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ScienceDirect Publication: Free Radical Biology and Medicine
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  • Tat-CIAPIN1 inhibits hippocampal neuronal cell damage through the MAPK and apoptotic signaling pathways

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Hyeon Ji Yeo, Min Jea Shin, Eun Ji Yeo, Yeon Joo Choi, Dae Won Kim, Duk-Soo Kim, Won Sik Eum, Soo Young Choi

    Abstract

    Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) protein is widely expressed in the brain and it is known that this protein is involved in cell survival including dopaminergic neuronal cells. Oxidative stress is known as one of the major causes of degenerative diseases including ischemia. In this study, we investigated the effect of CIAPIN1 protein on hippocampal neuronal (HT-22) cell damage induced by hydrogen peroxide (H2O2) and in an animal model of ischemia using Tat-CIAPIN1 fusion protein which can transduce into cells. Tat-CIAPIN1 protein transduced into HT-22 cells and significantly inhibited cell death, DNA fragmentation, and reactive oxygen species (ROS) generation. Also, Tat-CIAPIN1 protein enhances cell survival via the regulation of Akt, MAPK, NF-κB and apoptotic signaling pathways in the H2O2 treated cells. In an ischemic animal model, Tat-CIAPIN1 protein transduced into the brain and protected neuronal cell death of hippocampal CA1 region induced by ischemic insult. In conclusion, we demonstrated that Tat-CIAPIN1 protein has protective effects against hippocampal neuronal cell damage induced by ischemic injury, suggesting that Tat-CIAPIN1 protein may provide a potential therapeutic agent for ischemia.

    Graphical abstract

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  • Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Alberto Cruz-Bermúdez, Raquel Laza-Briviesca, Ramiro J. Vicente-Blanco, Aránzazu García-Grande, Maria José Coronado, Sara Laine-Menéndez, Sara Palacios-Zambrano, M. Rocío Moreno-Villa, Asunción Martin Ruiz-Valdepeñas, Cristina Lendinez, Atocha Romero, Fernando Franco, Virginia Calvo, Cristina Alfaro, Paloma Martin Acosta, Clara Salas, José Miguel Garcia, Mariano Provencio

    Abstract
    Background

    Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment.

    Methods

    Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone).

    Results

    Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α, and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles' heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone.

    Conclusion

    These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors.

    Graphical abstract

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  • Activation of Nrf2 attenuates delayed gastric emptying in obesity induced diabetic (T2DM) female mice

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Chethan Sampath, Jeremy C. Sprouse, Michael L. Freeman, Pandu R. Gangula

    Abstract

    Diabetic gastroparesis (GP) is a clinical syndrome characterized by delayed gastric emptying (DGE). Loss of Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) led to reduced nNOSα mediated gastric motility and DGE. The molecular signaling of cinnamaldehyde (CNM) mediated Nrf2 activation and its mechanistic role on DGE were further investigated in obese/T2D female mice. Adult female homozygous Nfe2l2−/− (C57BL/6J) and their wild-type (WT) littermates (Nfe2l2+/+) mice were fed with high fat diet (HFD; Obese/T2D model), or normal diet (ND) with or without CNM (50 mg/kg b.w; i.p). Supplementation of CNM attenuated (p < 0.05) DGE in WT female but not in Nrf2 KO Obese/T2D mice. CNM (1) normalized serum estradiol-17β levels, (2) induced gastric Nrf2 and phase II antioxidant enzymes through extracellular signal-regulated kinase, (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK), (3) reduced glucose synthase kinase 3 beta (GSK3β) and aryl hydrocarbon receptor (AhR) and this was associated with (4) increased estrogen receptor expression, BH4 (Cofactor of nNOS) biosynthesis enzyme GCH-1 and nNOSα dimerization in WT Obese/T2 diabetic female mice. In addition, CNM restored impaired nitrergic relaxation in hyperglycemic conditions. These findings emphasize the importance of Nrf2 in maintaining nNOSα mediated GE and may have a translational relevance to treat obese/diabetic gastroparesis in women.



  • A comprehensive study on the generation of reactive oxygen species in Cu-Aβ-catalyzed redox processes

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Hong Huang, Xiaobing Lou, Bingwen Hu, Zhongneng Zhou, Jinquan Chen, Yang Tian

    Abstract

    In the amyloid plaques, a signature of AD, abnormally high Cu2+ concentrations are found bound to Aβ. Most of previous studies reported that Cu-Aβ could contribute to oxidative stress, as H2O2 and •OH are catalytically generated by Cu-Aβ with the assistance of biological reductant, with only one recent report stated that free O2•- is also generated in the Cu-Aβ catalyzed processes, where an indirect technique was applied. To comprehensively investigate the free radicals produced during this Cu-Aβ-mediated process with a biological reductant, DNA-cleavage assay, an indirect method, and two direct methods including electron paramagnetic resonance (EPR) spectroscopy and transient absorption spectroscopy (TAS), both having qualitative and quantitative power, were employed in this work. All the experimental results obtained from the three methods demonstrated that Cu-Aβ in the biological reducing environment was not only able to catalyze the production of H2O2 and •OH, but also to generate free O2•-. The results further indicated that O2•- was the precursor of H2O2 and •OH. It is also important to note that the results obtained from EPR spectroscopy and TAS provided direct evidence for the presence of O2•- and •OH. By virtue of the direct techniques, we also found that the longest peptide fragments of Aβ16, Aβ40, and Aβ42 produced the least radicals with a lowest rate. More interestingly, the fibrillar forms of Aβ generated less O2•- and •OH compared with oligomeric and monomeric forms.

    Graphical abstract

    We have systematically investigated the Cu-Aβ-catalyzed redox cycling processes using three different methods including DNA-cleavage assay, electron paramagnetic resonance spectroscopy, and transient absorption spectroscopy. All the experimental results strongly confirm the generation of both free O2•- and •OH in the Cu-Aβ-catalyzed processes.

    Image 1



  • Sirt3 mediates the protective effect of hydrogen in inhibiting ROS-induced retinal senescence

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Ruichan Li, Yanli Liu, Jing Xie, Xudong Huang, Li Zhang, Hua Liu, Lihua Li

    Abstract

    Hydrogen possesses antioxidative effects and cures numerous types of ophthalmopathy, but the mechanism of hydrogen on ROS-induced retinal senescence remains elusive. In this study, retinal morphology revealed that hydrogen reduced the number and size of vitreous black deposits in Bruch's membrane in NaIO3 mice. Hydrogen also reduced ROS levels in the retina as assessed by DHE staining. Moreover, this result was consistent with the downregulation of expression of the oxidative stress hallmark OGG1. These findings suggested that hydrogen can reduce retinal oxidative stress induced by NaIO3, and this result was further verified using the antioxidant ALCAR. Mechanistic analysis revealed that hydrogen significantly inhibited the downregulation of Sirt3 expression, and this notion was confirmed using AICAR, which restores Sirt3 expression and activity. Moreover, hydrogen reduced the expression of p53, p21 and p16 and the number of blue-green precipitations in the retinas of NaIO3 mice as assessed by SA-β-gal staining. We also found that hydrogen decreased the expression of the DNA damage-related protein ATM, cyclinD1 and NF-κB but increased the expression of the DNA repair-related protein HMGB1, suggesting that hydrogen inhibits senescence in retinas of NaIO3 mice. Additionally, OCT examination revealed that hydrogen suppressed retinal high reflex formation significantly and prevented the retina from thinning. This result was supported by ERG assays that demonstrated that hydrogen prevented the reduction in a- and b-wave amplitude induced by NaIO3 in mice. Thus, our data suggest that hydrogen may inhibit retinal senescence by suppressing the downregulation of Sirt3 expression through reduced oxidative stress reactions.

    Graphical abstract

    A model illustrating how HRW protects the retina from NaIO3-induced retinal injury. NaIO3 down-regulated the Sirt3 expression and increased levels of oxidative stress, which leading to DNA damage response (DDR) and development of retinal cell senescence. While accompanied by retinal cell senescence, DNA is continuously damaged. Meanwhile, DNA damage eventually accelerated retinal cell senescence. HRW protects retina from oxidative stress-induced retinal cell senescence by reducing the down-regulation of Sirt3 expression.

    Image 1



  • Reduced lifespan of mice lacking catalase correlates with altered lipid metabolism without oxidative damage or premature aging

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): José Raúl Pérez-Estrada, David Hernández-García, Francisco Leyva-Castro, Javier Ramos-León, Osiris Cuevas-Benítez, Mauricio Díaz-Muñoz, Susana Castro-Obregón, Ramiro Ramírez-Solís, Celina García, Luis Covarrubias

    Abstract

    The relationship between the mechanisms that underlie longevity and aging and the metabolic alterations due to feeding conditions has not been completely defined. In the present work, through the deletion of the gene encoding catalase, hydrogen peroxide (H2O2) was uncovered as a relevant regulator of longevity and of liver metabolism. Mice lacking catalase (Cat−/−) fed ad libitum with a regular diet showed a shorter lifespan than wild type mice, which correlated with reduced body weight, blood glucose levels and liver fat accumulation, but not with increased oxidative damage or consistent premature aging. High fat diet (HFD) and fasting increased oxidative damage in the liver of wild type animals but, unexpectedly, this was not the case for that of Cat−/− mice. Interestingly, although HFD feeding similarly increased the body weight of Cat−/− and wild-type mice, hyperglycemia and liver steatosis did not develop in the former. Fat accumulation due to fasting, on the other hand, was diminished in mice lacking catalase, which correlated with increased risk of death and low ketone body blood levels. Alteration in expression of some metabolic genes in livers of catalase deficient mice was consistent with reduced lipogenesis. Specifically, Pparγ2 expression up-regulation in response to a HFD and down-regulation upon fasting was lower and higher, respectively, in livers of Cat−/− than of wild type mice, and a marked decay was observed during Cat−/− mice aging. We propose that catalase regulates lipid metabolism in the liver by an evolutionary conserved mechanism that is determinant of lifespan without affecting general oxidative damage.

    Graphical abstract

    Image 1



  • Inhibition of PDE4 by FCPR16 induces AMPK-dependent autophagy and confers neuroprotection in SH-SY5Y cells and neurons exposed to MPP+-induced oxidative insult

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Jiahong Zhong, Jinfeng Xie, Jiao Xiao, Dan Li, Bingtian Xu, Xinyi Wang, Huizhen Wen, Zhongzhen Zhou, Yufang Cheng, Jiangping Xu, Haitao Wang

    Abstract

    The etiology of Parkinson's disease (PD) is generally not well understood, but it is believed to involve excessive oxidative insult. Hence, identifying therapeutic targets and compounds that exhibit protective effects against oxidative damage is a reasonable strategy to slow down the progression of PD. FCPR16 is a novel phosphodiesterase 4 inhibitor with little emetic potential. Our previous studies showed that FCPR16 was able to block 1-Methyl-4-phenylpyridine (MPP+)-induced oxidative damage in SH-SY5Y cells and neurons. However, the detailed mechanism of this is unknown. Here, we found that FCPR16 triggered autophagy in SH-SY5Y cells, as evidenced by an increased level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62. Inhibition of autophagy by 3-MA or chloroquine decreased the effect of FCPR16 on the accumulation of autophagic vacuoles and the fluorescence signal of lysosomes. In SH-SY5Y cells treated with MPP+, we found that FCPR16 increased the level of LC3-II, and 3-MA attenuated the protective effect of FCPR16 against MPP+-induced toxicity. Treatment of SH-SY5Y cells with FCPR16 prevented MPP+-induced production of reactive oxygen species (ROS) and the decline of mitochondrial membrane potential (Δψm). Importantly, we also found that FCPR16 phosphorylated and thus activated AMP-activated protein kinase (AMPK) in SH-SY5Y cells treated with MPP+. In contrast, blockade of the AMPK pathway with compound C blocked the role of FCPR16 in autophagy enhancement. Similarly, the roles of FCPR16 in the production of ROS, decline of Δψm, and neuroprotection were blocked by compound C as well. Similar results were consistently obtained in primary cultured neurons. Taken together, these results suggest that FCPR16 is effective in protecting SH-SY5Y cells and neurons against oxidative stress via AMPK-dependent autophagy. Our findings indicate the potential application of FCPR16 in PD treatment.

    Graphical abstract

    Image 1



  • Differential response of immortalized human amnion mesenchymal and epithelial cells against oxidative stress

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Lu Guang Han, Qing-Li Zhao, Toshiko Yoshida, Motonori Okabe, Chika Soko, Mati Ur Rehman, Takashi Kondo, Toshio Nikaido

    Abstract

    Cells are equipped with various antioxidant defense factors to antagonize insults from reactive oxygen species (ROS), thus the antioxidant capacity has been characterized by a variety of cellular responses during the pathophysiological processes. Amniotic cells have been extensively applied in clinical practice for burn treatment, corneal repair, and tissue regeneration. However, the antioxidative properties of amniotic cells have not yet been fully understood. Therefore, the current study was aimed to observe the response of amniotic cells against ROS stimuli, and to investigate the underlying molecular mechanisms. The immortalized human amniotic mesenchymal cells (iHAMs) and immortalized human amniotic epithelial cells (iHAEs) were used. The human skin fibroblast (HSF) was used as a control cell line. Changes in intracellular ROS generation, cell viability, and cellular morphology were investigated to reveal the response of amniotic cells against oxidative stresses induced by x-rays and hydrogen peroxide. In addition, expression of apoptosis-related proteins and response to antioxidative stress was also examined. The intracellular ROS level and cell apoptosis in iHAMs was remarkably increased. iHAEs showed relatively high resistance to ROS stimulation, which can be attributed to the high SOD2 expression and up-regulation of Nrf2, HO-1 after x-rays exposure. In contrast, iHAMs were found sensitive to oxidative damage. Expression of caspase-3, caspase-8 and BAX was increased, whereas down-regulation of Bcl-xL, Nrf2, HO-1, and TrxR-1. Taken together, findings have highlighted the characterization of response of amniotic derived epithelial and mesenchymal cells to oxidative stress. In physiological processes, iHAMs may play an important role to maintain the homeostasis of the pregnancy environment. However, under oxidative stimulations, iHAEs provides protection against oxidative damage in amnion tissue.

    Graphical abstract

    Image 1



  • Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Chongyang Chen, Xin Jiang, Yingchao Li, Haitao Yu, Shupeng Li, Zaijun Zhang, Hua Xu, Ying Yang, Gongping Liu, Feiqi Zhu, Xiaohu Ren, Liangyu Zou, Benhong Xu, Jianjun Liu, Peter S. Spencer, Xifei Yang

    Abstract

    Excessive copper can cause neurotoxicity and contribute to the development of some neurological diseases; however, copper neurotoxicity and the potential mechanisms remain poorly understood. We used proteomics and phosphoproteomics to quantify protein changes in the hippocampus of wild-type and 3xTg-AD mice, both of which were treated at 6 months of age with 2 months of drinking water with or without added copper chloride (0.13 ppm concentration). A total of 3960 unique phosphopeptides (5290 phosphorylation sites) from 1406 phosphoproteins was identified. Differentially expressed phosphoproteins involved neuronal and synaptic function, transcriptional regulation, energy metabolism and mitochondrial function. In addition, low-dose copper treatment of wild-type mice decreased hippocampal mitochondrial copy number, mitochondrial biogenesis and disrupted mitochondrial dynamics; these changes were associated with increased hydrogen peroxide production (H2O2), reduced cytochrome oxidase activity and decreased ATP content. In 3xTg-AD mice, identical low-dose oral copper treatment increased axonal degeneration, which was associated with altered phosphorylation of Camk2α at T286 and phosphorylation of mitogen-activated protein kinase (ERK1/2), which involved long-term potentiation (LTP) signaling. Mitochondrial dysfunction was mainly related to changes in phosphorylation levels of glycogen synthase kinase-3 beta (GSK3β) and serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (Ppp3ca), which involved mitochondrial biogenesis signaling. In sum, low-dose oral copper treatment changes the phosphorylation of key hippocampal proteins involved in mitochondrial, synaptic and axonal integrity. These data showing that excess of copper speeds some early events of AD changes observed suggest that excess circulating copper has the potential to perturb brain function of wild-type mice and exacerbate neurodegenerative changes in a mouse model of AD.

    Graphical abstract

    Image 1



  • Fasting reduces oxidative stress, mitochondrial dysfunction and fibrosis induced by renal ischemia-reperfusion injury

    Publication date: 1 May 2019

    Source: Free Radical Biology and Medicine, Volume 135

    Author(s): Pedro Rojas-Morales, Juan Carlos León-Contreras, Omar Emiliano Aparicio-Trejo, Jazmin Gabriela Reyes-Ocampo, Omar Noel Medina-Campos, Angélica Saraí Jiménez-Osorio, Susana González-Reyes, Brenda Marquina-Castillo, Rogelio Hernández-Pando, Diana Barrera-Oviedo, Laura Gabriela Sánchez-Lozada, José Pedraza-Chaverri, Edilia Tapia

    Abstract

    Food deprivation protects against ischemia-reperfusion (IR) injury through unknown mechanisms. In an experimental rat model of acute IR injury, we found that preoperative fasting for 3 days protects rats from tubular damage and renal functional decline by increasing antioxidant protection independently of the NF-E2-related factor 2 (Nrf2), and by maintaining mitochondrial morphology and function. In addition, further analysis revealed that fasting protects against tubulointerstitial fibrosis. In summary, our results point out to fasting as a robust nutritional intervention to limit oxidative stress and mitochondrial dysfunction in early acute kidney injury and also to promote long-term protection against fibrosis.

    Graphical abstract

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Научная работа