bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2018‒12‒30
forty papers selected by
Gavin McStay
Staffordshire University
  1. Alpha lipoic acid attenuates hypoxia-induced apoptosis, inflammation and mitochondrial oxidative stress via inhibition of TRPA1 channel in human glioblastoma cell line.
  2. Methotrexate-induced apoptosis in human ovarian adenocarcinoma SKOV-3 cells via ROS-mediated bax/bcl-2-cyt-c release cascading.
  3. Senkyunolide H protects against MPP+-induced apoptosis via the ROS-mediated mitogen-activated protein kinase pathway in PC12 cells.
  4. Propofol attenuates high glucose-induced P66shc expression in human umbilical vein endothelial cells through Sirt1.
  5. Reactive oxygen and nitrogen species induce cell apoptosis via a mitochondria-dependent pathway in hyperoxia lung injury.
  6. Selenocystine inhibits JEG-3 cell growth in vitro and in vivo by triggering oxidative damage-mediated S-phase arrest and apoptosis.
  7. Induction of Apoptosis by an Extract of Persian Gulf Marine Mollusc, Turbo Coronatus through the Production of Reactive Oxygen Species in Mouse Melanoma Cells
  8. The Critical Role of X Chromosome-linked Inhibitor of Apoptosis (XIAP) in Differential Synergism Induced by Pentachlorophenol and Copper-1,10-phenanthroline Complex in Normal and Cancer Liver Cells.
  9. Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells.
  10. Repressing of NHERF1 inhibits liver cancer progression by promoting the production of ROS.
  11. Intestinal epithelial cell apoptosis due to a hemolytic toxin from Vibrio vulnificus and protection by a 36 kDa glycoprotein from Rhus verniciflua Stokes.
  12. Induction of autophagic cell death in human ovarian carcinoma cells by Antrodia salmonea through increased reactive oxygen species generation.
  13. l-arginine inhibited apoptosis of fish leukocytes via regulation of NF-κB-mediated inflammation, NO synthesis, and anti-oxidant capacity.
  14. INF2 regulates oxidative stress-induced apoptosis in epidermal HaCaT cells by modulating the HIF1 signaling pathway.
  15. Ferrocenyl-Triphenyltin Complexes as Lysosome-Targeted Imaging and Anticancer Agents.
  16. Gigantol has Protective Effects against High Glucose-Evoked Nephrotoxicity in Mouse Glomerulus Mesangial Cells by Suppressing ROS/MAPK/NF-κB Signaling Pathways.
  17. Carteolol hydrochloride reduces visible light-induced retinal damage in vivo and BSO/glutamate-induced oxidative stress in vitro.
  18. Caspase-3-like activity and proteasome degradation in grapevine suspension cell cultures undergoing silver-induced programmed cell death.
  19. Effect of photodynamic therapy with (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt on pancreatic cancer cells in vitro and in vivo.
  20. Xanthatin mediates G2/M cell cycle arrest, autophagy and apoptosis via ROS/XIAP signaling in human colon cancer cells.
  21. Nitric oxide prevents H2O2-induced apoptosis in SK-N-MC human neuroblastoma cells.
  22. Protection of Kaempferol on Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage.
  23. Impact of post-thaw supplementation of semen extender with antioxidants on the quality and function variables of stallion spermatozoa.
  24. Melatonin protects in vitro matured porcine oocytes from toxicity of Aflatoxin B1.
  25. 3-n-butylphthalide exerts neuroprotective effects by enhancing anti-oxidation and attenuating mitochondrial dysfunction in an in vitro model of ischemic stroke.
  26. Effect of myostatin inhibitor (myostatin pro-peptide) microinjection on in vitro maturation and subsequent early developmental stages of buffalo embryo.
  27. Potential adverse effects of nanoparticles on the reproductive system.
  28. NADPH oxidase inhibitor apocynin decreases mitochondrial dysfunction and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging model in rats.
  29. A derivative of betulinic acid protects human Retinal Pigment Epithelial (RPE) cells from cobalt chloride-induced acute hypoxic stress.
  30. Genipin protects against cerebral ischemia-reperfusion injury by regulating the UCP2-SIRT3 signaling pathway.
  31. Effect of pristine and functionalized multiwalled carbon nanotubes on rat renal cortex.
  32. Antioxidant Activities and Repair Effects on Oxidatively Damaged HK-2 Cells of Tea Polysaccharides with Different Molecular Weights.
  33. High Glucose-Induced ROS Production Stimulates Proliferation of Pancreatic Cancer via Inactivating the JNK Pathway.
  34. Mitochondrial division inhibitor-1 potentiates cisplatin-induced apoptosis via the mitochondrial death pathway in cholangiocarcinoma cells.
  35. Redox correlation in muscle lengthening and immune response in eccentric exercise.
  36. Nrf2 dependent antiaging effect of milk-derived bioactive peptide in old fibroblasts.
  37. Mitochondria modulate programmed neuritic retraction.
  38. Rosmarinic acid induces programmed cell death in Arabidopsis seedlings through reactive oxygen species and mitochondrial dysfunction.
  39. Protocatechuic acid protects against menadione-induced liver damage by up-regulating nuclear erythroid-related factor 2.
  40. Melatonin alleviates meiotic defects in fetal mouse oocytes induced by Di (2-ethylhexyl) phthalate in vitro.
  1. Biomed Pharmacother. 2018 Dec 24. pii: S0753-3322(18)35507-0. [Epub ahead of print]111 292-304
    Alpha lipoic acid attenuates hypoxia-induced apoptosis, inflammation and mitochondrial oxidative stress via inhibition of TRPA1 channel in human glioblastoma cell line.
    Haci Ahmet Deveci, Yener Akyuva, Gökhan Nur, Mustafa Nazıroğlu.
      Apoptosis, overload Ca2+ entry and oxidative stress are induced in neurons by hypoxia. Drug-resistant cancer cells are killed by hypoxic conditions. α-Lipoic acid (ALA) has antioxidant and pro-oxidant functions. The TRPA1 channel is activated by oxidative stress and pro-oxidant ALA may have a regulator role in the TRPA1 activity in the human glioblastoma (DBTRG) cells. The aim of this study was to evaluate if a combination therapy of ALA with a hypoxia can alter the effect of this hypoxia through TRPA1 activation in the DBTRG cells. The DBTRG cells were divided into four treatment groups as control, ALA (50 μM), and hypoxia and hypoxia + ALA. Hypoxia in the cells was induced by CoCl2 (200 μM). Apoptosis, Annexin V, mitochondrial membrane depolarization (JC-1), reactive oxygen species (ROS) production, IL-1β, IL-18, caspase 3 and 9 values were increased through activation of TRPA1 (cinnamaldehyde) in the cells by the hypoxia induction, although cell viability, reduced glutathione and glutathione peroxidase values were decreased by the treatments. The values were modulated in the cells by TRPA1 blocker (AP18) and ALA treatments. Involvements of TRPA1 activity on values in the cells were also confirmed by patch-clamp and laser confocal microscopy analyses. In conclusion, apoptotic, inflammatory and oxidant effects of hypoxia were increased by activation of TRPA1, but its action on the values was decreased by the ALA treatment. ALA treatment could be used as an effective strategy in the treatment of hypoxia-induced oxidative stress, apoptosis and inflammation in the neurons.
    Keywords:  Apoptosis; Glioblastoma cells; Hypoxia; Inflammation; TRPA1; α-Lipoic acid
    DOI:  https://doi.org/10.1016/j.biopha.2018.12.077
  2. Onco Targets Ther. 2019 ;12 21-30
    Methotrexate-induced apoptosis in human ovarian adenocarcinoma SKOV-3 cells via ROS-mediated bax/bcl-2-cyt-c release cascading.
    Gadah AlBasher, Abdullah A AlKahtane, Saud Alarifi, Daoud Ali, Mohammed S Alessia, Rafa S Almeer, Mohamed M Abdel-Daim, Nouf K Al-Sultan, Ahmed A Al-Qahtani, Huma Ali, Saad Alkahtani.
      Introduction: The communication between a substance and a cell may depend on whether the cell is normal or pathological. The disease cells and drug interaction may occasionally overcome beneficial action of the drug; subsequently, it is important to investigate the effect of the drug in both the normal and target cells. This study aimed to evaluate the methotrexate (MTX) antiproliferative effect and explore the mechanistic approach to investigate the cell death index in SKOV-3 ovarian cells during treatment with MTX.Methods: In vitro studies of SKOV-3 cells were examined by tetrazolium assay after exposure to various concentrations of MTX. Moreover, reactive oxygen species (ROS) generation, mitochondrial membrane potential, DNA damage, and AO/EtBr staining morphological analysis of necrotic/apoptotic cells were detected; cellular impairment in mitochondria and DNA was confirmed by JC-1 mitotracker/DAPI, respectively, and cell death pathway markers; bax/bcl-2 were analyzed.
    Results: A dose-dependent antiproliferative effect of MTX treatment was observed in SKOV-3 cells; the prominent inhibitory concentration was 40 µM of MTX (P<0.01). The growth inhibition rates of the cancer cells reached 24.07% in MTX. The MTX showed increase in ROS generation and mitochondrial depolarization, and DNA integrity cells collectively advocated the apoptotic cell death at higher concentration. In addition, the results of reverse transcription polymerase chain reaction also supported the apoptosis by upregulating the bax and downregulating the bcl-2 (P<0.01). Thus the MTX moderately provokes apoptosis.
    Conclusion: Our findings suggest that MTX acts on SKOV-3 cancer cells by increasing intracellular ROS levels, leading to DNA damage and altering the MMP along with apoptotic gene upregulation. This mechanism may provide new therapeutic targets to improve tumor treatment.
    Keywords:  MMP; ROS; SKOV-3 cells; apoptosis; methotrexate
    DOI:  https://doi.org/10.2147/OTT.S178510
  3. Environ Toxicol Pharmacol. 2018 Dec 13. pii: S1382-6689(18)30574-X. [Epub ahead of print]65 73-81
    Senkyunolide H protects against MPP+-induced apoptosis via the ROS-mediated mitogen-activated protein kinase pathway in PC12 cells.
    Yanyan Luo, Xueqin Li, Tingwu Liu, Yufeng Cao, Jianmei Zhang, Aftab Yaseen, Fengting Sun, Wancai Zheng, Yunyao Jiang, Chuan-Ling Si, Weicheng Hu.
      Senkyunolide H (SNH) is a phthalide isolated from the rhizome of Ligusticum chuanxiong Hort. that has been reported to have several pharmacological activities, including anti-atherosclerotic, antiproliferative, and cytoprotective effects. In this study, we investigated the neuroprotective effects and potential mechanisms of SNH against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress. We demonstrated that SNH pretreatment significantly attenuated MPP+-induced neurotoxicity and apoptosis in PC12 cells. In addition, SNH attenuated the effect of MPP+ on the expression of the pro-apoptotic factors Bax and caspase-3. Meanwhile, SNH prevented oxidative stress by reducing reactive oxygen species generation, mitochondrial membrane potential loss, cytochrome C release, and malondialdehyde levels while increasing antioxidant enzyme activity (e.g., superoxide dismutase, catalase, and glutathione peroxidase). In addition, SNH inhibited nuclear accumulation of nuclear factor-κB and c-Jun N-terminal kinase and phosphorylation p38 mitogen-activated protein kinases (MAPKs). Overall, this investigation provides novel evidence that SNH exerts neuroprotective effects via the ROS-mediated MAPK pathway and represents a potential preventive or therapeutic agent for neuronal disorders.
    Keywords:  Apoptosis; Nuclear factor-κB; Oxidative stress; Senkyunolide H
    DOI:  https://doi.org/10.1016/j.etap.2018.12.007
  4. Acta Biochim Biophys Sin (Shanghai). 2018 Dec 27.
    Propofol attenuates high glucose-induced P66shc expression in human umbilical vein endothelial cells through Sirt1.
    Jing Wang, Jie Qi, Qichao Wu, Hui Jiang, Yuehao Yin, Yan Huan, Yanjun Zhao, Minmin Zhu.
      Perioperative hyperglycemia is a common metabolic disorder in clinic settings. Hyperglycemia leads to endothelial inflammation, endothelial cell apoptosis, and dysfunction, thus resulting in endothelial injury. Propofol (2,6-diisopropylphenol) is a widely used intravenous anesthetic in clinic settings. Our previous study indicated that propofol inhibits mitochondrial reactive oxygen species (ROS) production via down-regulation of phosphatase A2 (PP2A) expression, inhibition of Ser36-p66shc dephosphorylation and mitochondrial translocation, thus improving high glucose-induced endothelial injury. The expression of p66shc was inhibited by propofol in hyperglycemic human umbilical vein endothelial cells (HUVECs). However, the mechanism by which propofol inhibits p66shc expression in hyperglycemic HUVECs is still obscure. In the present study, we mainly examined how propofol inhibited high glucose-induced p66shc expression in HUVECs. Compared with 5 mM glucose treatment, high glucose increased p66shc expression and decreased sirt1 expression, which was inhibited by propofol treatment. Moreover, EX527 (a sirt1 inhibitor) reversed the effect of propofol against high glucose-induced p66shc expression. However, EX527 did not reverse the effects of propofol against high glucose-induced ROS accumulation, endothelial inflammation, and apoptosis. Furthermore, when cells were incubated with propofol, EX527, and FTY720 (a PP2A activator) simultaneously, the effects of propofol against high glucose-induced ROS accumulation, inflammation, and apoptosis were reversed. Our results suggested that propofol inhibited high glucose-induced p66shc expression via upregulation of sirt1 expression in hyperglycemic HUVECs. Moreover, propofol protects against high glucose-mediated ROS accumulation and endothelial injury via both inhibition of p66shc expression and dephosphorylation of Ser36-p66shc.
    DOI:  https://doi.org/10.1093/abbs/gmy167
  5. J Cell Biochem. 2018 Dec 28.
    Reactive oxygen and nitrogen species induce cell apoptosis via a mitochondria-dependent pathway in hyperoxia lung injury.
    Dongmei Zou, Jing Li, Qianqian Fan, Xuemei Zheng, Jian Deng, Shaohua Wang.
      Hyperoxia-induced lung injury limits the application of mechanical ventilation on rescuing the lives of premature infants and seriously ill and respiratory failure patients, and its mechanisms are not completely understood. In this article, we focused on the relationship between hyperoxia-induced lung injury and reactive oxygen species (ROS), reactive nitrogen species (RNS), mitochondria damage, as well as apoptosis in the pulmonary epithelial II cell line RLE-6TN. After exposure to hyperoxia, the cell viability was significantly decreased, accompanied by the increase in ROS, nitric oxide (NO), inflammatory cytokines, and cell death. Furthermore, hyperoxia triggered the loss of mitochondrial membrane potential (▵Ψm), thereby promoting cytochrome c to release from mitochondria to cytoplasm. Further studies conclusively showed that the Bax/Bcl-2 ratio was enlarged to activate the mitochondria-dependent apoptotic pathway after hyperoxia treatment. Intriguingly, the effects of hyperoxia on the level of ROS, NO and inflammation, mitochondrial damage, as well as cell death were reversed by free radical scavengers N-acetylcysteine and hemoglobin. In addition, a hyperoxia model of neonatal Sprague-Dawley (SD) rats presented the obvious characteristics of lung injury, such as a decrease in alveolar numbers, alveolar mass edema, and disorganized pulmonary structure. The effects of hyperoxia on ROS, RNS, inflammatory cytokines, and apoptosis-related proteins in lung injury tissues of neonatal SD rats were similar to that in RLE-6TN cells. In conclusion, mitochondria are a primary target of hyperoxia-induced free radical, whereas ROS and RNS are the key mediators of hyperoxia-induced cell apoptosis via the mitochondria-dependent pathway in RLE-6TN cells.
    Keywords:  apoptosis; free radical; hyperoxia lung injury; mitochondria damage
    DOI:  https://doi.org/10.1002/jcb.27382
  6. J Cancer Res Ther. 2018 ;14(7): 1540-1548
    Selenocystine inhibits JEG-3 cell growth in vitro and in vivo by triggering oxidative damage-mediated S-phase arrest and apoptosis.
    Ming Zhao, Yajun Hou, Xiaoting Fu, Dawei Li, Jingyi Sun, Xiaoyan Fu, Zhigang Wei.
      Background: Selenocystine (SeC) is a nutritionally available selenoamino acid presenting novel anticancer potential against human cancers. However, neither the effects nor mechanism of SeC against choriocarcinoma growth has been clarified yet. This study investigated the anticancer effects and mechanism of SeC against JEG-3 human choriocarcinoma growth in vitro and in vivo.Materials and Methods: The in vitro anticancer efficiency was evaluated with cell viability, apoptosis, and oxidative stress. JEG-3 cell viability was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Cell cycle distribution and apoptosis were examined by flow cytometric analysis. Oxidative damage was detected with immunofluorescence and western blotting. The in vivo anticancer efficiency was evaluated in immunodeficient mouse model of choriocarcinoma. The mechanism was also investigated.
    Results: SeC dose and time dependently inhibited the viability of JEG-3 cells in vitro. The result of flow cytometry (FCM) analysis showed that obvious S-phase arrest and cell apoptosis were initiated by SeC in JEG-3 cells, which was further convinced by the decreased levels of cyclin A, poly-ADP-ribose polymerase cleavage, and activation of caspase-3,-7, and-9. In addition, SeC resulted in significant generation of reactive oxygen species (ROS) and superoxide anion, followed by the activation of DNA damage. However, SeC-induced oxidative damage and apoptosis were effectively blocked after ROS inhibition. Further investigation indicated that SeC effectively suppressed JEG-3 choriocarcinoma tumor xenograft growth in vivo. The mechanism may be the induction of cell apoptosis and oxidative damage through inhibiting cell proliferation (Ki-67) and angiogenesis (CD-31).
    Conclusions: Our findings supported that human choriocarcinoma growth could be inhibited by SeC in vitro and in vivo through triggering oxidative damage-mediated S-phase arrest and apoptosis. Thus, SeC may be promising in the treatment of human choriocarcinoma.
    Keywords:  Apoptosis; S-phase arrest; choriocarcinoma; reactive oxygen species; selenocystine
    DOI:  https://doi.org/10.4103/jcrt.JCRT_864_17
  7. Asian Pac J Cancer Prev. 2018 Dec 25. 19(12): 3479-3488
    Induction of Apoptosis by an Extract of Persian Gulf Marine Mollusc, Turbo Coronatus through the Production of Reactive Oxygen Species in Mouse Melanoma Cells
    Fatemeh Zangeneh, Amir Vazirizadeh, Mohammad Reza Mirshamsi, Amir Fakhri, Mehrdad Faizi, Jalal Pourahmad.
      Objective: A variety of approaches such as surgery, chemotherapy, radiotherapy, hormonal therapy and immunotherapy are used to treat melanomas, but unfortunately in most case, the response is very weak and often side effects are serious. This study concerns selective toxicity of an extract of Turbo coronatus on cells and mitochondria from a syngeneic mouse model of melanoma. Methods: Cells and mitochondria isolated from extra tumoral and melanoma tissues were exposed toa T. coronatus crude extract and fractions obtained by gel-filtration chromatography and assayed for mitochondrial and cellular parameters. Result: Crude extract (375, 750 and 1,500 μg/ml) and fraction 1; F1; (275, 550 and 1100 μg/ml) of T. coronatus extract induced a significant (p<0.05) increase of the reactive oxygen species (ROS) level, swelling of mitochondria, collapse of mitochondrial membrane potential (MMP), release of cytochrome c and caspase-3 activation only in the mitochondria and cells obtained from melanoma but not extra tumoral tissues. In addition, the F1 fraction decreased the percentage of viable cells and induced apoptosis in melanoma cells. Conclusion: For the first time we could demonstrate that the F1 fraction of a T. coronatus extract, selectively induces ROS mediated cytotoxicity by directly targeting mitochondria in melanoma tissues and it may be a suitable candidate for novel drug treatment of malignant melanomas.
    Keywords:  Melanoma; turbo coronatus; mitochondria; apoptosis; gel filtration; Persian Gulf
  8. Toxicol Sci. 2018 Dec 27.
    The Critical Role of X Chromosome-linked Inhibitor of Apoptosis (XIAP) in Differential Synergism Induced by Pentachlorophenol and Copper-1,10-phenanthroline Complex in Normal and Cancer Liver Cells.
    Zhi-Guo Sheng, Chen Shen, Rui-Mei Fan, Xi-Juan Chao, Yu-Xiang Liu, Ben-Zhan Zhu.
      Chemical pollutants often co-occur and can interact to cause unexpected combined toxic effects. Both pentachlorophenol (PCP) and copper-1,10-phenanthroline [Cu(OP)2], used as wood preservatives, co-exist in fluids and tissues of ordinary population. Our previous studies demonstrate that a combination of sub-toxic PCP and Cu(OP)2 causes synergistic toxicity on E.coli and hepatocarcinoma cells. However, it is not clear whether this effect also occurs in normal hepatocytes; and if so, what are the differences as compared to the hepatocarcinoma cells. We demonstrate that the combination of low-toxic PCP and Cu(OP)2 (0-1.6 µM; PCP/Cu(OP)2 molar ratio: 2:1) induces a concentration-dependent intracellular copper accumulation, apoptosis, caspase-3/9 activation, depolarization of mitochondrial membrane potential, oxidative stress (reactive oxygen species increasing and glutathione/oxidized glutathione ratio decreasing) in both normal hepatocytes HL-7702 and hepatocarcinoma HepG2 cells. However, HepG2 cells are more susceptible to the above molecular events as compared with HL-7702 cells. Further data reveal that PCP/Cu(OP)2 markedly decreases X chromosome-linked inhibitor of apoptosis (XIAP), p-ERK-1/2, and p-JNK protein expression in HepG2, but not HL-7702. Overexpression of XIAP gene in HepG2 significantly blocks PCP/Cu(OP)2-induced cytotoxicity, caspase activity, apoptosis, ROS accumulation, and antioxidant genes expression. These results suggest that the combination of low-toxic PCP and Cu(OP)2 preferentially induce synergistic cytotoxicity in human hepatocarcinoma cells by XIAP-ROS-apoptosis pathway, compared to the normal hepatocytes. The present data not only confirm the synergistic toxicity of PCP/Cu(OP)2 combination in normal liver cells, but also suggest a possible opportunity in developing new therapeutic approaches for liver cancer by sensitizing cancer cells to chemotherapy.
    DOI:  https://doi.org/10.1093/toxsci/kfy307
  9. Mol Med Rep. 2018 Dec 21.
    Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells.
    Yue Wang, Ying-Hua Luo, Xian-Ji Piao, Gui-Nan Shen, Ling-Qi Meng, Yi Zhang, Jia-Ru Wang, Jin-Qian Li, Hao Wang, Wan-Ting Xu, Yang Liu, Yu Zhang, Tong Zhang, Shi-Nong Wang, Hu-Nan Sun, Ying-Hao Han, Mei-Hua Jin, Yan-Qing Zang, Dong-Jie Zhang, Cheng-Hao Jin.
      Derivatives of 1,4‑naphthoquinone have excellent anti‑cancer effects, but their use has been greatly limited due to their serious side effects. To develop compounds with decreased side effects and improved anti‑cancer activity, two novel types of 1,4‑naphthoquinone derivatives, 2,3‑dihydro‑2,3‑epoxy‑2‑propylsulfonyl‑5,8‑dimethoxy‑1,4‑naphthoquinone (EPDMNQ) and 2,3‑dihydro‑2,3‑epoxy‑2‑nonylsulfonyl‑5,8‑dimethoxy‑1,4‑naphthoquinone (ENDMNQ) were synthesized and their anti‑tumor activities were investigated. The effects of EPDMNQ and ENDMNQ on cell viability, apoptosis and accumulation of reactive oxygen species (ROS) in liver cancer cells were determined by MTT cell viability assay and flow cytometry. The expression levels of mitochondrial, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway‑associated proteins in Hep3B liver cancer cells were analyzed by western blot analysis. The results demonstrated that EPDMNQ and ENDMNQ inhibited the proliferation of liver cancer Hep3B, HepG2, and Huh7 cell lines but not that of normal liver L‑02, normal lung IMR‑90 and stomach GES‑1 cell lines. The number of apoptotic cells and ROS levels were significantly increased following treatment with EPDMNQ and ENDMNQ, and these effects were blocked by the ROS inhibitor N‑acetyl‑L‑cysteine (NAC) in Hep3B cells. EPDMNQ and ENDMNQ induced apoptosis by upregulating the protein expression of p38 MAPK and c‑Jun N‑terminal kinase and downregulating extracellular signal‑regulated kinase and STAT3; these effects were inhibited by NAC. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROS‑modulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4‑naphthoquinone derivatives may be useful as anticancer agents for the treatment of liver cancer.
    DOI:  https://doi.org/10.3892/mmr.2018.9785
  10. Biochem Biophys Res Commun. 2018 Dec 20. pii: S0006-291X(18)32553-1. [Epub ahead of print]
    Repressing of NHERF1 inhibits liver cancer progression by promoting the production of ROS.
    Jing Sun, Peng Li, Jian Yang.
      NHERF1/EBP50 is a PDZ-scaffold protein initially identified as an organizer and modulator of transporters and channels at the apical side of epithelia via actin-binding ezrin-moesin-radixin proteins. Presently, hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world and has no effective therapeutic strategies. In the present study, we attempted to explore the role of NHERF1 in regulating liver cancer progression. The results indicated that NHERF1 was significantly expressed in liver tumor samples compared to the corresponding adjacent normal tissues. HCC patients with low NHERF1 exhibited better survival rate. Additionally, repressing NHERF1 expression markedly down-regulated the cell proliferation. G0/G1 transition was highly induced by NHERF1 knockdown, accompanied with reduced expressions of Cyclin D1 and cyclin-dependent kinase 4 (CDK4), as well as the enhanced expression of p27, phosphatase and tensin homolog (PTEN) and p53. Moreover, NHERF1 suppression significantly induced apoptosis in liver cancer cells by promoting the activation of Caspase-3 and poly (ADP-ribose) polymerase (PARP). We also observed a remarkable increase of reactive oxygen species (ROS) production in NHERF1-knockdown cells, along with c-Jun-N-terminal kinase (JNK) phosphorylation. Importantly, suppressing ROS production abolished NHERF1 knockdown-induced JNK activation. Moreover, cell cycle-regulatory proteins meditated by NHERF1 knockdown in liver cancer cells were abrogated by the pre-treatment of ROS scavenger. Further, restraining ROS generation also diminished NHERF1 knockdown-induced apoptosis. In vivo, we also found that NHERF1 knockdown markedly reduced the tumor growth. In conclusion, the results suggested that NHERF1 played an essential role in regulating liver cancer progression, and repressing NHERF1 expression exhibited significant anticancer effects via the induction of G0/G1 phase arrest, apoptosis and ROS generation.
    Keywords:  Apoptosis; G0/G1 phase; Liver cancer; NHERF1; ROS production
    DOI:  https://doi.org/10.1016/j.bbrc.2018.11.121
  11. Food Chem Toxicol. 2018 Dec 25. pii: S0278-6915(18)30923-2. [Epub ahead of print]
    Intestinal epithelial cell apoptosis due to a hemolytic toxin from Vibrio vulnificus and protection by a 36 kDa glycoprotein from Rhus verniciflua Stokes.
    Young-Min Lee, Jong Pil Park, Kye-Taek Lim, Sei-Jung Lee.
      Rhus verniciflua stokes (RVS) has been used as a functional food to cure inflammatory diseases in Korea. In the present study, we carry out an investigation of the cellular mechanism of a 36 kDa glycoprotein isolated from RVS fruit (RVS glycoprotein) during the apoptosis of human gastrointestinal epithelial HCT116 cells induced by the hemolytic toxin (VvhA) produced by V. vulnificus. Recombinant protein (r) VvhA produced by V. vulnificus stimulated apoptosis by activating the phosphorylation of protein kinase C (PKC) through the production of intracellular reactive oxygen species (ROS). However, RVS glycoprotein significantly inhibited the level of ROS production and PKC activation in rVvhA-stimulated HCT116 cells. Interestingly, we found that RVS glycoprotein has inhibitory effects on the phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB), which are responsible for the expression of Bax and cleaved caspase-3 in HCT116 cells treated with rVvhA, respectively. On the basis of these results, we suggest that RVS glycoprotein blocks mitochondrial apoptotic cell death induced by rVvhA via the inhibition of ROS-mediated signaling events in HCT116 cells.
    Keywords:  Apoptosis; Caspase-3; Gastrointestinal epithelial cells; Rhus verniciflua Stokes; Vibrio vulnificus; VvhA
    DOI:  https://doi.org/10.1016/j.fct.2018.12.041
  12. J Cell Physiol. 2018 Dec 24.
    Induction of autophagic cell death in human ovarian carcinoma cells by Antrodia salmonea through increased reactive oxygen species generation.
    Hsin-Ling Yang, Ruei-Wan Lin, Palaniyandi Karuppaiya, Dony Chacko Mathew, Tzong-Der Way, Hui-Chang Lin, Chuan-Chen Lee, You-Cheng Hseu.
      We reported in our previously executed studies that the fermented culture broth of Antrodia salmonea (AS), a mushroom used in Taiwanese folk medicine induced reactive oxygen species (ROS)-mediated apoptosis in human ovarian carcinoma cells. In this study, we studied the anticancer efficacies of AS (0-240 μg/ml) by examining the key molecular events implicated in cell death associated with autophagy in SKOV-3 and A2780 human ovarian carcinoma cells and clarified the fundamental molecular mechanisms. Treatment of ovarian carcinoma cells with AS-induced autophagic cell death mediated by increased microtubule-associated protein LC3-II, GFP-LC3 puncta, and acidic vesicular organelle (AVO) formation. These events are linked with the activation of p62/SQSTM1, the inhibition of ATG4B, the expression of ATG7, and the dysregulation of Beclin-1/Bcl-2 (i.e., B-cell lymphoma 2). N-acetylcysteine inhibited AS-induced ROS generation, which in turn constricted AS-induced LC3 conversion, AVO formation, and ATG4B inhibition, indicating ROS-mediated autophagy cell death. In addition, the 3-methyladenine (3-MA) or chloroquine (CQ)-induced autophagy inhibition decreased AS-induced apoptosis. Additionally, apoptosis inhibition by Z-VAD-FMK, a pan-caspase inhibitor, substantially suppressed AS-induced autophagy. Furthermore, AS-inhibited HER-2/ neu and PI3K/AKT signaling pathways which were reversed by autophagy inhibitors 3-MA and CQ. Thus, A. salmonea is a potential chemopreventive agent that is capable of activating ROS-mediated autophagic cell death in ovarian carcinoma cells.
    Keywords:  Antrodia salmonea; ROS; autophagy; human ovarian carcinoma
    DOI:  https://doi.org/10.1002/jcp.27749
  13. Biochimie. 2018 Dec 19. pii: S0300-9084(18)30355-9. [Epub ahead of print]158 62-72
    l-arginine inhibited apoptosis of fish leukocytes via regulation of NF-κB-mediated inflammation, NO synthesis, and anti-oxidant capacity.
    Haiou Zheng, Qian Guo, Xuzhuo Duan, Zhen Xu, Qingchao Wang.
      The increased apoptosis plays an important role in bacterial invasion. In addition, LPS can induce inflammation and apoptosis of leukocytes via the production of reactive oxygen and nitrogen species. In the present study, we investigated the potential protective role of l-arginine (L-Arg) against the apoptosis of fish leukocytes in vitro. The results of Annexin V-FITC/PI staining and TUNEL assay indicated that L-Arg significantly alleviated the apoptosis of fish leukocytes induced by LPS at 24 h and 72 h post incubation (hpi). High caspase-3 activities induced by LPS at 72 hpi were significantly inhibited by L-Arg. Moreover, L-Arg supplementation also significantly decreased the mRNA expression levels of caspases at most time points, which contributed to the anti-apoptotic roles of L-Arg. Further analysis showed that L-Arg significantly inhibited the expression of several pro-inflammatory cytokines including IL-8 and TNF-α, partially via the down-regulation of the genes involved in NF-κB/MyD88 including NF-κB, IKKα and IKKγ. The down-regulation of these pro-inflammatory cytokines by L-Arg supplementation led to the further decrease in the expression of death receptor FasL, contributing to the anti-apoptotic effect of L-Arg. In addition, L-Arg supplementation increased both iNOS mRNA expression and NO production. The mRNA expressions of several anti-oxidant enzymes including SOD, CAT and GSHPx were also significantly increased after L-Arg supplementation, which accelerated the clearance of reactive oxygen species. In all, L-Arg inhibited apoptosis of fish leukocytes both via the increased NO production and antioxidant capacity and via the inhibition of inflammation mediated by NF-κB/MyD88 pathway.
    Keywords:  Apoptosis; Fish leukocytes; L-Arg; NF-κB
    DOI:  https://doi.org/10.1016/j.biochi.2018.12.010
  14. Biomed Pharmacother. 2018 Dec 19. pii: S0753-3322(18)37810-7. [Epub ahead of print]111 151-161
    INF2 regulates oxidative stress-induced apoptosis in epidermal HaCaT cells by modulating the HIF1 signaling pathway.
    Zhixiong Chen, Chenyu Wang, Nanze Yu, Loubin Si, Lin Zhu, Ang Zeng, Zhifei Liu, Xiaojun Wang.
      Promoting epidermal cell survival in an oxidative stress microenvironment is vital for skin regeneration after burns and/or wounds. However, few studies have explored the mediators related to epidermal cell apoptosis in an oxidative stress microenvironment. Cellular viability was determined using the MTT assay, TUNEL staining, western blot analysis and LDH release assay. Two independent siRNAs were transfected into HaCaT cell to repress INF2 and/or HIF1 in the presence of H2O2. Mitochondrial function was determined using JC-1 staining, mitochondrial ROS staining, immunofluorescence staining and western blotting. In the present study, our data demonstrated that the expression of inverted formin-2 (INF2) increased rapidly when the cells were exposed to H2O2. Interestingly, INF2 knockdown promoted HaCaT cell survival via reducing H2O2-mediated cell apoptosis. Molecular investigations demonstrated that INF2 deletion attenuated mitochondrial ROS overloading, restored the cellular redox balance, sustained the mitochondrial membrane potential, improved mitochondrial respiratory function and corrected the mitochondrial dynamics disorder in an H2O2-mimicking oxidative stress microenvironment. In addition, INF2 deletion upregulated the expression of HIF1. Interestingly, the inhibition of HIF1 increased cell death and caused mitochondrial stress despite the deletion of INF2, suggesting that the HIF1 signaling pathway is required for INF2 deletion-mediated HaCaT cell survival and mitochondrial protection. Altogether, our results identified INF2 as a novel apoptotic mediator for oxidative stress-mediated HaCaT cell death via modulating mitochondrial stress and repressing the HIF1 signaling pathway. This finding provides evidence to support the critical role played by the INF2-HIF1 axis in regulating mitochondrial stress and epidermal cell viability in an oxidative stress microenvironment.
    Keywords:  HIF1; HaCaT cell; INF2; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2018.12.046
  15. Inorg Chem. 2018 Dec 28.
    Ferrocenyl-Triphenyltin Complexes as Lysosome-Targeted Imaging and Anticancer Agents.
    Juanjuan Li, Xicheng Liu, Haifeng Zhang, Xingxing Ge, Yanhua Tang, Zhishan Xu, Laijin Tian, Xiangai Yuan, Xudong Mao, Zhe Liu.
      In this paper, two ferrocenyl-triphenyltin complexes were synthesized and characterized. Complex 2 is constructed as new multifunctional therapeutic platform for lysosome-targeted imaging and displayed much higher cytotoxicity than its analogue 1 by the introduction of a methyl group instead of a hydrogen atom in acylhydrazone. The cyclic voltammograms and reaction with GSH (glutathione) further confirmed that complex 1 has a reversible redox peak and can react with GSH, which indicate that complex 1 might lose its anticancer effect by undergoing reaction with GSH once it enters the cancer cell. Complex 2 could effectively catalyze the oxidation of NADH (the reduced form of nicotinamide adenine dinucleotide) to NAD+ and induce the production of reactive oxygen species (ROS), lead to caspase-dependent apoptosis through damaged mitochondria, simultaneously, accounting for the mitochondrial vacuolization and karyorrhexis. The caspase-3 activation and cytoplasmic vacuolation karyorrhexis induced by complex 2 revealed that the A549 cell lines might undergo cell death primarily mediated by apoptosis and oncosis; however, 1 cannot reproduce this effect. Taken together, these results indicated that complex 2 has more potential for evolution as a new bioimaging and anticancer agent.
    DOI:  https://doi.org/10.1021/acs.inorgchem.8b03305
  16. Molecules. 2018 Dec 26. pii: E80. [Epub ahead of print]24(1):
    Gigantol has Protective Effects against High Glucose-Evoked Nephrotoxicity in Mouse Glomerulus Mesangial Cells by Suppressing ROS/MAPK/NF-κB Signaling Pathways.
    Mei-Fen Chen, Shorong-Shii Liou, Tang-Yao Hong, Shung-Te Kao, I-Min Liu.
      Gigantol is a bibenzyl compound derived from several medicinal orchids. This biologically active compound has shown promising therapeutic potential against diabetic cataracts, but whether this compound exerts beneficial effects on the other diabetic microvascular complications remains unclear. This study was carried out to examine effects of gigantol on high glucose-induced renal cell injury in cultured mouse kidney mesangial cells (MES-13). MES-13 cells were pretreated with gigantol (1, 5, 10 or 20 μmol/L) for 1 h followed by further exposure to high (33.3 mmol/L) glucose for 48 h. Gigantol concentration dependently enhanced cell viability followed by high glucose treatment in MES-13 cells. High glucose induced reactive oxygen species (ROS) generation, malondialdehyde production and glutathione deficiency were recoved in MES-13 cells pretreated with gigantol. High glucose triggered cell apoptosis via the the loss of mitochondrial membrane potential, depletion of adenosine triphosphate, upregulation of caspases 9 and 3, enhancement of cytochrome c release, and subsequent interruption of the Bax/Bcl-2 balance. These detrimental effects were ameliorated by gigantol. High glucose also induced activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in MES-13 cells, which were blocked by gigantol. The results suggest that treatment MES-13 cells with gigantol halts high glucose-induced renal dysfunction through the suppression of the ROS/MAPK/NF-κB signaling pathways. Our data are of value to the understanding the mechanism for gigantol, and would benefit the study of drug development or food supplement for diabetes and nephropathy.
    Keywords:  MES-13 cells; NF-κB; diabetic nephropathy; gigantol; high glucose; mitogen-activated protein kinase
    DOI:  https://doi.org/10.3390/molecules24010080
  17. J Pharmacol Sci. 2018 Dec 06. pii: S1347-8613(18)30214-7. [Epub ahead of print]
    Carteolol hydrochloride reduces visible light-induced retinal damage in vivo and BSO/glutamate-induced oxidative stress in vitro.
    Masato Matsuo, Yoshiki Kuse, Kei Takahashi, Keiichi Kuwahara, Masaki Tanito, Sachiko Kaidzu, Masamitsu Shimazawa, Hideaki Hara, Akihiro Ohira.
      The purpose of this study was to determine whether carteolol eye drops, a β-adrenoceptor antagonist used as an intraocular hypotensive agent, has protective effects against the light-induced oxidative stress in retina. Dark-adapted pigmented rats were pre-treated with topical carteolol ophthalmic solution or saline and then exposed to visible light. The effects on electroretinogram (ERG), morphology, oxidative stress, and expression of mRNAs in the retinas were determined. The l-buthionine-(S,R)-sulfoximine (BSO)/glutamate-induced oxidative stress in 661 W cells, a murine photoreceptor cell line, was evaluated by cell death assays, production of reactive oxygen species (ROS), and activation of caspase. In vivo studies showed that exposure to light caused a decrease in the amplitudes of ERGs and the outer nuclear layer (ONL) thickness and an increase of the 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the ONL. These changes were significantly reduced by pre-treatment with carteolol. Carteolol also significantly up-regulated the mRNA levels of thioredoxin 1 and glutathione peroxidase 1 compared to saline-treated group. Moreover, carteolol and timolol, another β-adrenoceptor antagonist, significantly inhibited BSO/glutamate-induced cell death and reduced caspase-3/7 activity and ROS production in vitro. Therefore, carteolol could protect retina from light-induced damage with multiple effects such as enhancing the antioxidative potential and decreasing the intracellular ROS production.
    Keywords:  Antioxidative potential; Carteolol hydrochloride; Light-induced retinal damage; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.jphs.2018.11.010
  18. J Plant Physiol. 2018 Dec 12. pii: S0176-1617(18)30475-9. [Epub ahead of print]233 42-51
    Caspase-3-like activity and proteasome degradation in grapevine suspension cell cultures undergoing silver-induced programmed cell death.
    Antonio Filippi, Marco Zancani, Elisa Petrussa, Enrico Braidot.
      Toxic metal contamination is one of the major environmental concerns of the recent decade, due to the large application of metals in industrial, healthcare and commercial products, even in the form of nanostructures and nanomaterials. Nevertheless, the effects of silver (Ag+) on plants have not yet thoroughly elucidated. Therefore, suspension cell cultures of grapevine were used as a model for investigating silver toxicity. To do this, oxidative stress and programmed cell death (PCD), evaluated as reactive oxygen species production, caspase-3-like activity and ubiquitin-proteasome system, were investigated. As a result, the highest concentration (10 μM) of Ag+ caused a rapid (within 24 h) induction of PCD (approx. 80%), accompanied by generation of reactive oxygen species and activation of caspase-3-like activity. In the presence of specific inhibitor of this enzyme, a partial recovery of cell viability and a strong inhibition of caspase-3-like activity was observed. In addition, silver-induced PCD was accompanied either by increase of poly-ubiquitin conjugated proteins and degradation of subunit PBA1 of the proteasome 20S core, similarly to what found for metal-induced neurotoxicity in animals. The present study shows that silver could induce PCD in grapevine suspension cell cultures, mediated by caspase-3-like activity and oxidative stress. These effects were associated to accumulation of poly-ubiquitin conjugated proteins, suggesting the impairment of ubiquitin-proteasome complex, confirmed by the decrease of the PBA1 subunit. These findings indicate that animal and plant cells could share a common pathway in response to toxic metal, which involves PCD and disassembling of proteasome complex.
    Keywords:  Caspase-like proteins; Programmed cell death; Proteasome; Reactive oxygen species; Silver metal; Vitis vinifera
    DOI:  https://doi.org/10.1016/j.jplph.2018.12.003
  19. World J Gastroenterol. 2018 Dec 14. 24(46): 5246-5258
    Effect of photodynamic therapy with (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt on pancreatic cancer cells in vitro and in vivo.
    Yu-Jie Shen, Jia Cao, Fang Sun, Xiao-Lei Cai, Ming-Ming Li, Nan-Nan Zheng, Chun-Ying Qu, Yi Zhang, Feng Shen, Min Zhou, Ying-Wei Chen, Lei-Ming Xu.
      AIM: To investigate the antitumor effects and underlying mechanisms of (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt (YLG-1)-induced photodynamic therapy (PDT) on pancreatic cancer in vitro and in vivo.METHODS: YLG-1 is a novel photosensitizer extracted from spirulina. Its phototoxicity, cellular uptake and localization, as well as its effect on reactive oxygen species (ROS) production, apoptosis, and expression of apoptosis-associated proteins were detected in vitro. An in vivo imaging system (IVIS), the Lumina K imaging system, and mouse models of subcutaneous Panc-1-bearing tumors were exploited to evaluate the drug delivery pathway and pancreatic cancer growth in vivo.
    RESULTS: YLG-1 was localized to the mitochondria, and the appropriate incubation time was 6 h. Under 650 nm light irradiation, YLG-1-PDT exerted a potent cytotoxic effect on pancreatic cancer cells in vitro, which could be abolished by the ROS scavenger N-acetyl-L-cysteine (NAC). The death mode caused by YLG-1-PDT was apoptosis, accompanied by upregulated Bax and cleaved Caspase-3 and decreased Bcl-2 expression. The results from the IVIS images suggested that the optimal administration route was intratumoral (IT) injection and that the best time to conduct YLG-1-PDT was 2 h post-IT injection. Consistent with the results in vitro, YLG-1-PDT showed great growth inhibition effects on pancreatic cancer cells in a mouse model.
    CONCLUSION: YLG-1 is a potential photosensitizer for pancreatic cancer PDT via IT injection, the mechanisms of which are associated with inducing ROS and promoting apoptosis.
    Keywords:  (17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt; Antitumor effect; Pancreatic neoplasm; Photodynamic therapy
    DOI:  https://doi.org/10.3748/wjg.v24.i46.5246
  20. Nat Prod Res. 2018 Dec 27. 1-5
    Xanthatin mediates G2/M cell cycle arrest, autophagy and apoptosis via ROS/XIAP signaling in human colon cancer cells.
    Ya-di Geng, Lei Zhang, Guo-Yu Wang, Xiao-Jun Feng, Zhao-Lin Chen, Ling Jiang, Ai-Zong Shen.
      Xanthatin is a natural plant bicyclic sesquiterpene lactone extracted from Xanthium plants (Asteraceae). In the present study, we demonstrated for the first time that Xanthatin inhibited cell proliferation and mediated G2/M phase arrest in human colon cancer cells. Xanthatin also activated caspase and mediated apoptosis in these cells. Concomitantly, Xanthatin triggered cell autophagic response. We found down-regulation of X-linked inhibitor of apoptosis protein (XIAP) contribute to the induction of apoptosis and autophagy. Moreover, reactive oxygen species (ROS) production was triggered upon exposure to Xanthatin in colon cancer cells. ROS inhibitor N-acetylcysteine (NAC) significantly reversed Xanthatin-mediated XIAP down-regulation, G2/M phase arrest, apoptosis and autophagosome accumulation. In summary, our findings demonstrated that Xanthatin caused G2/M phase arrest and mediated apoptosis and autophagy through ROS/XIAP in human colon cancer cells. We provided molecular bases for developing Xanthatin as a promising antitumor candidate for colon cancer therapy. Abbreviations ROS reactive oxygen species DMSO dimethyl sulfoxide 5-FU 5-Fluorouracil 3-MA 3-Methyladenine DCFH-DA 2'7'-dichlorfluorescein-diacetate NAC N-acetylcysteine XIAP X-linked inhibitor of apoptosis protein.
    Keywords:  XIAP; Xanthatin; apoptosis; autophagy; cell cycle; colon cancer
    DOI:  https://doi.org/10.1080/14786419.2018.1544976
  21. Int J Biol Sci. 2018 ;14(14): 1974-1984
    Nitric oxide prevents H2O2-induced apoptosis in SK-N-MC human neuroblastoma cells.
    Yeong-Min Yoo, Eui-Man Jung, Changhwan Ahn, Eui-Bae Jeung.
      Nitric oxide (NO) is a cellular signaling molecule in many physiological and pathological processes including neuroprotector. Here we examined the antiapoptotic effect of NO in SK-N-MC cells. H2O2 treatment (10-200 μM) induced cell death in a dose-dependent manner and pretreatment of cells with 100 μM S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, attenuated the occurrence of H2O2-induced cell death. DAPI staining showed H2O2-induced nuclear fragmentation and NO treatment suppressed it. NO inhibited the proteolytic activation of caspase-3 and mitochondrial cytochrome c release. Treatment of soluble guanylyl cyclase inhibitor ODQ decreased the protective effect of SNAP on H2O2-treated cells and increased caspase 3-like enzyme activity and activation, cytochrome c release, PARP cleavage, and DNA fragmentation, indicating that cGMP is a key mediator in NO-mediated antiapoptosis. The cGMP analog 8-Br-cGMP blocked H2O2-induced apoptotic cell death; reduction of caspase-3 enzyme, cytochrome c release, and caspase-8 and -9. These preventive effects of SNAP and 8-Br-cGMP were suppressed by PKG inhibitor KT5823. Levels of PKGI, PKGII, and p-VASP proteins were increased by SNAP and 8-Br-cGMP and suppressed by KT5823 treatment. These results indicate that PKG is a downstream signal mediator in the suppression of apoptosis by NO and cGMP. Akt activation was inhibited the PI3K inhibitors LY294002 and Wortmannin, resulting in the inhibition of cell viability and increase of cytochrome c release. SNAP induced phosphorylation of Akt and Bad and then increased the interactions between 14-3-3β and p-Bad. These data suggest that the NO suppresses H2O2-induced SK-N-MC cell apoptosis by suppressing apoptosis signal mediating the interaction between 14-3-3β and Bad phosphorylation via PKG/PI3K/Akt.
    Keywords:  Akt; Nitric oxide; PI3K; PKG; hydrogen peroxide
    DOI:  https://doi.org/10.7150/ijbs.28050
  22. Oxid Med Cell Longev. 2018 ;2018 1610751
    Protection of Kaempferol on Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage.
    Weiwei Du, Yuanlong An, Xiangdong He, Donglei Zhang, Wei He.
      The protection of retinal pigment epithelium (RPE) injury plays an important role in the prevention of or in delaying the pathological progress of retinal degeneration diseases, like age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa. Oxidative stress has been identified as a major inducer of RPE injury, which eventually could lead to a loss of vision. Kaempferol is a natural flavonoid widely distributed in many edible plants, fruits, and traditional medicines and has been reported to have antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. The present study demonstrates that the total antioxidant capacity of kaempferol is approximately two times stronger than that of lutein which is also a natural antioxidant that is widely used in the prevention or treatment of AMD. Our data indicates that kaempferol protects human RPE cells (ARPE-19) from hydrogen peroxide- (H2O2-) induced oxidative cell damage and apoptosis through the signaling pathways involving Bax/Bcl-2 and caspase-3 molecules proofed by real-time PCR and Western blot results. Kaempferol also inhibits the upregulated vascular endothelial growth factor (VEGF) mRNA expression levels induced by H2O2 in ARPE-19 cells and affects the oxidation and antioxidant imbalanced system in ARPE-19 cells treated by H2O2 through the regulations of both the activities of reactive oxygen species (ROS) and superoxide dismutase (SOD). Furthermore, our in vivo experimental results show that in sodium iodate-induced retinal degeneration rat model, kaempferol could protect sodium iodate-induced pathological changes of retina tissue and retinal cells apoptosis as well as the upregulated VEGF protein expression in RPE cells. In summary, these novel findings demonstrate that kaempferol could protect oxidative stressed-human RPE cell damage through its antioxidant activity and antiapoptosis function, suggesting that kaempferol has a potential role in the prevention and therapeutic treatment of AMD or other retinal diseases mediated by oxidative stress.
    DOI:  https://doi.org/10.1155/2018/1610751
  23. Anim Reprod Sci. 2018 Dec 20. pii: S0378-4320(18)30796-6. [Epub ahead of print]
    Impact of post-thaw supplementation of semen extender with antioxidants on the quality and function variables of stallion spermatozoa.
    Favián Treulen, Luis Aguila, María Elena Arias, Ignacio Jofré, Ricardo Felmer.
      During cryopreservation procedures, the spermatozoa are exposed to physical and chemical stressors that generate an increase in the intracellular concentration of reactive oxygen species (ROS). If ROS concentrations are too great, this can lead to a state of oxidative stress that are detrimental to sperm quality. The aim of this study was to ascertain the profile the ROS production and assess the effects of post-thaw supplementation of a semen extender with different antioxidant compounds on the quality and function variables of frozen-thawed stallion spermatozoa incubated in vitro. Frozen-thawed stallion spermatozoa (2 × 106 cells/mL) were incubated with three different antioxidants (MnTBAP, NAC and FeTPPS) for 4 h at 38 °C. An untreated sperm suspension and a fresh sample were included as controls. Plasma membrane integrity (SYBR-14/PI), intracellular ROS concentration (DHE and ROS-ID™ total ROS/Superoxide Detection Kit), lipid peroxidation (BODIPY), DNA damage (TUNEL) and mitochondrial membrane potential (ΔΨm; TMRE/SYTOX) were evaluated by flow cytometry and fluorescence microscopy. In addition, sperm motility was evaluated using the ISAS system. Evaluations were performed at 0 and 4 h of incubation. The results indicate that superoxide anion is the main ROS produced by frozen-thawed stallion spermatozoa and that the use of MnTBAP improved sperm motility and viability, decreased the lipid peroxidation and DNA damage. In conclusion, this study provides relevant data to improve in vitro incubations conditions and to establish futures therapies using MnTBAP after thawing with the aim being to overcome the deleterious effects of semen cryopreservation and consequently preserve the stallion sperm quality through avoiding oxidative stress.
    Keywords:  Antioxidants; Cryopreservation; Oxidative stress; Stallion sperm
    DOI:  https://doi.org/10.1016/j.anireprosci.2018.12.011
  24. J Pineal Res. 2018 Dec 25. e12543
    Melatonin protects in vitro matured porcine oocytes from toxicity of Aflatoxin B1.
    Linghua Cheng, Yusheng Qin, Xiao Hu, Likun Ren, Chao Zhang, Xiaodong Wang, Wenjuan Wang, Zhenni Zhang, Jin Hao, Min Guo, Zhonghong Wu, Jianhui Tian, Lei An.
      Aflatoxin B1 (AFB1) is a major food and feed contaminant that threaten public health. Previous studies indicate that AFB1 exposure disrupted oocyte maturation. However, an effective and feasible method is unavailable for protecting oocytes against toxicity of AFB1. In the present study, using in vitro matured porcine oocytes and parthenogenetic embryos as model, we confirmed that AFB1 exposure during in vitro oocyte maturation (IVM) significantly impaired both nuclear and cytoplasmic maturation in a dose and time-dependent manner. The different concentrations of melatonin were also tested for their protective effects on oocytes against the AFB1-induced toxicity. Our results showed that supplementation of a relative high concentration of melatonin (10-3 M) during IVM, efficiently reversed the impaired development rate and blastocyst quality, to the levels comparable to those of the control group. Further analysis indicated that melatonin application efficiently alleviated reactive oxygen species accumulation and initiation of apoptosis induced by AFB1 exposure. In addition, disrupted GSH/GPX system, as well as inhibited mitochondrial DNA (mtDNA) replication & mitochondrial biogenesis in AFB1-treated oocytes, can be notably reversed by melatonin application. Furthermore, cumulus cells may be important in mediating the toxicity of AFB1 to oocytes, and the metabolism of AFB1 in cumulus cells can be depressed by melatonin. To the best of our knowledge, this is the first report to confirm that melatonin application can efficiently protect oocytes from AFB1-induced toxicity. Our study provides a promising and practical strategy for alleviating or reversing AFB1-induced female reproductive toxicity in both clinical treatment and domestic reproductive management. This article is protected by copyright. All rights reserved.
    Keywords:  Aflatoxin B1; embryos; melatonin; oocytes; reactive oxygen species
    DOI:  https://doi.org/10.1111/jpi.12543
  25. Drug Des Devel Ther. 2018 ;12 4261-4271
    3-n-butylphthalide exerts neuroprotective effects by enhancing anti-oxidation and attenuating mitochondrial dysfunction in an in vitro model of ischemic stroke.
    Ningyuan Chen, Zhibing Zhou, Ji Li, Bocheng Li, Jihua Feng, Dan He, Yifeng Luo, Xiaowen Zheng, Jiefeng Luo, Jianfeng Zhang.
      Purpose: This study examined whether the neuroprotective drug, 3-n-butylphthalide (NBP), which is used to treat ischemic stroke, prevents mitochondrial dysfunction.Materials and methods: PC12 neuronal cells were pretreated for 24 hours with NBP (10 μmol/L), then exposed to oxygen and glucose deprivation (OGD) for 8 hours as an in vitro model of ischemic stroke. Indices of anti-oxidative response, mitochondrial function and mitochondrial dynamics were evaluated.
    Results: OGD suppressed cell viability, induced apoptosis and increased caspase-3 activity. NBP significantly reversed these effects. NBP prevented oxidative damage by increasing the activity of superoxide dismutase and lowering levels of malondialdehyde (MDA) and reactive oxygen species (ROS). At the same time, it increased expression of Nrf2, HO-1 and AMPK. NBP attenuated mitochondrial dysfunction by enhancing mitochondrial membrane potential and increasing the activity of mitochondrial respiratory chain complexes I-IV and ATPase. NBP altered the balance of proteins regulating mitochondrial fusion and division.
    Conclusion: NBP exerts neuroprotective actions by enhancing anti-oxidation and attenuating mitochondrial dysfunction. Our findings provide insight into how NBP may exert neuroprotective effects in ischemic stroke and raise the possibility that it may function similarly against other neurodegenerative diseases involving mitochondrial dysfunction.
    Keywords:  ischemic stroke; mitochondrial dynamics; mitochondrial dysfunction; neuroprotective
    DOI:  https://doi.org/10.2147/DDDT.S189472
  26. Theriogenology. 2018 Dec 18. pii: S0093-691X(18)31091-4. [Epub ahead of print]126 230-238
    Effect of myostatin inhibitor (myostatin pro-peptide) microinjection on in vitro maturation and subsequent early developmental stages of buffalo embryo.
    Mohammed A El-Magd, Amany M Ghoniem, Nashwa M Helmy, Ahmed Abdelfattah-Hassan, Ayman A Saleh, Emad A Abd Allah, Walaa M Essawi, Khaled A Kahilo.
      Expression of myostatin (MSTN, also known as growth differentiation factor 8, GDF8) was recently detected in cumulus-oocytes complexes (COCs), however little is known about its role in in vitro maturation (IVM) and fertilization (IVF) in large animals. Therefore, this study was designed to investigate the effect of MSTN inhibition on IVM of buffalo oocytes through investigation of IVM efficiency and expression of some specific genes in COCs from IVM till subsequent developmental stages following IVF. To reach this goal, we prepared a construct of adeno-associated virus (AAV) carrying MSTN pro-peptides (AAV-MSTNP) to inhibit MSTN. Over-expression of MSTNP was verified by upregulated expression of MSTNP and downregulated expression of the TGFβ receptor ActRIIb, the TGFβ signal transducer SMAD2 in COCs using qPCR. Microinjection of AAV-MSTNP to oocytes before IVM yielded a significant decrease in maturation rate as revealed by less cumulus cells expansion, fewer oocytes reaching metaphase II, and downregulation of cumulus expansion-related genes pentraxin 3 (Ptx3) and prostaglandin-endoperoxide synthase 2 (Ptgs2) as compared to the control and vehicle groups. These changes were also accompanied by elevated intracellular reactive oxygen species (ROS), upregulated expression of the apoptotic Bax gene, reduced antioxidant enzymes (SOD, CAT, GPX) activities, and downregulated expression of the antioxidant gene nuclear factor erythroid 2 like 2 (Nrf2), and the anti-apoptotic gene Bcl2 in COCs after IVM. Overexpression of MSTN inhibitor, MSTNP, also inhibited GDF9 and BMP15 genes expression in COCs. Additionally, both the fertilization efficiency and cleavage and blastocyst rates were significantly lower in MSTNP group than in the control and vehicle groups. The obtained data suggest an important role for MSTN during IVM and the subsequent developmental stages probably through, at least in part, inhibition of ROS production and apoptosis and modulation of IVM-related gene expression in COCs.
    Keywords:  Cumulus-oocytes complexes; In vitro maturation; Myostatin inhibition; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.theriogenology.2018.12.027
  27. Int J Nanomedicine. 2018 ;13 8487-8506
    Potential adverse effects of nanoparticles on the reproductive system.
    Ruolan Wang, Bin Song, Junrong Wu, Yanli Zhang, Aijie Chen, Longquan Shao.
      With the vigorous development of nanometer-sized materials, nanoproducts are becoming widely used in all aspects of life. In medicine, nanoparticles (NPs) can be used as nanoscopic drug carriers and for nanoimaging technologies. Thus, substantial attention has been paid to the potential risks of NPs. Previous studies have shown that numerous types of NPs are able to pass certain biological barriers and exert toxic effects on crucial organs, such as the brain, liver, and kidney. Only recently, attention has been directed toward the reproductive toxicity of nanomaterials. NPs can pass through the blood-testis barrier, placental barrier, and epithelial barrier, which protect reproductive tissues, and then accumulate in reproductive organs. NP accumulation damages organs (testis, epididymis, ovary, and uterus) by destroying Sertoli cells, Leydig cells, and germ cells, causing reproductive organ dysfunction that adversely affects sperm quality, quantity, morphology, and motility or reduces the number of mature oocytes and disrupts primary and secondary follicular development. In addition, NPs can disrupt the levels of secreted hormones, causing changes in sexual behavior. However, the current review primarily examines toxicological phenomena. The molecular mechanisms involved in NP toxicity to the reproductive system are not fully understood, but possible mechanisms include oxidative stress, apoptosis, inflammation, and genotoxicity. Previous studies have shown that NPs can increase inflammation, oxidative stress, and apoptosis and induce ROS, causing damage at the molecular and genetic levels which results in cytotoxicity. This review provides an understanding of the applications and toxicological effects of NPs on the reproductive system.
    Keywords:  ROS; nanoparticles; ovary; reproductive; sperm; toxic
    DOI:  https://doi.org/10.2147/IJN.S170723
  28. Neurochem Int. 2018 Dec 20. pii: S0197-0186(18)30577-1. [Epub ahead of print]124 31-40
    NADPH oxidase inhibitor apocynin decreases mitochondrial dysfunction and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging model in rats.
    Zheng-De Du, Shukui Yu, Yue Qi, Teng-Fei Qu, Lu He, Wei Wei, Ke Liu, Shu-Sheng Gong.
      Presbycusis has become a common sensory deficit in humans. Oxidative damage to mitochondrial DNA and mitochondrial dysfunction is strongly associated with the aging of the auditory system. A previous study established a mimetic rat model of aging using D-galactose (D-gal) and first reported that NADPH oxidase-dependent mitochondrial oxidative damage and apoptosis in the ventral cochlear nucleus (VCN) might contribute to D-gal-induced central presbycusis. In this study, we investigated the effects of apocynin, an NADPH oxidase inhibitor, on mitochondrial dysfunction and mitochondria-dependent apoptosis in the VCN of D-gal-induced aging model in rats. Our data showed that apocynin decreased NADPH oxidase activity, H2O2 levels, mitochondrial DNA common deletion, and 8-hydroxy-2-deoxyguanosine (8-OHdG) expression and increased total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activity in the VCN of D-gal-induced aging model in rats. Moreover, apocynin also decreased the protein levels of phospho-p47phox (p-p47phox), tumor necrosis factor alpha (TNFα), and uncoupling protein 2 (UCP2) in the VCN of D-gal-induced aging model in rats. Meanwhile, apocynin alleviated mitochondrial ultrastructure damage and enhanced ATP production and mitochondrial membrane potential (MMP) levels in the VCN of D-gal-induced aging model in rats. Furthermore, apocynin inhibited cytochrome c (Cyt c) translocation from mitochondria to the cytoplasm and suppressed caspase 3-dependent apoptosis in the VCN of D-gal-induced aging model in rats. Consequently, our findings suggest that neuronal survival promoted by an NADPH oxidase inhibitor is a potentially effective method to enhance the resistance of neurons to central presbycusis.
    Keywords:  Apocynin; Apoptosis; Central presbycusis; D-galactose; Mitochondrial dysfunction; NADPH oxidase
    DOI:  https://doi.org/10.1016/j.neuint.2018.12.008
  29. Exp Eye Res. 2018 Dec 19. pii: S0014-4835(18)30678-X. [Epub ahead of print]180 92-101
    A derivative of betulinic acid protects human Retinal Pigment Epithelial (RPE) cells from cobalt chloride-induced acute hypoxic stress.
    Zhengqi Cheng, Wenjuan Yao, Jian Zheng, Weimin Ding, Yang Wang, Ting Zhang, Ling Zhu, Fanfan Zhou.
      The Retinal Pigment Epithelium (RPE) is a monolayer of cells located above the choroid. It mediates human visual cycle and nourishes photoreceptors. Hypoxia-induced oxidative stress to RPE is a vital cause of retinal degeneration such as the Age-related Macular Degeneration. Most of these retinal diseases are irreversible with no efficient treatment, therefore protecting RPE cells from hypoxia stress is an important way to prevent or slow down the progression of retinal degeneration. Betulinic acid (BA) and betulin (BE) are pentacyclic triterpenoids with anti-oxidative property, but little is known about their effect on RPE cells. We investigated the protective effect of BA, BE and their derivatives against cobalt chloride-induced hypoxia stress in RPE cells. Human ARPE-19 cells were exposed to BA, BE and their eighteen derivatives (named as H3H20) that we customized through replacing moieties at C3 and C28 positions. We found that cobalt chloride reduced cell viability, increased Reactive Oxygen Species (ROS) production as well as induced apoptosis and necrosis in ARPE-19 cells. Interestingly, the pretreatment of 3-O-acetyl-glycyl- 28-O-glycyl-betulinic acid effectively protected cells from acute hypoxia stress induced by cobalt chloride. Our immunoblotting results suggested that this derivative attenuated the cobalt chloride-induced activation of Akt, Erk and JNK pathways. All findings were further validated in human primary RPE cells. In summary, this BA derivate has protective effect against the acute hypoxic stress in human RPE cells and may be developed into a candidate agent effective in the prevention of prevalent retinal diseases.
    Keywords:  Betulinic acid; Cobalt chloride; Hypoxic stress; Retinal Pigment Epithelium; Signaling pathways
    DOI:  https://doi.org/10.1016/j.exer.2018.12.011
  30. Eur J Pharmacol. 2018 Dec 21. pii: S0014-2999(18)30739-8. [Epub ahead of print]
    Genipin protects against cerebral ischemia-reperfusion injury by regulating the UCP2-SIRT3 signaling pathway.
    Busi Zhao, Sun Lian-Kun, Xianrui Jiang, Yong Zhang, Jinsong Kang, Hao Meng, Hongyan Li, Su Jing.
      Cerebral ischemia-reperfusion injury is a thorny issue in the treatment of stroke. Energy depletion and oxidative stress are the core mechanisms underlying cerebral ischemia-reperfusion injury. Mitochondrial function is involved in energy production and oxidative stress. It has been reported that mitochondrial uncoupling protein 2 (UCP2) may be involved in the regulation of cerebral ischemia-reperfusion injury. We hypothesized that UCP2 can regulate cerebral ischemia-reperfusion injury by regulating energy supply and oxidative stress. To test this hypothesis, we used a middle cerebral artery occlusion model in male C57BL/6 mice with/without genipin--an UCP2-specific inhibitor. We measured the expression and/or activity of UCP2, SIRT3, the levels of ATP, and antioxidant-related molecules in the cerebral cortex and the LDH in serum after ischemia-reperfusion, the level of apoptosis was reflected by the level of cleaved-caspase3 and tunel staining. The results showed an increase in the expression of UCP2, coinciding with an increase in the level of apoptosis, NAD+/NADH ratio, SIRT3 activity, LDH release and a decrease in the level of ATP and antioxidant-related molecules after 1h of ischemia and 24h of reperfusion. These findings suggest that UCP2 may regulate energy supply and oxidative stress in ischemia-reperfusion injury. Interestinly, above changes can be reserved by administration of genipin with the brain damage level going down. In conclusion, the UCP2-SIRT3 signaling pathway is involved in the regulation of cerebral ischemia-reperfusion injury as a bridge between energy metabolism and oxidative stress. Genipin protects against cerebral ischemia-reperfusion injury by inhibiting UCP2.
    Keywords:  Genipin; Ischemia-reperfusion injury; Mitochondria; SIRT3; UCP2
    DOI:  https://doi.org/10.1016/j.ejphar.2018.12.028
  31. Acta Histochem. 2018 Dec 24. pii: S0065-1281(18)30320-9. [Epub ahead of print]
    Effect of pristine and functionalized multiwalled carbon nanotubes on rat renal cortex.
    Maha Abu Gazia, Mohammed Abu El-Magd.
      The increasing application of carbon nanotubes (CNTs) within environmental, occupational and consumer settings has raised concerns regarding their biosafety and adverse effects on human health. The present study was designed to investigate the possible adverse effect of pristine and functionalized (amylated and polyethelene glycol coated) multi-walled (MW) CNTs on rat kidney with special concern to the histological alterations and the associated oxidative stress, apoptosis and inflammation. Healthy male albino rats (n = 40) were randomly divided into 4 groups: group I (control), group II (pristine MWCNTs), group III (amylated MWCNTs) and group IV [polyethelene glycol (PEG)-coated MWCNTs]. Animals of groups II, III and IV received a single dose of 1 mg/kg body weight of MWCNTs via intra-tracheal (IT) instillation at the beginning of the experiment and all rats were sacrificed after 30 days. Rats in groups II and III showed, nearly similar, renal tissue damage (evidenced by thin collapsed glomeruli, packed mesangial and endothelial cells as well as edematous hemorrhagic glomeruli with apoptotic changes) and functional disruptions (indicated by high serum levels of urea and creatinine) probably through induction of oxidative stress [revealed by high level of the lipid peroxidation marker malondialdehyde (MDA) and lower levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx)], apoptosis (indicated by high caspase 3 activity), and inflammation (evidenced by high level of IL1β). However, PEG-coated MWCNTs-treated group (group IV) showed nearly normal renal structure and function. It could be concluded that pristine and functionalized amylated MWCNTs have nephrotoxic effect, while PEG-coated MWCNTs had lowest, or none, toxic effects making them safer for therapy and diagnosis of a variety of diseases.
    Keywords:  Apoptosis; Carbon nanotubes; Inflammation; Oxidative stress; Renal damage
    DOI:  https://doi.org/10.1016/j.acthis.2018.12.005
  32. Oxid Med Cell Longev. 2018 ;2018 5297539
    Antioxidant Activities and Repair Effects on Oxidatively Damaged HK-2 Cells of Tea Polysaccharides with Different Molecular Weights.
    Xin-Yuan Sun, Jian-Min Wang, Jian-Ming Ouyang, Li Kuang.
      This study aims at investigating the antioxidant activity and repair effect of green tea polysaccharide (TPS) with different molecular weights (Mw) on damaged human kidney proximal tubular epithelial cells (HK-2). Scavenging activities on hydroxyl radical (·OH) and ABTS radical and reducing power of four kinds of TPS with Mw of 10.88 (TPS0), 8.16 (TPS1), 4.82 (TPS2), and 2.31 kDa (TPS3) were detected. A damaged cell model was established using 2.6 mmol/L oxalate to injure HK-2 cells. Then, different concentrations of TPSs were used to repair the damaged cells. Index changes of subcellular organelles of HK-2 cells were detected before and after repair. The four kinds of TPSs possessed radical scavenging activity and reducing power, wherein TPS2 with moderate Mw presented the strongest antioxidant activity. After repair by TPSs, cell morphology of damaged HK-2 cells was gradually restored to normal conditions. Reactive oxygen species production decreased, and mitochondrial membrane potential (Δψm) of repaired cells increased. Cells of G1 phase arrest were inhibited, and cell proportion in the S phase increased. Lysosome integrity improved, and cell apoptotic rates significantly reduced in the repaired group. The four kinds of TPSs with varying Mw displayed antioxidant activity and repair effect on the mitochondria, lysosomes, and intracellular DNA. TPS2, with moderate Mw, showed the strongest antioxidant activity and repair effect; it may become a potential drug for prevention and treatment of kidney stones.
    DOI:  https://doi.org/10.1155/2018/5297539
  33. Oxid Med Cell Longev. 2018 ;2018 6917206
    High Glucose-Induced ROS Production Stimulates Proliferation of Pancreatic Cancer via Inactivating the JNK Pathway.
    Jiao Luo, Yukai Xiang, Xiangxiang Xu, Dazhang Fang, Ding Li, Fubiao Ni, Xiandong Zhu, Bicheng Chen, Mengtao Zhou.
      Aberrant glucose metabolism of diabetes mellitus or hyperglycemia stimulates pancreatic tumorigenesis and progression. Hyperglycemic environment can increase the ROS level of tumors, but the role of upregulation of ROS levels in pancreatic cancer (PC) still remains controversial. Here, the same as other reports, we demonstrate that high glucose promoted pancreatic cancer cell growth and resulted in an increase in the level of ROS. However, it is interesting that the phosphorylation of JNK was reduced. When treating PC cells with N-acetyl-L-cysteine (NAC), the intracellular ROS generation is repressed, but the expression of phosphorylation of JNK and c-Jun increased. Moreover, the JNK inhibitor SP600125 significantly promoted cell proliferation and suppressed cell apoptosis of pancreatic cancer cells under high glucose conditions. Collectively, high levels of ROS induced by high glucose conditions stimulated the proliferation of pancreatic cancer cells, and it may be achieved by inactivating the JNK pathway.
    DOI:  https://doi.org/10.1155/2018/6917206
  34. Biomed Pharmacother. 2018 Dec 19. pii: S0753-3322(18)36650-2. [Epub ahead of print]111 109-118
    Mitochondrial division inhibitor-1 potentiates cisplatin-induced apoptosis via the mitochondrial death pathway in cholangiocarcinoma cells.
    Ornanong Tusskorn, Tueanjai Khunluck, Auemduan Prawan, Laddawan Senggunprai, Veerapol Kukongviriyapan.
      AIMS: Mdivi-1, a selective Drp-1 inhibitor, impedes mitochondrial dynamics and suppresses cancer proliferation and progression. Cholangiocarcinoma (CCA) is a very aggressive malignancy which is refractory to chemotherapy. The study investigated the mechanism of the chemosensitizing effect of mdivi-1 in cholangiocarcinoma.MAIN METHODS: CCA cells and HEK293 T cells were employed in the study. Cell viability and induction of apoptotic cell death were determined by the MTT and acridine orange-ethidium bromide methods. Cellular glutathione content and reactive oxygen species (ROS) formation were assessed using thiol green and 2',7'-dichlorofluorescin diacetate fluorescent probes, respectively. Mitochondrial transmembrane potential and autophagy were detected by JC-1 dye and autophagy assay. Cell cycle progression was analyzed by flow cytometry. Cell migration was measured using the wound healing assay. Proteins involved in cell proliferation and cell cycle were analyzed by western immunoblotting.
    KEY FINDINGS: Mdivi-1 enhanced cisplatin-induced cytotoxicity in CCA cells but not in HEK293 T cells. Mdivi-1 enhanced cisplatin induced glutathione redox stress, ROS formation, and loss of mitochondrial transmembrane potential. Moreover, mdivi-1 also inhibited autophagic flux and suppressed CCA cell migration.
    SIGNIFICANCE: Mdivi-1 sensitized CCA cells to cytotoxicity of cisplatin in association with increases of oxidative stress and autophagosomes, and induced cell death via the mitochondrial pathway. Disruption of mitochondrial dynamics may be a novel strategy to improve the efficacy of chemotherapy to treat CCA.
    Keywords:  Cholangiocarcinoma; Cisplatin; Mdivi-1; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biopha.2018.12.051
  35. PLoS One. 2018 ;13(12): e0208799
    Redox correlation in muscle lengthening and immune response in eccentric exercise.
    Feng He, Chia-Chen Chuang, Tingyang Zhou, Qing Jiang, Darlene A Sedlock, Li Zuo.
      This study was designed to examine the potential involvement of reactive oxygen species in skeletal muscle dysfunction linked with stretching in a mouse model and to explore the effects of combined antioxidant intake on peripheral leukocyte apoptosis following eccentrically-biased downhill runs in human subjects. In the mouse model, diaphragmatic muscle was stretched by 30% of its optimal length, followed by 5-min contraction. Muscle function and extracellular reactive oxygen species release was measured ex vivo. In human models, participants performed two trials of downhill running either with or without antioxidant supplementation, followed by apoptotic assay of inflammatory cells in the blood. The results showed that stretch led to decreased muscle function and prominent ROS increase during muscle contraction. In human models, we observed an elevation in circulating leukocyte apoptosis 24-48 hours following acute downhill runs. However, there is an attenuated leukocyte apoptosis following the second bout of downhill run. Interestingly, the combination of ascorbic acid (vitamin C) and α-tocopherol (vitamin E) supplementation attenuated the decrease in B-cell lymphoma 2 (Bcl-2) at 24 hours following acute downhill running. These data collectively suggest that significant ROS formation can be induced by muscle-lengthening associated with eccentric exercise, which is accompanied by compromised muscle function. The combination of antioxidants supplementation appears to have a protective role via the attenuation of decrease in anti-apoptotic protein.
    DOI:  https://doi.org/10.1371/journal.pone.0208799
  36. J Cell Biochem. 2018 Dec 28.
    Nrf2 dependent antiaging effect of milk-derived bioactive peptide in old fibroblasts.
    Naveen Kumar, Srinu Reddi, Savita Devi, Sanusi Bello Mada, Rajeev Kapila, Suman Kapila.
      Prolonged passaging of primary fibroblast cells totally shapes the natural biological phenomena and leads to the appearance of features related to senescence. As a result, it is a good natural tool to delineate the molecular mechanism of cellular aging. The present investigation revealed the antiaging effect of milk-derived novel bioactive peptide (VLPVPQK). The peptide played an important role in downregulating apoptosis-related markers in late passages of cultured fibroblast cells. The peptide treatment to aged fibroblasts caused enhancement in cell migration, DNA integrity, and decrease in the lipid peroxidation, reactive oxygen species, nitric oxide production as well as pro-inflammatory cytokines, TNF-α and IL-6. Moreover, the peptide decreased the expression of apoptotic caspases, Bax, and senescence-associated β-galactosidase (SA-β-gal) proteins. The peptide pretreatment also enhanced the extracellular collagen protein and antiapoptotic, Bcl-xL. In addition, the peptide treatment reversed the senescence-related activity in fibroblasts by stimulating Nrf2 mediated antioxidative defense system and inhibiting the action of NFkB/p38MAPK signaling, similar to the commercially available inhibitor (SB203580) of p38MAPK. Thus, the peptide exhibits the antiaging effect in dermal fibroblast cells.
    Keywords:  bioactive peptide; p38MAP kinase; prolonged serial passage; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1002/jcb.28246
  37. Proc Natl Acad Sci U S A. 2018 Dec 24. pii: 201811021. [Epub ahead of print]
    Mitochondria modulate programmed neuritic retraction.
    Sergei V Baranov, Oxana V Baranova, Svitlana Yablonska, Yalikun Suofu, Alberto L Vazquez, Takashi D Y Kozai, X Tracy Cui, Lisa M Ferrando, Timothy M Larkin, Yulia Y Tyurina, Valerian E Kagan, Diane L Carlisle, Bruce S Kristal, Robert M Friedlander.
      Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon "neuritosis." Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability.
    Keywords:  caspase-3; mitochondrial membrane potential; mutant huntingtin; neurite retraction; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.1811021116
  38. PLoS One. 2018 ;13(12): e0208802
    Rosmarinic acid induces programmed cell death in Arabidopsis seedlings through reactive oxygen species and mitochondrial dysfunction.
    Fabrizio Araniti, Aitana Costas-Gil, Luz Cabeiras-Freijanes, Antonio Lupini, Francesco Sunseri, Manuel J Reigosa, Maria Rosa Abenavoli, Adela M Sánchez-Moreiras.
      Phytotoxic potential of rosmarinic acid (RA), a caffeic acid ester largely found in aromatic species, was evaluated on Arabidopsis through metabolomic and microscopic approaches. In-vitro bioassays pointed out that RA affected root growth and morphology, causing ROS burst, ROS scavengers activity inhibition and consequently, an alteration on cells organization and ultrastructure. In particular, RA-treatment (175 μM) caused strong vacuolization, alteration of mitochondria structure and function and a consistent ROS-induced reduction of their transmembrane potential (ΔΨm). These data suggested a cell energy deficit also confirmed by the metabolomic analysis, which highlighted a strong alteration of both TCA cycle and amino acids metabolism. Moreover, the increase in H2O2 and O2- contents suggested that RA-treated meristems underwent oxidative stress, resulting in apoptotic bodies and necrotic cells. Taken together, these results suggest that RA inhibits two of the main ROS scavengers causing high ROS accumulation, responsible of the alterations on mitochondrial ultrastructure and activity through ΔΨm dissipation, TCA-cycle alteration, cell starvation and consequently cell death on Arabidopsis seedlings. All these effects resulted in a strong inhibition on root growth and development, which convert RA in a promising molecule to be explored for further use in weed management.
    DOI:  https://doi.org/10.1371/journal.pone.0208802
  39. Drug Chem Toxicol. 2018 Dec 26. 1-7
    Protocatechuic acid protects against menadione-induced liver damage by up-regulating nuclear erythroid-related factor 2.
    O B Ibitoye, T O Ajiboye.
      Menadione (Vitamin K3) is an over-the-counter (OTC) drug used in the treatment of abdominal cramps, colitis, diarrhea, hay fever, hemorrahage, hypoprothrombinemia, and joint pains. In this study, we evaluated the protective influence of protocatechuic acid on menadione-induced hepatotoxicity in rats. Rats were randomized into five groups (A-E) of five rats each. Control rats orally received 1% dimethyl sulfoxide (DMSO) in distilled water (the vehicle for protocatechuic administration) for 7 days. In addition, control rats intraperioneally received olive oil (vehicle for menadione administration) on the 7th day. Groups B, D, and E received single dose of 100 mg/kg body weight menadione on day 7. Furthermore, groups C-E were pretreated with protocatechuic acid for 7 days. Pretreatment of rats with protocatechuic acid significantly halted menadione mediated-alterations in serum alkaline phosphatase, alanine and aspartate aminotransferases, albumin, and total bilirubin. Furthermore, menadione-mediated increase in superoxide ion and hydrogen peroxide with concomitant decrease in the activities of superoxide dismutase and catalase were significantly reversed by protocatechuic acid. Protocatechuic acid annulled menadione-mediated decrease in glutathione S-transferase and NADH: quinone oxidoreductase-1 through nuclear erythroid related factor-2 (Nrf-2). In addition, the decreased glutathione and increased glutathione disulfide, caspase-3, fragmented DNA, malondialdehyde and protein carbonyl were reversed. Results of this study show that protocatechuic acid protects against menadione-induced oxidative stress in rats by enhancing the antioxidant and phase II enzymes through Nrf-2.
    Keywords:  DNA fragmentation; Phenolic acid; antioxidant enzymes; lipid peroxidation; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1080/01480545.2018.1523187
  40. Aging (Albany NY). 2018 Dec 26.
    Melatonin alleviates meiotic defects in fetal mouse oocytes induced by Di (2-ethylhexyl) phthalate in vitro.
    Zhong-Yi Sun, Pan Zhang, Jun-Jie Wang, Jing-Cai Liu, Lan Li, Wei Shen, Qiu-Yue Zhai.
      Di (2-ethylhexyl) phthalate (DEHP), an estrogen-like compound that is a ubiquitous environmental contaminant, has been reported to adversely affect human and mammalian reproduction. Many studies have found that exposure to DEHP during pregnancy perturbs female germ cell meiosis and is detrimental to oogenesis. Previous studies have demonstrated that melatonin (MLT) is beneficial to reproductive endocrinology, oogenesis, and embryonic development as the ability to antioxidative and antiapoptotic. However, whether the meiotic defect of germ cells exposed to DEHP could be rescued by MLT is not clear. Here, we cultured 12.5 days post coitum (dpc) fetal mouse ovaries for 6 days, exposed them to 100 μM DEHP with or without 1 μM MLT in vitro.. The results showed that DEHP exposure induced the abnormal formation of DNA double-strand breaks (DSBs), and inhibited the repair of DSBs during meiotic recombination. In addition, we found defective oocytes were prone to undergo apoptosis. Notably, this defect could be remarkably ameliorated by the addition of MLT via a reduction of the levels of reactive oxygen species and an inhibition of apoptosis. In conclusion, our data revealed that MLT had a protective action against the meiotic deterioration of fetal oocytes induced by DEHP in the mouse in vitro.
    Keywords:  DEHP; apoptosis; meiosis; melatonin; oocyte
    DOI:  https://doi.org/10.18632/aging.101715
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