavin site (site IIF) ≥ complex I flavin site (site IF) > complex I ubiquinone-binding site (site IQ). Rotenone marginally increased succinate-driven H2O2 emis
Publication date: Available online 9 December 2019 Source: Free Radical Biology and Medicine Author(s): Shu Li, Qisheng Lin, Xinghua Shao, Xuying Zhu, Jingkui Wu, Bei Wu, Minfang Zhang, Wenyan Zhou, Yijun Zhou, Haijiao Jin, Zhen Zhang, Chaojun Qi, Jianxiao Shen, Shan Mou, Leyi Gu, Zhaohui Ni AbstractMitophagy is a principle mechanism to degrade damaged mitochondria though PARK2-dependent or PARK2-independent pathway. Mitophagy has been identified to play an important role in acute kidney disease, whereas its role in renal fibrosis remains ill-defined. We sought to investigate the involvement and regulation of mitophagy in renal tubular epithelial cell(RTEC) injury and renal fibrosis after UUO. Mitochondrial damage, mitochondrial reactive oxygen species (ROS) production was increased in kidney after obstruction of the left ureter. Mitophagy was increased in kidneys following UUO and HK-2 cells under hypoxia exposure, assessed by electron microscopy of mitophagosome, colocalization of MitotrackerRed-stained mitochondria and LC3 staining. The upregulation of PINK1, PARK2, and LC3 II in mitochondrial fraction was observed in the obstructed kidney and hypoxia-exposed HK-2 cells. Pink1 or Park2 gene deletion markedly increased mtROS production, mitochondrial damage, TGFβ1 expression in RTEC, and renal fibrosis in UUO. Mitochondrial recruitment of Drp1 was also induced after UUO. The Drp1 inhibitor, Mdivi-1, decreased mitochondrial PINK1, PARK2 and LC3II level, increased mtROS production both in vivo and in vitro, activated TGFβ1-Smad2/3 signaling in HK-2 cells under hypoxia and worsened renal fibrosis following UUO. The upregulation of TGFβ1 signaling in hypoxia-treated HK-2 cells due to PINK1 or PARK2 silencing, or worsened renal fibrosis after UUO due to Pink1-or Park2-KO mice was rescued by mitoTEMPO, a mitochondria-targeted antioxidant. The findings of this study suggest that Drp1-regulated PARK2-dependent mitophagy plays a critical role in hypoxia-induced renal tubular epithelial cell injury and renal fibrosis in
Publication date: Available online 9 December 2019 Source: Free Radical Biology and Medicine Author(s): Maria José Alcaraz, María Luisa Ferrándiz AbstractJoint conditions pose an important public health problem as they are a leading cause of pain, functional limitation and physical disability. Oxidative stress is related to the pathogenesis of many chronic diseases affecting the joints such as rheumatoid arthritis and osteoarthritis. Cells have developed adaptive protection mechanisms to maintain homeostasis such as nuclear factor erythroid 2 (NF-E2)-related transcription factor (Nrf2) which regulates the transcription of many genes involved in redox balance, detoxification, metabolism and inflammation. Activation of Nrf2 results in the synthesis of heme oxygenase-1 (HO-1) leading to the formation of a number of bioactive metabolites, mainly CO, biliverdin and bilirubin. Ample evidence supports the notion that Nrf2 and HO-1 can confer protection against oxidative stress and inflammatory and immune responses in joint tissues. As a consequence, this pathway may control the activation and metabolism of articular cells to play a regulatory role in joint destruction thus offering new opportunities for better treatments. Further studies are necessary to identify improved strategies to regulate Nrf2 and HO-1 activation in order to enable the development of drugs with therapeutic applications in joint diseases. Graphical abstract
Publication date: Available online 7 December 2019 Source: Free Radical Biology and Medicine Author(s): Shuting Cao, Chunchun Wang, Jintao Yan, Xin Li, Jiashu Wen, Caihong Hu AbstractThe gut epithelial is known as the most critical barrier for protection against harmful antigens and pathogens. Oxidative stress has been implicated in the dysfunction of the intestine barrier. Hence, effective and safe therapeutic approaches for maintaining intestinal redox balance are urgently needed. Curcumin has gained attention for its vast beneficial biological function via antioxidative stress. However, whether the curcumin can relief intestine damage and mitochondrial injury induced by oxidative stress is still unclear. In this study, we found that curcumin can effectively ameliorate hydrogen peroxide (H2O2)-induced oxidative stress, intestinal epithelial barrier injury and mitochondrial damage in porcine intestinal epithelial cells (IPEC-J2 cells) in a PTEN-induced putative kinase (PINK1)-Parkin mitophagy dependent way. Mechanistically, depletion of Parkin (a mitophagy related protein) abolished curcumin's protective action on anti-oxidative stress, improving intestinal barrier and mitochondrial function in porcine intestinal epithelial cells (IPEC-J2) induced by H2O2. Consistently, the protective effect of curcumin was not found in cells transfected with GFP-ParkinΔUBL, which encodes a mutant Parkin protein without the ubiquitin E3 ligase activity, indicating that the ubiquitin E3 ligase of Parkin is required for curcumin's protective effects. On the other hand, we also found that the protective function of curcumin was diminished when PRKAA1 was depleted in IPEC-J2 cells treated with H2O2. Immunofluorescence and luciferase assay showed that curcumin dramatically enhanced nuclear translocation and transcriptional activity of transcription factor EB (TFEB) in IPEC-J2 cells treated with H2O2, and it was ameliorated by co-treated with compound C, an Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, wh
Publication date: Available online 6 December 2019 Source: Free Radical Biology and Medicine Author(s): Fernando E. García-Arroyo, Guillermo Gonzaga, Itzel Muñoz-Jiménez, Horacio Osorio-Alonso, Alison Iroz, Mariacristina Vecchio, Edilia Tapia, Carlos A. Roncal-Jiménez, Richard J. Johnson, Laura G. Sánchez-Lozada
Publication date: January 2020 Source: Redox Biology, Volume 28 Author(s): Anna Lewinska, Jagoda Adamczyk-Grochala, Dominika Bloniarz, Jakub Olszowka, Magdalena Kulpa-Greszta, Grzegorz Litwinienko, Anna Tomaszewska, Maciej Wnuk, Robert Pazik AbstractCellular senescence may contribute to aging and age-related diseases and senolytic drugs that selectively kill senescent cells may delay aging and promote healthspan. More recently, several categories of senolytics have been established, namely HSP90 inhibitors, Bcl-2 family inhibitors and natural compounds such as quercetin and fisetin. However, senolytic and senostatic potential of nanoparticles and surface-modified nanoparticles has never been addressed. In the present study, quercetin surface functionalized Fe3O4 nanoparticles (MNPQ) were synthesized and their senolytic and senostatic activity was evaluated during oxidative stress-induced senescence in human fibroblasts in vitro. MNPQ promoted AMPK activity that was accompanied by non-apoptotic cell death and decreased number of stress-induced senescent cells (senolytic action) and the suppression of senescence-associated proinflammatory response (decreased levels of secreted IL-8 and IFN-β, senostatic action). In summary, we have shown for the first time that MNPQ may be considered as promising candidates for senolytic- and senostatic-based anti-aging therapies. Graphical abstract
Publication date: January 2020 Source: Redox Biology, Volume 29 Author(s): Manuel Matzinger, Katrin Fischhuber, Daniel Pölöske, Karl Mechtler, Elke H. Heiss AbstractThe transcription factor Nrf2 (nuclear factor (erythroid-derived 2)-like 2) and the kinase AMPK (AMP-activated protein kinase) participate in the cellular adaptive response to redox or energy stress. Despite accumulating evidence for positive cooperativity between both proteins, information about direct post-translational modification of Nrf2 by AMPK in living cells is scarce. Here, MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. Notably, the genes susceptible to the mutation of the phosphorylation sites in Nrf2 consistently showed reduced induction in AMPKα1 −/−cells. Overall, our data reveal AMPK-triggered phosphorylation of Nrf2 at three serine residues, apparently determining the extent of transactivation of selected target genes. Graphical abstract
Publication date: January 2020 Source: Redox Biology, Volume 29 Author(s): Yunjiang Zhou, Keke Wang, Yang Zhou, Tao Li, Mengdi Yang, Rui Wang, Yaxin Chen, Mengran Cao, Rong Hu AbstractThe human HEAT repeat-containing protein 1 (HEATR1), consisting of 2144 amino acids, is a member of the UTP10 family and contains one HEAT repeat at its C-terminal. HEATR1 has been reported to regulate cytotoxic T lymphocytes and rRNA synthesis, while its functions in tumors are poorly understood. Here, we found that HEATR1 competed with Keap1 for binding to p62/sequestosome 1 (SQSTM1), resulted in up-regulation of Keap1, which then inhibited Nrf2 signaling in pancreatic cancer cells. HEATR1 knockdown enhanced proliferation and gemcitabine resistance of pancreatic cancer cells. Moreover, HEATR1 deficiency significantly improved xenografts growth and led to gemcitabine resistance in pancreatic cancer cell-derived xenografts through up-regulating Nrf2 signaling. By analyzing tumor tissue samples from pancreatic cancer patients, we found that low expression of HEATR1 was closely correlated with poor prognosis and clinicopathological features. Collectively, we suggest that HEATR1 deficiency promotes proliferation and gemcitabine resistance of pancreatic cancer through up-regulating Nrf2 signaling, indicating that HEATR1 may be a promising therapeutic target for pancreatic cancer.
Publication date: January 2020 Source: Redox Biology, Volume 28 Author(s): Lin Yang, Zihao He, Jingyue Yao, Renxiang Tan, Yejin Zhu, Zhiyu Li, Qinglong Guo, Libin Wei
Publication date: January 2020 Source: Redox Biology, Volume 28 Author(s): Nabil A. Rashdan, Christopher B. Pattillo AbstractOxidative protein folding in the endoplasmic reticulum (ER) is a significant source of hydrogen peroxide (H2O2). For correct protein folding the redox state of the ER must be efficiently regulated. As such, several mechanisms with varying degrees of overlap manage the redox state of the ER. H2O2 also functions as a second messenger playing a role in most aspects of cellular physiology and pathology, requiring tight control of the concentration and flux of H2O2. Bestetti et al. have demonstrated a role for Aquaporin 11 in transport of H2O2 out of the ER. Graphical abstract
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