bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019–03–03
sixty-two papers selected by
Gavin McStay, Staffordshire University
  1. Dihydrocaffeic Acid Prevents UVB-Induced Oxidative Stress Leading to the Inhibition of Apoptosis and MMP-1 Expression via p38 Signaling Pathway.
  2. Paraoxonase 2 protects against acute myocardial ischemia-reperfusion injury by modulating mitochondrial function and oxidative stress via the PI3K/Akt/GSK-3β RISK pathway.
  3. Acer okamotoanum protects SH-SY5Y neuronal cells against hydrogen peroxide-induced oxidative stress.
  4. Betaine protects against heat exposure-induced oxidative stress and apoptosis in bovine mammary epithelial cells via regulation of ROS production.
  5. Liraglutide protects renal mesangial cells against hyperglycemia‑mediated mitochondrial apoptosis by activating the ERK‑Yap signaling pathway and upregulating Sirt3 expression.
  6. Renalase attenuates mitochondrial fission in cisplatin-induced acute kidney injury via modulating sirtuin-3.
  7. The role of SIPK signaling pathway in antioxidant activity and programmed cell death of tobacco cells after exposure to cadmium.
  8. Relevance of Erk1/2-PI3K/Akt signaling pathway in CEES-induced oxidative stress regulates inflammation and apoptosis in keratinocytes.
  9. Differential response of immortalized human amnion mesenchymal and epithelial cells against oxidative stress.
  10. Ginsenoside Rk1 induces cell cycle arrest and apoptosis in MDA-MB-231 triple negative breast cancer cells.
  11. Isoliquiritigenin Induces Mitochondrial Dysfunction and Apoptosis by Inhibiting mitoNEET in a Reactive Oxygen Species-Dependent Manner in A375 Human Melanoma Cells.
  12. Tat-CIAPIN1 inhibits hippocampal neuronal cell damage through the MAPK and apoptotic signaling pathways.
  13. Propofol Ameliorates H9c2 Cells Apoptosis Induced by Oxygen Glucose Deprivation and Reperfusion Injury via Inhibiting High Levels of Mitochondrial Fusion and Fission.
  14. Notch pathway deactivation mediated by F-box/WD repeat domain-containing 7 ameliorates hydrogen peroxide-induced apoptosis in rat periodontal ligament stem cells.
  15. N-acetylcysteine attenuates PM2.5-induced apoptosis by ROS-mediated Nrf2 pathway in human embryonic stem cells.
  16. Effects of a novel biflavonoid of Lonicera japonica flower buds on modulating apoptosis under different oxidative conditions in hepatoma cells.
  17. Camellia euphlebia protects against corticosterone-induced apoptosis in differentiated PC12 cells by regulating the mitochondrial apoptotic pathway and PKA/CREB/BDNF signaling pathway.
  18. CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition.
  19. Ferulic Acid Protects Hyperglycemia-Induced Kidney Damage by Regulating Oxidative Insult, Inflammation and Autophagy.
  20. Long-chain noncoding RNA GAS5 mediates oxidative stress in cardiac microvascular endothelial cells injury.
  21. Toxicity of Fe2 O3 nanoparticles on human blood lymphocytes.
  22. Knockdown of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Sensitizes Glioma Cells to Hypoxia, Irradiation and Temozolomide.
  23. Cadmium-induced apoptosis through reactive oxygen species-mediated mitochondrial oxidative stress and the JNK signaling pathway in TM3 cells, a model of mouse Leydig cells.
  24. Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells.
  25. Baicalein inhibits matrix metalloproteinase 1 expression via activation of TRPV1-Ca-ERK pathway in ultraviolet B irradiated human dermal fibroblasts.
  26. Amino Acid Composition, Antioxidant, and Cytoprotective Effect of Blue Mussel (Mytilus edulis) Hydrolysate through the Inhibition of Caspase-3 Activation in Oxidative Stress-Mediated Endothelial Cell Injury.
  27. Phenethyl Isothiocyanate Exposure Promotes Oxidative Stress and Suppresses Sp1 Transcription Factor in Cancer Stem Cells.
  28. Ursolic Acid Induces Apoptotic Cell Death Through AIF and Endo G Release Through a Mitochondria-dependent Pathway in NCI-H292 Human Lung Cancer Cells In Vitro.
  29. Activation of TAp73 and inhibition of TrxR by Verteporfin for improved cancer therapy in TP53 mutant pancreatic tumors.
  30. In vitro antitumor potential of astaxanthin nanoemulsion against cancer cells via mitochondrial mediated apoptosis.
  31. Proanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway.
  32. Resveratrol alleviates hypoxia/reoxygenation injury‑induced mitochondrial oxidative stress in cardiomyocytes.
  33. Glycyrrhizin protects against sodium iodate-induced RPE and retinal injury though activation of AKT and Nrf2/HO-1 pathway.
  34. Hydrogen sulfide attenuates lung ischemia-reperfusion injury through SIRT3-dependent regulation of mitochondrial function in type 2 diabetic rats.
  35. Protective effect of myricetin derivatives from Syzygium malaccense against hydrogen peroxide-induced stress in ARPE-19 cells.
  36. Luteolin protects PC-12 cells from H2O2-induced injury by up-regulation of microRNA-21.
  37. Deltamethrin exposure induces oxidative stress and affects meiotic maturation in mouse oocyte.
  38. Inhibition of Caspase-1-dependent pyroptosis attenuates copper-induced apoptosis in chicken hepatocytes.
  39. Amyloid β Oligomers Increase ER-Mitochondria Ca2+ Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca2+ Remodeling.
  40. Plasticizer bis(2-ethylhexyl) phthalate causes meiosis defects and decreases fertilization ability of mouse oocytes in vivo.
  41. FCPR03, a novel phosphodiesterase 4 inhibitor, alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β/ β-catenin signaling pathway.
  42. Trametenolic acid B protects against cerebral ischemia and reperfusion injury through modulation of microRNA-10a and PI3K/Akt/mTOR signaling pathways.
  43. Mechanisms of vascular endothelial cell injury in response to intermittent and/or continuous hypoxia exposure and protective effects of anti-inflammatory and anti-oxidant agents.
  44. A new pyridazinone exhibits potent cytotoxicity on human cancer cells via apoptosis and poly-ubiquitinated protein accumulation.
  45. Inhibition of double-stranded RNA-dependent protein kinase prevents oxytosis and ferroptosis in mouse hippocampal HT22 cells.
  46. Altered Micro-RNA Regulation and Neuroprotection Activity of Eremostachys labiosiformis in Alzheimer's Disease Model.
  47. Combination of carnosine and asiatic acid provided greater anti-inflammatory protection for HUVE cells and diabetic mice than individual treatments of carnosine or asiatic acid alone.
  48. Isoliquiritigenin as an antioxidant phytochemical ameliorates the developmental anomalies of zebrafish induced by 2,2',4,4'-tetrabromodiphenyl ether.
  49. Evaluation of the anticancer potential of a sulphonamide carbonic anhydrase IX inhibitor on cervical cancer cells.
  50. Neuroprotection of hydroxysafflor yellow A in experimental cerebral ischemia/reperfusion injury via metabolic inhibition of phenylalanine and mitochondrial biogenesis.
  51. Chlorophyllin e6‑mediated photodynamic therapy inhibits proliferation and induces apoptosis in human bladder cancer cells.
  52. Anti-apoptotic Regulation Contributes to the Successful Nuclear Reprogramming Using Cryopreserved Oocytes.
  53. Baicalin improves IVM of pig oocytes and subsequent preimplantation embryo development by inhibiting apoptosis.
  54. Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice.
  55. Caffeic acid has antipromastigote activity by apoptosis-like process; and anti-amastigote by TNF-α/ROS/NO production and decreased of iron availability.
  56. Astaxanthin supplementation reduces dichlorvos-induced cytotoxicity in Saccharomyces cerevisiae.
  57. Duck Plague Virus Promotes DEF Cell Apoptosis by Activating Caspases, Increasing Intracellular ROS Levels and Inducing Cell Cycle S-Phase Arrest.
  58. Treatment with maresin 1, a docosahexaenoic acid-derived pro-resolution lipid, protects skin from inflammation and oxidative stress caused by UVB irradiation.
  59. F3, a novel active fraction of Valeriana jatamansi Jones induces cell death via DNA damage in human breast cancer cells.
  60. Effects of bradykinin on the survival of multiterritory perforator flaps in rats.
  61. Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4+ and CD8+ T-lymphocytes.
  62. ERRATUM.
  1. Oxid Med Cell Longev. 2019 ;2019 2419096
    Dihydrocaffeic Acid Prevents UVB-Induced Oxidative Stress Leading to the Inhibition of Apoptosis and MMP-1 Expression via p38 Signaling Pathway.
    Mariana M Oliveira, Bianca A Ratti, Regina G Daré, Sueli O Silva, Maria da Conceição T Truiti, Tânia Ueda-Nakamura, Rachel Auzély-Velty, Celso V Nakamura.
      Chronic UVB exposure promotes oxidative stress, directly causes molecular damage, and induces aging-related signal transduction, leading to skin photoaging. Dihydrocaffeic acid (DHCA) is a phenolic compound with potential antioxidant capacity and is thus a promising compound for the prevention of UVB-induced skin photodamage. The aim of this study was to evaluate the antioxidant and protective effect of DHCA against oxidative stress, apoptosis, and matrix metalloproteinase (MMP) expression via the mitogen-activated protein kinase (MAPK) signaling pathway on L929 fibroblasts irradiated with UVB. DHCA exhibited high antioxidant capacity on 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2-azinobis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS•+), and xanthine/luminol/xanthine oxidase (XOD) assays and reduced UVB-induced cell death in the neutral red assay. DHCA also modulated oxidative stress by decreasing intracellular reactive oxygen species (ROS) and extracellular hydrogen peroxide (H2O2) production, enhancing catalase (CAT) and superoxide dismutase (SOD) activities and reduced glutathione (GSH) levels. Hence, cellular damage was attenuated by DHCA, including lipid peroxidation, apoptosis/necrosis and its markers (loss of mitochondria membrane potential, DNA condensation, and cleaved caspase 9 expression), and MMP-1 expression. Furthermore, DHCA reduced the phosphorylation of MAPK p38. These findings suggest that DHCA can be used in the development of skin care products to prevent UVB-induced skin damage.
    DOI:  https://doi.org/10.1155/2019/2419096
  2. J Mol Cell Cardiol. 2019 Feb 22. pii: S0022-2828(19)30038-0. [Epub ahead of print]
    Paraoxonase 2 protects against acute myocardial ischemia-reperfusion injury by modulating mitochondrial function and oxidative stress via the PI3K/Akt/GSK-3β RISK pathway.
    Dawoud Sulaiman, Jingyuan Li, Asokan Devarajan, Christine Marie Cunningham, Min Li, Gregory A Fishbein, Alan M Fogelman, Mansoureh Eghbali, Srinivasa T Reddy.
       OBJECTIVE: To investigate the novel role of Paraoxonase 2 (PON2) in modulating acute myocardial ischemia-reperfusion injury (IRI).
    APPROACH: IRI was induced both in vivo and ex vivo in male, C57BL6/J (WT) and PON2-deficient (PON-def) mice. In addition, in vitro hypoxia-reoxygenation injury (HRI) was induced in H9c2 cells expressing empty vector (H9c2-EV) or human PON2 (H9c2-hPON2) ± LY294002 (a potent PI3K inhibitor). Infarct size, PON2 gene expression, mitochondrial calcium retention capacity (CRC), reactive oxygen species (ROS) generation, mitochondrial membrane potential, CHOP and pGSK-3β protein levels, and cell apoptosis were evaluated.
    RESULTS: PON2 gene expression is upregulated in WT mice following in vivo IRI. PON2-def mice exhibit a 2-fold larger infarct, increased CHOP levels, and reduced pGSK-3β levels compared to WT controls. Global cardiac mitochondria isolated from PON2-def mice exhibit reduced CRC and increased ROS production. Cardiomyocytes isolated from PON2-def mice subjected to ex vivo IRI have mitochondria with reduced CRC (also seen under non-IRI conditions), and increased ROS generation and apoptosis compared to WT controls. PON2 knockdown in H9c2 cells subjected to HRI leads to an increase in mitochondrial membrane depolarization. H9c2-hPON2 cells exhibit i) improvement in mitochondrial membrane potential, pGSK-3β levels and mitochondrial CRC, and ii) decrease in CHOP levels, mitochondrial ROS generation and cell apoptosis, when compared to H9c2-EV controls. Treatment with LY294002 resulted in a decrease of mitochondrial CRC and increase in mitochondrial ROS production and cell apoptosis in the H9c2-hPON2 group versus H9c2-EV controls.
    CONCLUSION: PON2 protects against acute myocardial IRI by reducing mitochondrial dysfunction and oxidative stress in cardiomyocytes via activation of the PI3K/Akt/GSK-3β RISK pathway.
    Keywords:  Calcium; Cardiomyocytes; Ischemia-reperfusion injury; Mitochondria; Myocardial infarction; Paraoxonase 2; Permeability transition pore; RISK pathway (PI3K/Akt/GSK-3β); Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.yjmcc.2019.02.008
  3. Food Sci Biotechnol. 2019 Feb;28(1): 191-200
    Acer okamotoanum protects SH-SY5Y neuronal cells against hydrogen peroxide-induced oxidative stress.
    Ji Hyun Kim, Sanghyun Lee, Eun Ju Cho.
      Oxidative stress by over-production of reactive oxygen species (ROS) in brain is widely known as a cause of neurodegenerative disease. We investigated protective effects of Acer okamotoanum against oxidative stress by hydrogen peroxide (H2O2) in SH-SY5Y neuronal cells. Acer okamotoanum reduced ROS production and lactate dehydrogenase release in H2O2-induced SH-SY5Y cells, resulting in elevation of cell viability. To elucidate protective mechanisms, we measured inflammation and apoptosis-associated protein expressions. Treatment with A. okamotoanum dose-dependently decreased pro-inflammatory proteins such as inducible nitric oxide synthase and cyclooxygenase-2. Treatment with A. okamotoanum showed down-regulation of pro-apoptosis genes such as cleaved caspase-3, cleaved caspase-9, and Bax, and up-regulation of anti-apoptosis protein including Bcl-2, in H2O2-induced SH-SY5Y cells. We demonstrated potential anti-inflammatory and anti-apoptotic effect of A. okamotoanum in H2O2-induced SH-SY5Y cells. These results suggest that A. okamotoanum may possess neuroprotective potential, but further study is necessary to elucidate its pharmacological effects in neurodegenerative diseases.
    Keywords:  Acer okamotoanum; Apoptosis; Hydrogen peroxide; Inflammation; Oxidative stress
    DOI:  https://doi.org/10.1007/s10068-018-0381-6
  4. Cell Stress Chaperones. 2019 Feb 25.
    Betaine protects against heat exposure-induced oxidative stress and apoptosis in bovine mammary epithelial cells via regulation of ROS production.
    Chengmin Li, Yiru Wang, Lian Li, Zhaoyu Han, Shengyong Mao, Genlin Wang.
      Heat stress is one of the wide varieties of factors which cause oxidative stress in vivo; elevated temperature can lead to oxidative stress of dairy cows that affects milk production. The aim of this study was to determine the capacity of the betaine to act as an antioxidant against oxidative stress induced by heat exposure and apoptosis in mammary epithelial cells (mammary alveolar cells, MAC-T). The MAC-T were divided into four treatment groups: control (37 °C), heat stress (HS, 42 °C), betaine (37 °C), and HS + betaine. MAC-T under heat stress (HS) showed increased ROS accumulation, malondialdehyde (MDA) content, superoxide dismutase (SOD) concentration, and catalase (CAT) activity. During heat stress, betaine decreased the mRNA expression level of HSP70 and HSP27 in MAC-T. Bax/Bcl-2 ratio and caspase-3, the markers of apoptosis, were also elevated in MAC-T under heat stress. The markers of oxidative stress Nrf-2/HO-1 genes were also elevated in MAC-T under heat stress. Pretreatment of betaine reversed the heat-induced depletion in total antioxidant status, ROS accumulation, and SOD and CAT contents in MAC-T. Bax/Bcl-2 ratio and Nrf-2/HO-1 expression of heat-exposed MAC-T were also reduced with betaine supplementation. In conclusion, betaine alleviated oxidative stress and apoptosis of MAC-T by inhibiting ROS accumulation.
    Keywords:  Apoptosis; Betaine; Heat stress; Mammary epithelial cells; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1007/s12192-019-00982-4
  5. Mol Med Rep. 2019 Feb 08.
    Liraglutide protects renal mesangial cells against hyperglycemia‑mediated mitochondrial apoptosis by activating the ERK‑Yap signaling pathway and upregulating Sirt3 expression.
    Jian Li, Nan Li, Shuangtong Yan, Yanhui Lu, Xinyu Miao, Zhaoyan Gu, Yinghong Shao.
      Diabetic nephropathy results from hyperglycemia‑mediated renal glomerular cell death via mitochondrial apoptosis. There is an emerging requirement for novel approaches with mitochondrial protective effects that alleviate the hyperglycemia‑induced loss of functional cells during diabetic renal damage. Liraglutide, a type of glucagon‑like peptide‑1 agonist, has been suggested to inhibit the progression of obesity and hyperglycemia. However, the contributions and mechanism of action of liraglutide on hyperglycemia‑mediated cell mitochondrial apoptosis in diabetic kidneys have not been illustrated. The present study demonstrated that liraglutide may protect human renal mesangial cells (HRMCs) against hyperglycemia‑induced cell death by inhibiting mitochondrial apoptosis. Liraglutide administration also maintained HRMC viability and promoted HRMC proliferation within a high glucose stress environment. Functional studies demonstrated that hyperglycemia triggered mitochondrial dysfunction, including mitochondrial potential reduction, mitochondrial permeability transition pore opening, reactive oxygen species overproduction and the activation of the mitochondrial apoptotic pathway. However, liraglutide treatment preserved mitochondrial function and prevented activation of mitochondrial apoptosis by upregulating sirtuin 3 (Sirt3) expression. Deletion of Sirt3 abrogated the protective effects of liraglutide on mitochondrial homeostasis following high glucose challenge. In addition, molecular analysis confirmed that liraglutide upregulated Sirt3 via activating the extracellular signal‑regulated kinase‑Yes‑associated protein (ERK‑Yap) signaling pathway. Inhibition of the ERK‑Yap axis negated the action of liraglutide on Sirt3 activation, leading to mitochondrial injury and HRMC apoptosis. Taken together, the present study illustrated that liraglutide protected renal mesangial cells from hyperglycemia‑mediated mitochondrial apoptosis by upregulating Sirt3 expression and activation of the ERK‑Yap signaling pathway.
    DOI:  https://doi.org/10.3892/mmr.2019.9946
  6. Life Sci. 2019 Feb 21. pii: S0024-3205(19)30132-8. [Epub ahead of print]
    Renalase attenuates mitochondrial fission in cisplatin-induced acute kidney injury via modulating sirtuin-3.
    Zhimin Huang, Qing Li, Yanggang Yuan, Chengning Zhang, Lin Wu, Xi Liu, Wei Cao, Honglei Guo, Suyan Duan, Xueqiang Xu, Bo Zhang, Changying Xing.
       AIMS: Acute kidney injury (AKI) can limit the clinical use of cisplatin in cancer treatment. The drivers of cisplatin-induced AKI include oxidative stress, mitochondrial dysfunction and apoptosis. Previous studies showed renalase protected cultured human renal proximal tubular cell (HK-2) against cisplatin induced necrosis, and renalase-knockout mice subjected to cisplatin showed exacerbated kidney injury. Therefore, it is necessary to determine the exact mechanisms of renalase in cisplatin-induced nephrotoxicity.
    MAIN METHODS: To study the protective effect of renalase on cell viability, renal function, apoptosis, reactive oxygen species (ROS) production and mitochondrial dynamics, cultured HK-2 cells and male mice were subjected to cisplatin. Signaling proteins related to apoptosis, survival, and mitochondrial fission were analyzed by Western blot.
    KEY FINDINGS: In this study, we showed that the protective effect of recombinant renalase in cisplatin-induced AKI was associated with the regulation of ROS production, mitochondrial dynamics and sirtuin-3 (Sirt3) levels in vivo and in vitro. After cisplatin treatment, recombinant renalase restored Sirt3 expression, reduced mitochondrial fission and ROS generation. In HK-2 cells, downregulation of endogenous Sirt3 expression by siRNA transfection abrogated the renalase cytoprotection.
    SIGNIFICANCE: Our study suggests that renalase protects against cisplatin-induced AKI by improving mitochondrial function and inhibiting oxidative stress, and in vitro, it functions in a Sirt3-dependent manner.
    Keywords:  Cisplatin nephrotoxicity; Mitochondrial fission; Renalase; Sirtuin-3
    DOI:  https://doi.org/10.1016/j.lfs.2019.02.042
  7. Plant Sci. 2019 Mar;pii: S0168-9452(18)31316-5. [Epub ahead of print]280 416-423
    The role of SIPK signaling pathway in antioxidant activity and programmed cell death of tobacco cells after exposure to cadmium.
    Mohammad Pormehr, Faezeh Ghanati, Mohsen Sharifi, Paul F McCabe, Saman Hosseinkhani, Hassan Zare-Maivan.
      Cadmium (Cd) toxicity induces oxidative burst and leads to programmed cell death (PCD) in plant cells. The role of salicylic acid-induced protein kinase (SIPK) signaling pathway in Cd-induced oxidative stress was investigated in suspension-cultured tobacco (Nicotiana tabacum L. cv. Barley 21). The cells were pretreated with 40 μM PD98059 (inhibitor of MAPKK) and then exposed to 50 μM Cd for 24 h. The percentages of cell viability, apoptosis, necrosis, and the content of reactive oxygen species (ROS) were monitored by flow cytometry. Expression of PCD related gene (Hsr203J) and the contents of certain signaling molecules were measured as well. The results showed that Cd increased the expression of SIPK, Hsr203J, and CAT genes, the activities of catalase and caspase-3-like enzymes. Addition of PD98059 inhibitor reduced the expression of Hsr203J and CAT genes, decreased CAT activity, but increased ROS and SA contents, and caspase-3-like activity and apoptosis rate. The highest apoptosis level was accompanied by the highest level of Hsr203J gene expression. From the results it can be suggested that upon treatment of tobacco cells with Cd, internal SA content increased and induced the SIPK signaling pathway, thereby inhibited the antioxidant system and led to PCD.
    Keywords:  Cadmium; Nicotiana tabacum; Oxidative burst; Programmed cell death; SIPK; Salicylic acid
    DOI:  https://doi.org/10.1016/j.plantsci.2018.12.028
  8. Cell Biol Toxicol. 2019 Feb 25.
    Relevance of Erk1/2-PI3K/Akt signaling pathway in CEES-induced oxidative stress regulates inflammation and apoptosis in keratinocytes.
    Silpa Sabnam, Arttatrana Pal.
      2-Chloroethyl ethyl sulfide (CEES) is a well-known chemical warfare agent that induces cellular stress in exposed individuals. However, molecular mechanisms of CEES-induced oxidative stress-mediated metabolic deregulation are not clearly elucidated. Here we investigated CEES-induced free radical production act as key functional mediators of metabolic stress via Erk1/2 mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K/Akt) signaling cascades in keratinocytes. We observed that CEES exposure disrupts the cellular antioxidant defense capacities leading to increase in free oxygen and nitrogen radical accumulation in keratinocytes. These unusual cellular abnormalities initiate cellular stress via Erk1/2-PI3K/Akt signaling pathways. Biochemical tools were used to analyze the changes in metabolites including sulfur amino acids (SAAs), namely, L-glutathione (GSH) and L-cysteine (Cys), in the presence of selective inhibitors of reactive oxygen/nitrogen species (ROS/RNS), Erk1/2, or PI3K/Akt after CEES exposure. Importantly, these metabolite changes were accompanied by a decrease in the glycolytic flux, consistent with the observed decrease in 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) concentration and these CEES-induced phenomena were attenuated by pretreatment of Erk1/2 or PI3-K/Akt inhibitors. On the other hand, CEES exposure disrupts the protein carbonylation (PC) and lipid peroxidation (LPO) in keratinocytes leading to inflammation, crash of the cell-cell communication, cell cycle deregulation, and apoptosis via Erk1/2-PI3K/Akt pathways. However, pretreatment of Erk1/2 or PI3K/Akt inhibitors attenuated the CEES action. Collectively, these results illustrated that accumulated free radicals act as key functional mediators for inflammation, and apoptosis via Erk1/2-PI3K/Akt regulatory signaling cascades induced by CEES exposure. Treatment of pharmacological Erk1/2-PI3K/Akt inhibitors attenuated the CEES-induced keratinocyte injury that may provide the basis for the development of therapeutic strategy to work against CEES exposure.
    Keywords:  Apoptosis; CEES; Erk1/2-PI3K/Akt; Inflammation; Metabolites; Oxidative stress
    DOI:  https://doi.org/10.1007/s10565-019-09467-7
  9. Free Radic Biol Med. 2019 Feb 23. pii: S0891-5849(18)31708-8. [Epub ahead of print]
    Differential response of immortalized human amnion mesenchymal and epithelial cells against oxidative stress.
    Lu Guang Han, Qing-Li Zhao, Toshiko Yoshida, Motonori Okabe, Chika Soko, Mati Ur Rehman, Takashi Kondo, Toshio Nikaido.
      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.
    Keywords:  Amniotic cells; Apoptosis; Radiology; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.02.017
  10. Toxicology. 2019 Feb 21. pii: S0300-483X(18)30719-4. [Epub ahead of print]
    Ginsenoside Rk1 induces cell cycle arrest and apoptosis in MDA-MB-231 triple negative breast cancer cells.
    Yinan Hong, Daidi Fan.
      Ginsenoside Rk1 (Rk1) is a component presented in processed ginseng and it possess anti-insulin resistance, anti-inflammation and anti-cancer activities. However, there are few reports on the anti-triple negative breast cancer effect of Rk1. In this study, the anti-proliferation effects and mechanisms of Rk1 in MDA-MB-231 triple negative breast cancer cells were investigated. A breast cancer xenograft model showed that Rk1 significantly repressed tumor growth with low toxicity for major organs. Moreover, Rk1 dramatically inhibited cell proliferation, colony formation, promoted LDH release, and induced G0/G1 phase arrest. Rk1 also triggered intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential reduction. Western blot results revealed that Rk1 increased the expression of Bax, cytochrome C, cleaved caspase 3, 8 and 9 levels and decreased Bcl-2 level. Furthermore, Rk1 inhibited the phosphorylation of PI3K, Akt and mTOR. Pretreatment with pan-caspase inhibitor Z-VAD-FMK, PI3K specific inhibitor LY294002 and ROS scavenger N-acetylcysteine (NAC) further demonstrated that ROS/PI3K/Akt pathway was responsible for Rk1-induced apoptosis. Taken together, this work first illustrated the anti-triple negative breast cancer effects and mechanisms of Rk1 and ginsenoside Rk1 could be a new promising anti-tumor drug for breast cancer.
    Keywords:  MDA-MB-231 cells; ROS/PI3K/Akt signaling pathway; apoptosis; cell cycle arrest; ginsenoside Rk1
    DOI:  https://doi.org/10.1016/j.tox.2019.02.010
  11. Oxid Med Cell Longev. 2019 ;2019 9817576
    Isoliquiritigenin Induces Mitochondrial Dysfunction and Apoptosis by Inhibiting mitoNEET in a Reactive Oxygen Species-Dependent Manner in A375 Human Melanoma Cells.
    Xiao-Yu Chen, Huan-Huan Ren, Dan Wang, Ying Chen, Chuan-Jun Qu, Zhao-Hai Pan, Xiao-Na Liu, Wen-Jin Hao, Wen-Juan Xu, Ke-Jun Wang, De-Fang Li, Qiu-Sheng Zheng.
      The mitochondrial protein mitoNEET is a type of iron-sulfur protein localized to the outer membrane of mitochondria and is involved in a variety of human pathologies including cystic fibrosis, diabetes, muscle atrophy, and neurodegeneration. In the current study, we found that isoliquiritigenin (ISL), one of the components of the root of Glycyrrhiza glabra L., could decrease the expression of mitoNEET in A375 melanoma cells. We also demonstrated that mitoNEET could regulate the content of reactive oxygen species (ROS), by showing that the ISL-mediated increase in the cellular ROS content could be mitigated by the mitoNEET overexpression. We also confirmed the important role of ROS in ISL-treated A375 cells. The increased apoptosis rate and the decreased mitochondrial membrane potential were mitigated by the overexpression of mitoNEET in A375 cells. These findings indicated that ISL could decrease the expression of mitoNEET, which regulated ROS content and subsequently induced mitochondrial dysfunction and apoptosis in A375 cells. Our findings also highlight mitoNEET as a promising mitochondrial target for cancer therapy.
    DOI:  https://doi.org/10.1155/2019/9817576
  12. Free Radic Biol Med. 2019 Feb 25. pii: S0891-5849(19)30126-1. [Epub ahead of print]
    Tat-CIAPIN1 inhibits hippocampal neuronal cell damage through the MAPK and apoptotic signaling pathways.
    Hyeon Ji Yeo, Min Jea Shin, Eun Ji Yeo, Yeon Joo Choi, Dae Won Kim, Duk-Soo Kim, Won Sik Eum, Soo Young Choi.
      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.
    Keywords:  Apoptosis; Ischemia; Protein therapy; ROS; Tat-CIAPIN1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.02.028
  13. Front Pharmacol. 2019 ;10 61
    Propofol Ameliorates H9c2 Cells Apoptosis Induced by Oxygen Glucose Deprivation and Reperfusion Injury via Inhibiting High Levels of Mitochondrial Fusion and Fission.
    Lidong Zhao, Jinqiang Zhuang, Yihui Wang, Dandan Zhou, Dandan Zhao, Shun Zhu, Jinjun Pu, Hongyu Zhang, Ming Yin, Wenjuan Zhao, Zejian Wang, Jiang Hong.
      Background: The cardioprotective effect of propofol on ischemia-reperfusion injury (I/R injury) is partly due to suppressing apoptosis. Mitochondrial dynamics are also involved in apoptosis. Mitochondrial fusion and fission lead to mitochondrial morphological changes. However, whether suppressing apoptosis effect of propofol against ischemia-reperfusion injury in the heart is via regulating mitochondrial morphology remains unclear. Methods: H9c2 cells underwent oxygen glucose deprivation (OGD) followed by reperfusion to simulate cardiomyocytes ischemia/reperfusion injury. Cell viability, apoptosis ratio and intracellular reactive oxygen species (ROS) were assessed, respectively. Mitochondrial membrane dynamin family proteins, extracellular signal regulated kinase 1 and 2 (ERK1/2), phosphorylated extracellular signal regulated kinase 1 and 2 (p-ERK1/2) and proteins related to intrinsic apoptosis pathways were detected by western blotting. The mitochondrial morphology and the distribution of dynamin-related protein 1 (Drp1) were observed by using laser confocal microscopy. Results: Propofol enhanced the survival of H9c2 cells, decreased ROS levels and inhibited apoptosis during oxygen glucose deprivation/reperfusion (OGD/R) injury. Mitochondrial fission in H9c2 cells was inhibited by propofol during OGD injury. Propofol alleviated high levels of mitochondrial fusion and fission during OGD/R in H9c2 cells, by regulating mitochondrial membrane remodeling dynamin family proteins. Propofol inhibited Drp1 colocalization with mitochondria in H9c2 cells during OGD/R injury. Moreover, Drp1 phosphorylation was inhibited by propofol through decreasing ERK activation during OGD/R injury. We found that propofol ameliorated H9c2 cells apoptosis during OGD/R via inhibiting mitochondrial cytochrome c release and caspase-9, caspase-6, caspase-7 and caspase-3 activation. Conclusion: Propofol suppresses H9c2 cells apoptosis during OGD/R injury via inhibiting intrinsic apoptosis pathway, which may be partly due to reducing high levels of mitochondrial fusion and fission induced by OGD/R injury.
    Keywords:  apoptosis; ischemia; mitochondrial dynamics; propofol; reperfusion
    DOI:  https://doi.org/10.3389/fphar.2019.00061
  14. Arch Oral Biol. 2019 Feb 19. pii: S0003-9969(18)30516-8. [Epub ahead of print]100 93-99
    Notch pathway deactivation mediated by F-box/WD repeat domain-containing 7 ameliorates hydrogen peroxide-induced apoptosis in rat periodontal ligament stem cells.
    Yimiao Feng, Xiaohui Fu, Xintian Lou.
       OBJECTIVE: To investigate the protective role of F-box/WD repeat domain-containing 7 in rat periodontal ligament stem cells under oxidative stress.
    MATERIALS AND METHODS: The apoptosis of rat periodontal ligament stem cells was induced by exposure to various concentrations of hydrogen peroxide for 24 h, after which cell viability and the cleaved caspase-3 and -9 levels were determined. The levels of proteins in the Notch signaling pathway were determined by western blotting.
    RESULTS: The overexpression of F-box/WD repeat domain-containing 7 increased cell viability following hydrogen peroxide administration and suppressed the activation of caspases-3 and -9. The overexpression of F-box/WD repeat domain-containing 7 inhibited Notch signaling. Furthermore, the protective effect of F-box/WD repeat domain-containing 7 could be resumed by PF-03084014, a Notch-specific inhibitor.
    CONCLUSIONS: These observations suggest a protective role of F-box/WD repeat domain-containing 7 against hydrogen peroxide-induced oxidative stress in rat periodontal ligament stem cells. These findings will facilitate the in vitro culturing of periodontal ligament stem cell for clinical usage and promote stem cell-based therapy for periodontal tissue regeneration.
    Keywords:  Apoptosis; F-box/WD repeat domain-containing 7; Notch; Rat periodontal ligament stem cells; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.archoralbio.2019.02.010
  15. Sci Total Environ. 2019 Feb 20. pii: S0048-9697(19)30806-X. [Epub ahead of print]666 713-720
    N-acetylcysteine attenuates PM2.5-induced apoptosis by ROS-mediated Nrf2 pathway in human embryonic stem cells.
    Lifang Jin, Jian Ni, Yuan Tao, Xinyi Weng, Yuling Zhu, Junyan Yan, Baowei Hu.
      While the effects of fine particulate matter (PM2.5) on embryonic toxicity are widely accepted, its exact mechanisms have not yet been fully elucidated, which partially attribute to lack of ideal research model. Embryonic stem cells (ESCs) have the capacity to differentiate into all cell types of three germ layers. Thus, they are ideal resources for the reproductive toxicity assessment in vitro. In the present study, we investigated the effects of PM2.5 exposure on the oxidative stress and apoptosis of human ESCs (hESCs) and its possible mechanism. Our results showed that strong cytotoxicity high reactive oxygen species (ROS) level and fragmentation of nuclei were observed in the PM2.5-treated hESCs. Meanwhile, up-regulation of apoptosis as well as down-regulation of Nrf2 signaling pathway were also observed after PM2.5 treatment. However, we did not detect significant expression change or phosphorylation of Akt and Erk in PM2.5-treated hESCs. Interestingly, scavenging of PM2.5-induced ROS by N-acetylcysteine (NAC) could block cell apoptosis and rescue the activity of Nrf2 signaling pathway. In conclusion, we demonstrate that PM2.5 is toxic to hESCs by inhibition of ROS-mediated Nrf2 pathway activity. Our findings suggest activation of Nrf2 pathway will help develop new strategies for the prevention and treatment of PM2.5-associated disease.
    Keywords:  Apoptosis; Human embryonic stem cells; N-acetylcysteine; Nrf2 pathway; Oxidative stress; PM(2.5)
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.02.307
  16. Phytomedicine. 2018 Dec 31. pii: S0944-7113(18)30636-6. [Epub ahead of print]57 282-291
    Effects of a novel biflavonoid of Lonicera japonica flower buds on modulating apoptosis under different oxidative conditions in hepatoma cells.
    Haoqiang Wan, Lanlan Ge, Jiemei Li, Keda Zhang, Weigang Wu, Shusong Peng, Xiaoting Zou, Huirong Zhou, Boping Zhou, Xiaobin Zeng.
       BACKGROUND: In our previous work, we purified a novel biflavonoid named Japoflavone D (JFD) from Lonicera japonica flower buds. Biflavonoids are chemical compounds characterized by their high levels of antioxidative activity.
    PURPOSE: The present study aimed to investigate the function and molecular mechanism of JFD under different oxidative conditions in hepatoma cells.
    METHODS: MTT assay and apoptosis assay were used to evaluate the cytotoxic effect of JFD. The activities of SOD and CAT were detected to evaluate the oxidative level. Oxidative stress was induced by H2O2 stimulation. The molecular mechanism of JFD was investigated by analyzing relative signaling pathway.
    RESULTS: JFD inhibited cell viability in all hepatoma cell lines we examined. Under quiescent conditions, JFD treatment of SMMC-7721 cells resulted in upregulation of AKT/mTOR signal pathway and ERK activities and downregulation of KEAP1/NRF2/ARE signaling axis, together with apoptosis. However, under oxidative stress, JFD played a quite different role. Treatment of JFD suppressed the activation of ERK and mTOR and activated the KEAP1/NRF2/ARE signaling axis, which is a predominant regulator of cytoprotective responses to oxidative stress, thereby lessening the damage caused by excess reactive oxygen species (ROS). A molecular docking analysis suggested that JFD may interrupt the interaction between KEAP1 and NRF2 by competitively anchoring to the NRF2 binding site on KEAP1.
    CONCLUSION: The results indicate that JFD functions as a potent antioxidant and plays dual roles in modulating apoptosis under different oxidative conditions. JFD has the potential to be developed as a protective drug for diseases related with excess ROS.
    Keywords:  Apoptosis; Biflavonoids; ERK; KEAP1/NRF2/ARE; Liver diseases; ROS
    DOI:  https://doi.org/10.1016/j.phymed.2018.12.044
  17. Food Chem Toxicol. 2019 Feb 25. pii: S0278-6915(19)30081-X. [Epub ahead of print]
    Camellia euphlebia protects against corticosterone-induced apoptosis in differentiated PC12 cells by regulating the mitochondrial apoptotic pathway and PKA/CREB/BDNF signaling pathway.
    Dongye He, Ning Wang, Xuan Sai, Xiaoyu Li, Yongping Xu.
      Camellia euphlebia is a Chinese folk medicine, known for its multiple pharmacological properties. Our previous studies have demonstrated its antidepressant activity by several animal models of depression. The possible underlying mechanism was further explored by investigating the neuroprotective effect of Camellia euphlebia extract (CEE) on corticosterone-induced apoptosis in neuronally differentiated PC12 cells. The results of methyl-thiazolyl-tetrazolium assay, lactate dehydrogenase release assay, Hoechst 33342 staining, propidium iodide staining, AV-FITC/PI double staining and DNA fragmentation analysis consistently indicated that pretreatment of PC12 cells with CEE at 20-80 μg/mL significantly reversed 300 μmol/L corticosterone-induced apoptosis in a dose dependent manner. Furthermore, intracellular mitochondrial membrane potential, reactive oxygen species accumulation, calcium level, Bcl-2/Bax ratio, caspase activity were assessed, and the results indicated that CEE exhibited its anti-apoptotic effect through the regulation of mitochondrial apoptosis pathway. Additionally, CEE increased the cyclic adenosine monophosphate-dependent protein kinase (PKA) level, which phosphorylated cAMP response element binding protein (CREB), and finally elevated the mRNA expression of brain-derived neurotrophic factor (BDNF) gene. It is speculated that the antidepressant effect of CEE in vivo may be associated with the cytoprotection of neuron damaged by corticosterone, and the cellular mechanism involves the mitochondrial-mediated apoptosis and PKA-CREB-BDNF signaling pathway.
    Keywords:  Apoptosis; Brain derived neurotrophic factor; Camellia euphlebia; Corticosterone; Differentiated PC12 cells; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.fct.2019.02.028
  18. Int J Gynecol Cancer. 2017 Sep;27(7): 1306-1317
    CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition.
    Yen-Yun Wang, Pei-Wen Hsieh, Yuk-Kwan Chen, Stephen Chu-Sung Hu, Ya-Ling Hsu, Chun-Hao Tsai, Shyng-Shiou F Yuan.
       OBJECTIVE: The β-nitrostyrene family has been reported to possess anticancer properties. However, the anticancer activity of β-nitrostyrenes on cervical cancer cells and the underlying mechanisms involved remain unexplored. In this study, a β-nitrostyrene derivative CYT-Rx20 (3'-hydroxy-4'-methoxy-β-methyl-β-nitrostyrene) was synthesized, and its anticancer activity on cervical cancer cells and the mechanisms involved were investigated.
    METHODS: The effect of CYT-Rx20 on human cervical cancer cell growth was evaluated using cell viability assay. Reactive oxygen species (ROS) generation and annexin V staining were detected by flow cytometry. The protein expression levels of cleaved caspase-3, cleaved caspase-9, cleaved poly (ADPribose) polymerase, γH2AX, β-catenin, Vimentin, and Twist were measured by Western blotting. DNA double-strand breaks were determined by γ-H2AX foci formation and neutral comet assay. Migration assay was used to determine cancer cell migration. Nude mice xenograft was used to investigate the antitumor effects of CYT-Rx20 in vivo.
    RESULTS: CYT-Rx20 induced cytotoxicity in cervical cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited cervical cancer cell migration by regulating the expression of epithelial-to-mesenchymal transition markers. In nude mice, CYT-Rx20 inhibited cervical tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of mesenchymal markers β-catenin and Twist.
    CONCLUSIONS: CYT-Rx20 inhibits cervical cancer cells in vitro and in vivo and has the potential to be further developed into an anti-cervical cancer drug clinically.
    Keywords:  Apoptosis; Cervical cancer; DNA damage; Migration; ROS; β-Nitrostyrene
    DOI:  https://doi.org/10.1097/IGC.0000000000001033
  19. Front Pharmacol. 2019 ;10 27
    Ferulic Acid Protects Hyperglycemia-Induced Kidney Damage by Regulating Oxidative Insult, Inflammation and Autophagy.
    Sayantani Chowdhury, Sumit Ghosh, Abhishek Kumar Das, Parames C Sil.
      Oxidative insult, inflammation, apoptosis and autophagy play a pivotal role in the etiology of diabetic nephropathy, a global health concern. Ferulic acid, a phytochemical, is reported to protect against varied diseased conditions. However, the ameliorative role and mechanisms of ferulic acid in averting STZ-mediated nephrotoxicity largely remains unknown. For in vivo study, a single intraperitoneal injection of streptozotocin (50 mg kg-1 body wt.) was administered in experimental rats to induce diabetes. The diabetic rats exhibited a rise in blood glucose level as well as kidney to body weight ratio, a decrease in serum insulin level, severe kidney tissue damage and dysfunction. Elevation of intracellular ROS level, altered mitochondrial membrane potential and cellular redox balance impairment shown the participation of oxidative stress in hyperglycemia-triggered renal injury. Treatment with ferulic acid (50 mg kg-1 body wt., orally for 8 weeks), post-diabetic induction, could markedly ameliorate kidney injury, renal cell apoptosis, inflammation and defective autophagy in the kidneys. The underlying mechanism for such protection involved the modulation of AGEs, MAPKs (p38, JNK, and ERK 1/2), NF-κB mediated inflammatory pathways, mitochondria-dependent and -independent apoptosis as well as autophagy induction. In cultured NRK-52E cells, ferulic acid (at an optimum dose of 75 μM) could counter excessive ROS generation, induce autophagy and inhibit apoptotic death of cells under high glucose environment. Blockade of autophagy could significantly eradicate the protective effect of ferulic acid in high glucose-mediated cell death. Together, the study confirmed that ferulic acid, exhibiting hypoglycemic, antioxidant, anti-inflammatory, anti-apoptotic activities and role in autophagy, could circumvent oxidative stress-mediated renal cell damage.
    Keywords:  apoptosis; autophagy; diabetes; ferulic acid; inflammation; kidney; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2019.00027
  20. J Cell Physiol. 2019 Mar 01.
    Long-chain noncoding RNA GAS5 mediates oxidative stress in cardiac microvascular endothelial cells injury.
    Liwei Diao, Long Bai, Xingpei Jiang, Jianjun Li, Qinghua Zhang.
      This study is performed to figure out the role of long-chain noncoding RNA growth-arrest specific transcript 5 (GAS5) in homocysteine (HCY)-induced cardiac microvascular endothelial cells (CMECs) injury. CMECs were cultured and the model of CMECs injury was established by coincubation with HCY. To construct stable overexpression of GAS5 cells, the expression of GAS5, microRNA-33a-5p (miR-33a-5p) and ATP-binding cassette transporter A1 (ABCA1), and biological characteristics of cells were determined. The messenger RNA (mRNA) level and secretion of vascular endothelial growth factor (VEGF), activity of reactive oxygen species (ROS) and superoxide dismutase (SOD), and the content of malondialdehyde (MDA) were measured. The binding site between GAS5 and miR-33a-5p and between miR-33a-5p and ABCA1 was verified. CMECs were successfully cultured. Reduction of GAS5 expression and ABCA1 expression together with increased expression of miR-33a-5p was found in CMECs induced by HCY. After overexpression of GAS5, there showed increased proliferative activity, decreased cell apoptosis rate and apoptosis index, enhanced cell migration ability, increased number of lumen formation, increased mRNA expression of VEGF in cells and the secretion in the supernatant, decreased activity of ROS and SOD in cells, and decreased content of ROS in cells. miR-33a-5p could promote the enrichment of GAS5 and ABCA1 was the direct target gene of miR-33a-5p. Our study suggests that the low expression of GAS5 was observed in HCY-induced CMECs injury, and the upregulation of GAS5 could attenuate HCY-induced CMECs injury by mediating oxidative stress, and its mechanism is related to the upregulation of ABCA1 expression by competitively binding with miR-33a-5p.
    Keywords:  GAS5; angiogenesis; apoptosis; cardiac microvascular endothelial cells; migration; oxidative stress injury; proliferation
    DOI:  https://doi.org/10.1002/jcp.28388
  21. J Biochem Mol Toxicol. 2019 Feb 27. e22303
    Toxicity of Fe2 O3 nanoparticles on human blood lymphocytes.
    Evelyn Assadian, Hamid Dezhampanah, Enayatollah Seydi, Jalal Pourahmad.
      Magnetic nanoparticles (NPs) are used to a large extent in the targeted delivery of therapeutic agents. In this study, we aimed to investigate the possible toxicity of Fe2 O 3 NPs on human cells, including blood lymphocytes. We isolated blood lymphocytes from healthy humans using Ficoll polysaccharide and subsequently by gradient centrifugation. Then, the toxicity parameters, including cell viability, reactive oxygen species (ROS) formation, lipid peroxidation, cellular glutathione (GSH) level, mitochondrial and lysosomal damage, were measured in blood lymphocytes after exposure to Fe 2 O 3 NPs. Our results indicated that Fe 2 O 3 NPs significantly (dependent on concentration) reduced the cell viability, and the IC 50 was determined to be 1 mM. With increasing concentrations, we found that Fe 2 O 3 NPs-induced cell toxicity was associated with a significant increase in intracellular ROS and loss of mitochondrial membrane potential and lysosomal membrane leakiness. Consequently, these NPs at different concentrations affect GSH level and cause oxidative stress in human lymphocytes.
    Keywords:  Fe2O3 NPs; cytotoxicity; lysosomes; mitochondria; oxidative stress (OS)
    DOI:  https://doi.org/10.1002/jbt.22303
  22. Int J Mol Sci. 2019 Mar 01. pii: E1061. [Epub ahead of print]20(5):
    Knockdown of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Sensitizes Glioma Cells to Hypoxia, Irradiation and Temozolomide.
    Gabriele D Maurer, Sonja Heller, Christina Wanka, Johannes Rieger, Joachim P Steinbach.
      The TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to decrease glycolysis, to activate the pentose phosphate pathway, and to provide protection against oxidative damage. Hypoxic regions are considered characteristic of glioblastoma and linked with resistance to current treatment strategies. Here, we established that LNT-229 glioma cell lines stably expressed shRNA constructs targeting TIGAR, and exposed them to hypoxia, irradiation and temozolomide. The disruption of TIGAR enhanced levels of reactive oxygen species and cell death under hypoxic conditions, as well as the effectiveness of irradiation and temozolomide. In addition, TIGAR was upregulated by HIF-1α. As a component of a complex network, TIGAR contributes to the metabolic adjustments that arise from either spontaneous or therapy-induced changes in tumor microenvironment.
    Keywords:  TP53-induced glycolysis and apoptosis regulator; glioma; hypoxia; hypoxia-inducible factor; irradiation; reactive oxygen species; temozolomide
    DOI:  https://doi.org/10.3390/ijms20051061
  23. Toxicol Appl Pharmacol. 2019 Feb 21. pii: S0041-008X(19)30069-9. [Epub ahead of print]368 37-48
    Cadmium-induced apoptosis through reactive oxygen species-mediated mitochondrial oxidative stress and the JNK signaling pathway in TM3 cells, a model of mouse Leydig cells.
    Susu Wang, Xiangmei Ren, Xindi Hu, Li Zhou, Chaoqin Zhang, Meirong Zhang.
      Cadmium (Cd) is a heavy metal that widely exists in the environment and industry, and which causes serious damages to reproductive system. Recent studies have reported that cadmium induces apoptosis of various germ cells in testes, resulting in male infertility. However, the exact mechanism of cadmium-induced apoptosis remains unclear. In this study, we hypothesized that reactive oxygen species (ROS)-mediated c-jun N-terminal kinase (JNK) signaling pathway was involved in cadmium-induced apoptosis in TM3 cells, a model of mouse Leydig cells. TM3 cells were exposed for various times to a range of cadmium concentrations. We found that cadmium reduced TM3 cell viability and increased apoptosis in a time- and dose- dependent manner. Moreover, the levels of ROS generation and the phosphorylation of JNK were elevated by cadmium treatment. In addition, the nuclear transcription factor c-jun was significantly activated, which led to increased expression of downstream c-jun targets and Bcl-2 was decreased, accompanied with downstream activation of apoptosis-related proteins such as Cleaved-Caspase3 and Cleaved-PARP. However, pretreatment with the ROS inhibitor N-acetyl-L-cysteine (NAC) and JNK inhibitor JNK-IN-8, ROS, JNK and cadmium-induced TM3 cell apoptosis were remarkably suppressed. Based on above-mentioned results, this study provides a mechanistic understanding of cadmium induced TM3 cell apoptosis through the ROS/JNK signaling pathways.
    Keywords:  Apoptosis; Cadmium; JNK; ROS; TM3 cells
    DOI:  https://doi.org/10.1016/j.taap.2019.02.012
  24. Cell Death Dis. 2019 Feb 25. 10(3): 193
    Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells.
    Junhui Yu, Shan Li, Jie Qi, Zilu Chen, Yunhua Wu, Jing Guo, Kai Wang, Xuejun Sun, Jianbao Zheng.
      Pyroptosis, a form of programmed cell death (PCD), has garnered increasing attention as it relates to innate immunity and diseases. However, the involvement of pyroptosis in the mechanism by which lobaplatin acts against colorectal cancer (CRC) is unclear. Our study revealed that treatment with lobaplatin reduced the viability of HT-29 and HCT116 cells in a dose-dependent manner. Morphologically, HT-29 and HCT116 cells treated with lobaplatin exhibited microscopic features of cell swelling and large bubbles emerging from the plasma membrane, and transmission electron microscopy (TEM) revealed multiple pores in the membrane. GSDME, rather than GSDMD, was cleaved in lobaplatin-induced pyroptosis in HT-29 and HCT116 cells due to caspase-3 activation. Knocking out GSDME switched lobaplatin-induced cell death from pyroptosis to apoptosis but did not affect lobaplatin-mediated inhibition of growth and tumour formation of HT-29 and HCT116 cells in vivo and in vitro. Further investigation indicates that lobaplatin induced reactive oxygen species (ROS) elevation and JNK phosphorylation. NAC, a ROS scavenger, completely reversed the pyroptosis of lobaplatin-treated HT-29 and HCT116 and JNK phosphorylation. Activated JNK recruited Bax to mitochondria, and thereby stimulated cytochrome c release to cytosol, followed by caspase-3/-9 cleavage and pyroptosis induction. Therefore, in colon cancer cells, GSDME mediates lobaplatin-induced pyroptosis downstream of the ROS/JNK/Bax-mitochondrial apoptotic pathway and caspase-3/-9 activation. Our study indicated that GSDME-dependent pyroptosis is an unrecognized mechanism by which lobaplatin eradicates neoplastic cells, which may have important implications for the clinical application of anticancer therapeutics.
    DOI:  https://doi.org/10.1038/s41419-019-1441-4
  25. Exp Dermatol. 2019 Mar 02.
    Baicalein inhibits matrix metalloproteinase 1 expression via activation of TRPV1-Ca-ERK pathway in ultraviolet B irradiated human dermal fibroblasts.
    Kuo-Feng Huang, Kuo-Hsing Ma, Yen-Jung Chang, Liang-Chuan Lo, Tian-You Jhap, Yu-Hua Su, Pei-Shan Liu, Sheau-Huei Chueh.
      Increased matrix metalloproteinase 1 (MMP-1) expression is a feature of photo-aged skin. We investigated the effects of baicalein and sulforaphane on ultraviolet B (UVB) irradiation induced MMP-1 expression and apoptosis using human dermal fibroblasts. UVB irradiation not only increased MMP-1 expression, but also caused apoptosis. Both baicalein and sulforaphane protected cells from UVB irradiation induced apoptosis, but only baicalein inhibited MMP-1 expression. UVB irradiation activated 12-lipoxygenase, and its product, 12-hydroxyeicosatetraenoic acid, activated TRPV1 channels. The resulting UVB irradiation induced Ca2+ increase was blocked by the 12-lipoxygenase inhibitor baicalein and the TRPV1 blocker capsazepine, but not by the Nrf2 inducer sulforaphane. UVB irradiation also increased ROS generation and decreased Nrf2 protein levels. UVB irradiation induced MMP-1 expression was blocked by the Ca2+ chelator BAPTA, by capsazepine and by TRPV1silencing. However, induction was unaffected by the antioxidant N-acetylcysteine. ERK and JNK phosphorylation were induced by UVB irradiation, but only ERK phosphorylation was Ca2+ sensitive. Increased MMP-1 expression was blocked by PD98059, but not by SP600125. Thus, increased MMP-1 expression is mediated by increased cytosolic Ca2+ and ERK phosphorylation. UVB irradiation induced ROS generation is also Ca2+ sensitive and UVB irradiation induced apoptosis is caused by increased ROS. Thus baicalein, by blocking the UVB irradiation induced cytosolic Ca2+ increase, protects cells from UVB irradiation induced MMP-1 expression and apoptosis. In contrast, sulforaphane, by decreasing cellular ROS, protects cells from only UVB induced apoptosis. Thus targeting 12-lipoxygenase may provide a therapeutic approach to improving the health of photo-aged human skin. This article is protected by copyright. All rights reserved.
    Keywords:  12-lipoxygenase; ERK phosphorylation; Nrf2; cytosolic Ca2+ increase; reactive oxygen species
    DOI:  https://doi.org/10.1111/exd.13912
  26. Mar Drugs. 2019 Feb 25. pii: E135. [Epub ahead of print]17(2):
    Amino Acid Composition, Antioxidant, and Cytoprotective Effect of Blue Mussel (Mytilus edulis) Hydrolysate through the Inhibition of Caspase-3 Activation in Oxidative Stress-Mediated Endothelial Cell Injury.
    Yunok Oh, Chang-Bum Ahn, Ki-Ho Nam, Yeon-Kye Kim, Na Young Yoon, Jae-Young Je.
      Enhanced oxidative stress plays a central role in promoting endothelial dysfunction, leading to the development of atherosclerosis. In this study, we investigated the protective effects of the hydrolysates derived from blue mussel (Mytilus edulis) against H₂O₂-mediated oxidative injury in human umbilical vein endothelial cells (HUVECs). The blue mussel hydrolysates were prepared by enzymatic hydrolysis with eight proteases, and blue mussel-α-chymotrypsin hydrolysate (BMCH) showed the highest antioxidant activities in DPPH radical scavenging, ABTS⁺ radical scavenging, and ORAC value compared to those of the other hydrolysates. BMCH also inhibited Cu2+-mediated low density lipoprotein (LDL) oxidation. Treatment of H₂O₂ resulted in the decreased HUVEC viability whereas pre-treatment with BMCH increased HUVEC viability and reduced reactive oxygen species (ROS) generation. BMCH pre-treatment increased cellular antioxidant capacities, including levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) against H₂O₂-mediated oxidative stress in HUVECs. Flow cytometry and western blot analysis revealed that BMCH pre-treatment significantly reduced H₂O₂-mediated HUVEC apoptosis through inhibition of caspase-3 activation. Real-time-qPCR analysis showed that BMCH down-regulated expression of p53 and caspase-3 genes, as well as decreased the bax/bcl-2 ratio. Taken together, these results indicate that BMCH may be useful as functional food ingredients for protecting endothelial dysfunction or related disease.
    Keywords:  bioactive peptide; blue mussel; caspase-3 activation; endothelial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/md17020135
  27. Int J Mol Sci. 2019 Feb 27. pii: E1027. [Epub ahead of print]20(5):
    Phenethyl Isothiocyanate Exposure Promotes Oxidative Stress and Suppresses Sp1 Transcription Factor in Cancer Stem Cells.
    Bijaya Upadhyaya, Yi Liu, Moul Dey.
      Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of oxidative stress than regular cancer cells. Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells. However, this pro-oxidant role of PEITC in CSCs is poorly understood and is investigated here. In a HeLa CSCs model (hCSCs), the sphere-culture and tumorsphere assay showed significantly enriched ALDHhi CSCs from HeLa parental cells (p < 0.05). Aldefluor assay and cell proliferation assay revealed that PEITC treatments resulted in a reduced number of ALDHhi hCSCs in a concentration-dependent manner (p < 0.05). In the ROS assay, PEITC promoted oxidative stress in hCSCs (p ≤ 0.001). Using immunoblotting and flow cytometry techniques, we reported that PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein) (both, p < 0.05). Furthermore, PEITC-treatment of hCSCs, prior to xenotransplantation in mice, lowered the in vivo tumor-initiating potential of hCSCs. In summary, PEITC treatment suppressed the proliferation of ALDH1 expressing cancer stem cells as well as key factors that are involved with drug-resistance, while promoting oxidative stress and apoptosis in hCSCs.
    Keywords:  ALDH1; apoptosis; cancer stem cells; phenethyl isothiocyanate; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms20051027
  28. In Vivo. 2019 Mar-Apr;33(2):33(2): 383-391
    Ursolic Acid Induces Apoptotic Cell Death Through AIF and Endo G Release Through a Mitochondria-dependent Pathway in NCI-H292 Human Lung Cancer Cells In Vitro.
    Chiung-Ju Chen, Yung-Luen Shih, Ming-Yang Yeh, Nien-Chieh Liao, Hsueh-Yu Chung, Ko-Lin Liu, Mei-Hui Lee, Pei-Yi Chou, Hsin-Yu Hou, Jiann-Shang Chou, Jing-Gung Chung.
       BACKGROUND/AIM: Ursolic acid (UA), a triterpene compound present in natural plants, has been shown to induce cytotoxic effects on many human cancer cells through induction of cell-cycle arrest and apoptosis. This study investigated the effects of UA on human lung cancer NCI-H292 cells in vitro.
    MATERIALS AND METHODS: Flow cytometric assay was used to measure the percentage of cell viability, apoptotic cell death by double staining of annexin V and propidium iodide (PI), production of reactive oxygen species (ROS) and Ca2+, and mitochondriaI membrane potential (Ψm). UA-induced chromatin condensation and DNA fragmentation were examined by 4',6-diamidino-2-phenylindole staining and DNA gel electrophoresis, respectively. Western blotting was used to examine the changes of apoptosis-associated protein expression in NCI-H292 cells.
    RESULTS: UA reduced cell viability and induced apoptotic cell death. UA increased Ca2+ production, reduced Ψm, but did not affect ROS production in NCI-H292 cells. UA increased apoptosis-inducing factor (AIF) and endonuclease G in NCI-H292 cells.
    CONCLUSION: Based on these observations, we suggest UA induces apoptotic cell death via AIF and Endo G release through a mitochondria-dependent pathway in NCI-H292 cells.
    Keywords:  DNA fragmentation; NCI-H292 human lung cancer cells; Ursolic acid (UA); apoptosis
    DOI:  https://doi.org/10.21873/invivo.11485
  29. Future Sci OA. 2019 Feb;5(2): FSO366
    Activation of TAp73 and inhibition of TrxR by Verteporfin for improved cancer therapy in TP53 mutant pancreatic tumors.
    Pilar Acedo, Aristi Fernandes, Joanna Zawacka-Pankau.
       Aim: TAp73 is a tumor suppressor, which compensates for p53 loss and induces apoptosis in tumors in response to genotoxic stress or small-molecule treatments. Pancreatic ductal adenocarcinoma has a late onset of the disease, responds poorly to the existing therapies and has a very low survival rates.
    Result: Here, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and benzoporphyrin derivative (BPD) monoacid ring A activate TAp73 and induce apoptosis in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit thioredoxin reductase 1.
    Conclusion: Thus, PpIX and BPD target cancer cells' vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic Trx1. Our findings may contribute to faster repurposing of PpIX and BPD to treat pancreatic tumors.
    Keywords:  ROS; TAp73; apoptosis; benzoporphyrin derivative; drug repurposing; mutant p53; pancreatic cancer; protoporphyrin IX; thioredoxin reductase
    DOI:  https://doi.org/10.4155/fsoa-2018-0082
  30. Int J Pharm. 2019 Feb 20. pii: S0378-5173(19)30138-3. [Epub ahead of print]560 334-346
    In vitro antitumor potential of astaxanthin nanoemulsion against cancer cells via mitochondrial mediated apoptosis.
    Karuppusamy Shanmugapriya, Hyejin Kim, Hyun Wook Kang.
      Astaxanthin and alpha-tocopherol have various biological potential with induction of intracellular ROS production in cytosol, endoplasmic reticulum and mitochondrial site. The present study was performed to prepare nanoemulsion (NEs) formulation of astaxanthin and alpha-tocopherol with sodium caseinate (AS-AT/SC NEs) using spontaneous emulsification and ultrasonication for analyzing intracellular ROS production in apoptosis. NEs was characterized with standard analysis, which revealed a high stability of normal pH with a small size and unique zeta potential of spherical structure droplets with no toxicity and faster cell migration. It induced ROS production and confirmed using fluorescent stains due to their unique physicochemical and functional properties. Therefore, it played a significant role in the induction of oxidative stress inside the cell as dose-dependent cytotoxicity at different concentrations. AS-AT/SC NEs with protective effect in maintaining intracellular ROS, oxidative stress and mitochondrial membrane potential to reduced apoptosis morphology in cancer cells through mitochondria-mediated apoptosis that inhibits cell death, thus cell survival was initiated at greater extent. Thereby exhibiting a significant remarkable therapeutic effect in cancer field. To best of our knowledge, this is first study concluded that induction of apoptosis potential by AS-AT/SC NEs emerged as a potential way to eradicate cancer cells.
    Keywords:  Alpha-tocopherol; Astaxanthin; Cytotoxicity; Fluorescent stains; Nanoemulsion; ROS; Tocopherol
    DOI:  https://doi.org/10.1016/j.ijpharm.2019.02.015
  31. Oxid Med Cell Longev. 2019 ;2019 8549035
    Proanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway.
    Mengchuan Xu, Qiang Niu, Yunhua Hu, Gangling Feng, Haixia Wang, Shugang Li.
       Purpose: To investigate the effects of grape seed proanthocyanidin extract (GSPE) on oxidative damage and arsenic (As) methylation and to clarify the role of Nrf2 in the process.
    Methods: L-02 cells were treated with arsenic (25 μM) and GSPE (10, 25, and 50 mg/L) for 24 h. Cell viability was analyzed by MTT assay. Cell apoptosis and ROS fluorescence were detected by flow cytometry. Oxidative stress marker levels were measured using commercial kits. mRNA and protein expression were detected by qRT-PCR and western blotting. The cellular concentrations of methylation products were measured by HPLC-HGAFS. Arsenic methylation ability of cells was determined.
    Results: Cell survival rate was significantly lower in the As group than in the control group (P < 0.05), while cell apoptosis increased and the number of apoptotic cells decreased gradually after GSPE intervention. Superoxide dismutase, glutathione, and sulfhydryl levels in the intervention group were significantly higher (P < 0.05), while MDA and ROS levels were significantly lower (P < 0.05) than those in the As group. The mRNA and protein expression of Nrf2, HO-1, NQO1, and glutathione-S-transferase increased in the As + GSPE group compared with that in the As group (P < 0.05). GSPE significantly increased methylated As level, primary methylation index, secondary methylation index, average growth rate of methylation, and average methylation speed compared with the GSPE untreated group (P < 0.05). After Nrf2 inhibition, the effect of GSPE decreased significantly.
    Conclusion: GSPE activates the Nrf2 signaling pathway to antagonize As-induced oxidative damage and to promote As methylation metabolism. Therefore, GSPE may be a potential agent for relieving As-induced hepatotoxicity.
    DOI:  https://doi.org/10.1155/2019/8549035
  32. Mol Med Rep. 2019 Feb 07.
    Resveratrol alleviates hypoxia/reoxygenation injury‑induced mitochondrial oxidative stress in cardiomyocytes.
    Tao Li, Linlin Chen, Yiyan Yu, Binbin Yang, Pengyun Li, Xiao-Qiu Tan.
      Resveratrol (RES) is a naturally occurring antioxidant compound found in red wine. Although it has been demonstrated to have a cardioprotective effect, the mechanism underlying this effect remains to be fully elucidated. The aim of the present study was to determine whether RES exerts a protective effect against mitochondrial oxidative stress and apoptosis in neonatal rat cardiomyocytes (NRCMs) induced by hypoxia/reoxygenation (H/R) injury. Primary cultured NRCMs were used as a model system and were divided into four experimental groups: Control, H/R, H/R + DMSO (H/R with 0.2% DMSO) and H/R + RES (H/R with 100 µM RES) groups. Mitochondrial oxidative stress was determined by measuring the alteration in the mitochondrial membrane potential (ΔΨm) of NRCMs, the release of lactate dehydrogenase (LDH) and the ratio of B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X protein (Bax) from NRCMs. Cell apoptosis was assessed by measuring cell apoptotic rates and the activity of caspase 3. In the H/R+RES group, RES significantly alleviated structural impairment, including disordered α‑actin and F‑actin, in the NRCMs induced by H/R injury. RES attenuated H/R injury‑induced mitochondria oxidative stress. RES also attenuated H/R injury‑induced cell apoptosis; it decreased the NRCM apoptotic rate from 84.25±7.41% (H/R) to 46.39±5.43% (H/R+RES) (P<0.05, n=4), rescued the decrease in the Bcl2/Bax ratio induced by H/R from 0.53±0.08‑fold (H/R) to 0.86±0.06‑fold (H/R+RES) (P<0.05, n=5) and alleviated the increased activity of caspase 3 induced by H/R from 1.32±0.06‑fold to 1.02±0.04‑fold (P<0.05, n=5). Furthermore, RES significantly attenuated the increment of LDH release induced by H/R injury in NRCMs from 1.41±0.03‑fold (H/R) to 1.02±0.06‑fold (H/R+RES) (P<0.01, n=4) and alleviated the depolarization of ΔΨm induced by H/R, shifting the ratio of JC‑1 monomer from 62.39±1.82% (H/R) to 35.31±8.63% (H/R+RES) (P<0.05, n=4). RES alleviated the decrease in sirtuin 1 induced by H/R injury from 0.61±0.06‑fold (H/R) to 1.01±0.05‑fold (H/R+RES) (P<0.05, n=5). In conclusion, the present study is the first, to the best of our knowledge, to demonstrate that RES provides cardioprotection against H/R injury through decreasing mitochondria‑mediated oxidative stress injury and structural impairment in NRCMs. These results provide scientific evidence for the clinical application of RES in the treatment of cardiac conditions.
    DOI:  https://doi.org/10.3892/mmr.2019.9943
  33. J Cell Mol Med. 2019 Mar 01.
    Glycyrrhizin protects against sodium iodate-induced RPE and retinal injury though activation of AKT and Nrf2/HO-1 pathway.
    Huijun He, Daheng Wei, Hua Liu, Chen Zhu, Yue Lu, Zongwen Ke, Shuang Jiang, Jianhua Huang.
      Glycyrrhizin is a bioactive triterpenoid saponin extracted from a traditional Chinese medicinal herb, glycyrrhiza, and has been reported to protect the organs such as liver and heart from injuries. However, there is no report about the effects of glycyrrhizin on atrophic age-related macular degeneration (AMD). This study investigated the effects of glycyrrhizin on retinal pigment epithelium (RPE) in vitro and retina of mice in vivo treated with sodium iodate (SI). Glycyrrhizin significantly inhibited SI-induced reactive oxygen species (ROS), and decreased apoptosis of RPE in vitro. The underlying mechanisms included increased phosphorylation of Akt, and increased expression of nuclear factor erythroid 2-related factor2 (Nrf-2) and HO-1, thereby protecting RPE from SI-induced ROS and apoptosis. Furthermore, glycyrrhizin significantly decreased the apoptosis of retinal cells in vivo, resulting in the inhibition of thinning of retina, decreasing the number of drusen and improving the function of retina. These findings suggested that glycyrrhizin may be a potential candidate for the treatment of atrophic AMD in clinical practice.
    Keywords:  Nrf2/HO-1 pathway; glycyrrhizin; retinal injury AKT pathway; retinal pigment epithelium
    DOI:  https://doi.org/10.1111/jcmm.14246
  34. Surgery. 2019 Feb 26. pii: S0039-6060(19)30003-0. [Epub ahead of print]
    Hydrogen sulfide attenuates lung ischemia-reperfusion injury through SIRT3-dependent regulation of mitochondrial function in type 2 diabetic rats.
    Tao Jiang, Yanhong Liu, Qiuming Meng, Xiangqi Lv, Ziyong Yue, Wengang Ding, Tianhua Liu, Xiaoguang Cui.
       BACKGROUND: Lung ischemia-reperfusion injury is a complex pathophysiologic process associated with high morbidity and mortality. We have demonstrated elsewhere that diabetes mellitus aggravated ischemia-induced lung injury. Oxidative stress and mitochondrial dysfunction are drivers of diabetic lung ischemia-reperfusion injury; however, the pathways that mediate these events are unexplored. In this study using a high-fat diet-fed model of streptozotocin-induced type 2 diabetes in rats, we determined the effect of hydrogen sulfide on lung ischemia-reperfusion injury with a focus on Sirtuin3 signaling.
    METHODS: Rats with type 2 diabetes were exposed to GYY4137, a slow release donor of hydrogen sulfide with or without administration of the Sirtuin3 short hairpin ribonucleic acid plasmid, and then subjected to a surgical model of ischemia-reperfusion injury of the lung (n = 8). Lung function, oxidative stress, inflammation, cell apoptosis, and mitochondrial function were measured.
    RESULTS: Compared with nondiabetic rats, animals with type 2 diabetes at baseline exhibited significantly decreased Sirtuin3 signaling in lung tissue and increased oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction (P < .05 each). In addition, further impairment in Sirtuin3 signaling was found in diabetic rats subjected to this model of lung ischemia-reperfusion. Simultaneously, the indexes showed further aggravation. Treatment with hydrogen sulfide restored Sirtuin3 expression and decreased lung ischemia-reperfusion injury in animals with type 2 diabetes mellitus by improving lung functional recovery, decreasing oxidative damage, suppressing inflammation, ameliorating cell apoptosis, and preserving mitochondrial function (P < .05). Conversely, these protective effects were largely reversed in Sirtuin3 knockdown rats.
    CONCLUSION: Impaired lung Sirtuin3 signaling associated with type 2 diabetic conditions was further attenuated by an ischemia-reperfusion insult. Hydrogen sulfide ameliorated reperfusion-induced oxidative stress and mitochondrial dysfunction via activation of Sirtuin3 signaling, thereby decreasing lung ischemia-reperfusion damage in rats with a model of type II diabetes.
    DOI:  https://doi.org/10.1016/j.surg.2018.12.018
  35. Mol Vis. 2019 ;25 47-59
    Protective effect of myricetin derivatives from Syzygium malaccense against hydrogen peroxide-induced stress in ARPE-19 cells.
    Bavani Arumugam, Uma Devi Palanisamy, Kek Heng Chua, Umah Rani Kuppusamy.
       Purpose: Oxidative stress is implicated in the etiology of diabetes and its debilitating complications, such as diabetic retinopathy (DR). Various flavonoids have been reported to be useful in reducing DR progression. Myricetin derivatives (F2) isolated from leaf extract of Syzygium malaccense have the potential to serve as functional food as reported previously. The present study was performed with the aim of determining the antioxidant potential and protective effect of myricetin derivatives (F2) isolated from leaf extract of S. malaccense against glucose oxidase (GO)-induced hydrogen peroxide (H2O2) production that causes oxidative stress in ARPE-19 (RPE) cells.
    Methods: Antioxidant properties were assessed through various radical (DPPH, ABTS, and nitric oxide) scavenging assays and determination of total phenolic content and ferric reducing antioxidant power level. ARPE-19 cells were preincubated with samples before the addition of GO (to generate H2O2). Cell viability, change in intracellular reactive oxygen species (ROS), H2O2 levels in cell culture supernatant, and gene expression were assessed.
    Results: F2 showed higher antioxidant levels than the extract when assessed for radical scavenging activities and ferric reducing antioxidant power. F2 protected the ARPE-19 cells against GO-H2O2-induced oxidative stress by reducing the production of H2O2 and intracellular reactive oxygen species. This was achieved by the activation of nuclear factor erythroid 2-related factor 2 (Nrf2/NFE2L2) and superoxide dismutase (SOD2), as well as downregulation of nitric oxide producer (NOS2) at the transcriptional level.
    Conclusions: The results showed that myricetin derivatives from S. malaccense have the capacity to exert considerable exogenous antioxidant activities and stimulate endogenous antioxidant activities. Therefore, these derivatives have excellent potential to be developed as therapeutic agents for managing DR.
  36. Biomed Pharmacother. 2019 Feb 21. pii: S0753-3322(18)34174-X. [Epub ahead of print]112 108698
    Luteolin protects PC-12 cells from H2O2-induced injury by up-regulation of microRNA-21.
    Zhiti Zhang, Peng Xu, Haiyan Yu, Lei Shi.
       BACKGROUND: Ischemic cerebrovascular disease (ICVD) is the third leading cause of death worldwide. Luteolin is a naturally flavonoid widely distributed in many plant leaves. This study aimed to explore the effects of luteolin on H2O2-induced ICVD cell oxidative injury model, as well as underlying molecular mechanisms.
    METHODS: Viability and apoptosis of PC-12 cells and rat brain microvascular endothelial cells (rBMECs) were detected using CCK-8 assay and FITC-Annexin V/PI staining, respectively. The levels of ROS and MDA were measured using DCFH-DA staining and MDA assay kit, respectively. Cell transfection was conducted to change the expression level of miR-21. Expression levels of key factors involved in cell proliferation, oxidative stress, apoptosis, PI3K/AKT and PDCD4/p21 pathways were evaluated using western blotting.
    RESULTS: Low concentration of luteolin had no significant effect on PC-12 cell viability and presented protective effects on H2O2-induced PC-12 cell viability loss, proliferation inhibition, ROS generation, oxidative stress increase and apoptosis. Moreover, luteolin up-regulated the expression level of miR-21 in H2O2-treated PC-12 cells. Overexpression of miR-21 strengthened the protective effects of luteolin on H2O2-induced PC-12 cell oxidative injury. Suppression of miR-21 had opposite effects. Furthermore, luteolin alleviated H2O2-induced inactivation of PI3K/AKT pathway and activation of PDCD4/p21 pathway in PC-12 cells by up-regulating miR-21. Besides, luteolin also protected rBMECs from H2O2-induced oxidative injury.
    CONCLUSION: Our research revealed the protective effects of luteolin on H2O2-induced ICVD cell oxidative injury. Luteolin protected PC-12 cells from H2O2-induced oxidative injury by up-regulating miR-21, activating PI3K/AKT pathway and inactivating PDCD4/p21 pathway.
    Keywords:  H(2)O(2); Ischemic cerebrovascular disease; Luteolin; MicroRNA-21; PDCD4/p21 pathway; PI3K/AKT pathway
    DOI:  https://doi.org/10.1016/j.biopha.2019.108698
  37. Chemosphere. 2019 Feb 15. pii: S0045-6535(19)30314-5. [Epub ahead of print]223 704-713
    Deltamethrin exposure induces oxidative stress and affects meiotic maturation in mouse oocyte.
    Zhen-Zhen Jia, Jing-Wen Zhang, Di Zhou, Ding-Qi Xu, Xi-Zeng Feng.
      Pyrethroid insecticides are commonly used as insecticides and considered to be less toxic to mammals, but may still impair the reproduction of animals and humans. The aim of this research was to evaluate the tendency of deltamethrin induced oxidative stress and its effects on meiosis, apoptosis and autophagy of mouse oocytes in vitro maturation after deltamethrin exposure. Especially, the maturation rate of oocytes decreased significantly after 14 h exposure of deltamethrin in concentration-dependent manners, which was manifested as abnormal spindle morphology and DNA double strand breaks. Oxidative stress was found in mouse oocytes exposed to deltamethrin, as shown by changes in the expression of CAT and SOD2. Our results also show that deltamethrin affects the quality of oocytes by causing abnormal mitochondrial distribution and by decreasing mitochondrial membrane potential. The apoptosis of oocyte regulated by the expression of Bax and Bcl-2 protein was obviously affected by deltamethrin. Compared with the control group, the expression of key regulatory factors in the autophagy pathway, LC3, Atg12, Atg14, and Beclin, increased in the experimental group. In summary, these results revealed that deltamethrin might inhibit the maturation of mouse oocytes and adversely affect the survival of oocytes.
    Keywords:  Apoptosis; Autophagy; Deltamethrin; Meiotic maturation; Mice oocyte; Oxidative stress
    DOI:  https://doi.org/10.1016/j.chemosphere.2019.02.092
  38. Ecotoxicol Environ Saf. 2019 Feb 26. pii: S0147-6513(19)30228-3. [Epub ahead of print]174 110-119
    Inhibition of Caspase-1-dependent pyroptosis attenuates copper-induced apoptosis in chicken hepatocytes.
    Jianzhao Liao, Fan Yang, Zhaoxin Tang, Wenlan Yu, Qingyue Han, Lianmei Hu, Ying Li, Jianying Guo, Jiaqiang Pan, Feiyang Ma, Xinyan Ma, Yuyin Lin.
      The purpose of this study was to investigate the effects of copper (Cu) on hepatocyte pyroptosis and the relationship between pyroptosis and apoptosis in the mechanisms of Cu toxicity. Primary chicken hepatocytes were cultured in different concentrations of Cu sulfate (CuSO4) (0, 10, 50, and 100 μM), N-acetylcysteine (NAC) (1 mM), and Z-YVAD-fluoromethylketone (Z-YVAD-FMK) (10 μM) for 24 h, and the combination of Cu and NAC or Z-YVAD-FMK for 24 h. Cellular morphology and function, cell viability, mitochondria membrane potential (MMP), apoptosis rate, mRNA expression of pyroptosis-related and apoptosis-related genes, and Caspase-1, Caspase-3 proteins expression were determined. These results indicated that Cu markedly induced the mRNA expression of pyroptosis-related genes (Caspase-1, IL-1β, IL-18, and NLRP3) and Caspase-1 protein expression. Furthermore, contents of Caspase-1, IL-1β, and IL-18 in the supernatant fluid of culture hepatocytes were significantly increased in hepatocytes. NAC relieved excess Cu-caused the changes of above genes and proteins. Additionally, Z-YVAD-FMK, caspase-1 inhibitor, which attenuated Cu-induced the increased lactic dehydrogenase (LDH), aspartate amino transferase (AST), alanine aminotransferase (ALT) activities. Furthermore, treatment with Cu and Z-YVAD-FMK could down-regulate the mRNA levels of Caspase-3, Bak1, Bax, and CytC and Caspase-3 protein expression, up-regulate the mRNA expression of Bcl2, increase the MMP and reduce cell apoptosis compared to treatment with Cu in hepatocytes. Collectively, these finding evidenced that excess Cu induced pyroptosis by generating ROS in hepatocytes, and the inhibition of Caspase-1-dependent pyroptosis might attenuate Cu-induced apoptosis.
    Keywords:  Apoptosis; Copper; Hepatocyte; Pyroptosis; ROS
    DOI:  https://doi.org/10.1016/j.ecoenv.2019.02.069
  39. Front Cell Neurosci. 2019 ;13 22
    Amyloid β Oligomers Increase ER-Mitochondria Ca2+ Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca2+ Remodeling.
    Maria Calvo-Rodriguez, Elena Hernando-Perez, Lucia Nuñez, Carlos Villalobos.
      Alzheimer's disease (AD) is the most common neurodegenerative disorder and strongly associated to aging. AD has been related to excess of neurotoxic oligomers of amyloid β peptide (Aβo), loss of intracellular Ca2+ homeostasis and mitochondrial damage. However, the intimate mechanisms underlying the pathology remain obscure. We have reported recently that long-term cultures of rat hippocampal neurons resembling aging neurons are prone to damage induced by Aβ oligomers (Aβo) while short-term cultured cells resembling young neurons are not. In addition, we have also shown that aging neurons display critical changes in intracellular Ca2+ homeostasis including increased Ca2+ store content and Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria. Aging also promotes the partial loss of store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway involved in memory storage. Here, we have addressed whether Aβo treatment influences differentially intracellular Ca2+ homeostasis in young and aged neurons. We found that Aβo exacerbate the remodeling of intracellular Ca2+ induced by aging. Specifically, Aβo exacerbate the loss of SOCE observed in aged neurons. Aβo also exacerbate the increased resting cytosolic Ca2+ concentration, Ca2+ store content and Ca2+ release as well as increased expression of the mitochondrial Ca2+ uniporter (MCU) observed in aging neurons. In contrast, Aβo elicit none of these effects in young neurons. Surprisingly, we found that Aβo increased the Ca2+ transfer from ER to mitochondria in young neurons without having detrimental effects. Consistently, Aβo increased also colocalization of ER and mitochondria in both young and aged neurons. However, in aged neurons, Aβo suppressed Ca2+ transfer from ER to mitochondria, decreased mitochondrial potential, enhanced reactive oxygen species (ROS) generation and promoted apoptosis. These results suggest that modulation of ER-mitochondria coupling in hippocampal neurons may be a novel physiological role of Aβo. However, excess of Aβo in the face of the remodeling of intracellular Ca2+ homeostasis associated to aging may lead to loss of ER-mitochondrial coupling and AD.
    Keywords:  Alzheimer’s disease; aging; calcium; endoplasmic reticulum; hippocampal neurons; mitochondria; store-operated calcium entry
    DOI:  https://doi.org/10.3389/fncel.2019.00022
  40. J Agric Food Chem. 2019 Feb 28.
    Plasticizer bis(2-ethylhexyl) phthalate causes meiosis defects and decreases fertilization ability of mouse oocytes in vivo.
    Zhenzhen Lu, Chengtu Zhang, Chengquan Han, Quanli An, Yuyao Cheng, Yongzhong Chen, Ru Meng, Yong Zhang, Jianmin Su.
      Bis(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer in polyvinyl chloride (PVC) plastics. Humans and animals are widely and continuously exposed to DEHP, especially in dietary respect, which is associated with reproductive diseases. Nevertheless, the effects and underlying mechanisms of DEHP exposure on oocytes in vivo remain ambiguous. In this study, we found that oral administration of DEHP (40 µg/kg body weight per day for 14 days) markedly reduced the maturation and fertilization of oocytes in vivo. In addition, DEHP caused oxidative stress, increased reactive oxygen species generation, promoted early apoptosis, and resulted in DNA damage in mouse oocytes. Moreover, DEHP exposure caused mitochondrial damage, reduced ATP content, down-regulated actin expression, and disturbed the spindle assembly and chromosome alignment in mouse oocytes. Furthermore, DEHP exposure remarkably impaired the localization and protein level of Juno, the sperm receptor on the membrane of oocytes. The levels of DNA methylation, H3K9me3, and H3K9ac were aslo altered in the DEHP-exposed mouse oocytes. Thus, our results indicated that DEHP exposure reduced the maturation and fertilization capabilities of mouse oocytes by affecting cytoskeletal dynamics, oxidative stress, early apoptosis, meiotic spindle morphology, mitochondria, ATP content, Juno expression, DNA damage, and epigenetic modifications in mouse oocytes.
    DOI:  https://doi.org/10.1021/acs.jafc.9b00121
  41. Biochem Pharmacol. 2019 Feb 21. pii: S0006-2952(19)30061-9. [Epub ahead of print]
    FCPR03, a novel phosphodiesterase 4 inhibitor, alleviates cerebral ischemia/reperfusion injury through activation of the AKT/GSK3β/ β-catenin signaling pathway.
    Bingtian Xu, Tiantian Wang, Jiao Xiao, Wenli Dong, Hui-Zhen Wen, Xinyi Wang, Yunyun Qin, Ningbo Cai, Zhongzhen Zhou, Jiangping Xu, Haitao Wang.
      Inhibition of phosphodiesterase 4 (PDE4) is a promising strategy for the treatment of ischemic stroke. However, the side effects of nausea and vomiting from the current PDE4 inhibitors have limited their clinical applications. FCPR03 is a novel PDE4 inhibitor with little emetic potential. This study aimed to investigate the effects of FCPR03 on neuronal injury after cerebral ischemia/reperfusion and the underlying signaling pathway. The effects of FCPR03 on cellular apoptosis, intracellular accumulation of reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated in HT-22 neuronal cells and cortical neurons exposed to oxygen-glucose deprivation (OGD). The impact of FCPR03 on brain injury, neurological scores and behavioral performance was investigated in rats subjected to middle cerebral artery occlusion (MCAO). The protein kinase B (AKT) inhibitor MK-2206 and β-catenin siRNA were used to investigate the underlying pathways. FCPR03 dose-dependently protected against OGD-induced cellular apoptosis in both HT-22 cells and cortical neurons. The levels of MMP and ROS were also restored by FCPR03. FCPR03 increased the levels of phosphorylated AKT, glycogen synthase kinase-3β (GSK3β), and β-catenin. Interestingly, the role of FCPR03 was reversed by MK-2206 and β-catenin siRNA. Consistently, FCPR03 reduced the infarct volume and improved neurobehavioral outcomes in rats following MCAO. Moreover, FCPR03 increased the levels of phosphorylated AKT, GSK3β and β-catenin within the ischemic penumbra of rats following cerebral ischemia-reperfusion. Taken together, FCPR03 has therapeutic potential in cerebral ischemia-reperfusion. The neuroprotective effects of FCPR03 are mediated through activation of the AKT/GSK3β/β-catenin pathway.
    Keywords:  AKT; FCPR03; Ischemic stroke; Neuroprotection; Phosphodiesterase 4
    DOI:  https://doi.org/10.1016/j.bcp.2019.02.023
  42. Biomed Pharmacother. 2019 Feb 21. pii: S0753-3322(19)30052-6. [Epub ahead of print]112 108692
    Trametenolic acid B protects against cerebral ischemia and reperfusion injury through modulation of microRNA-10a and PI3K/Akt/mTOR signaling pathways.
    Junzhi Wang, Ailing Wang, Haibo He, Xinxin She, Yumin He, Shi Li, Lanqing Liu, Tao Luo, Nianyu Huang, Huajun Luo, Kun Zou.
      Trametenolic acid B (TAB) was a lanostane-type triterpenoid isolated from the trametes lactinea (Berk.) Pat. We have previously reported that extract from trametes lactinea (Berk.) Pat and TAB could efficiently improve learning and memory ability of the cerebral ischemia injury rats and suppress mitochondrial-mediated apoptosis in hydrogen peroxide damaged SH-SY5Y cells. However, the potential mechanisms have not been fully understood yet. The current study was to further investigate the protective effect of TAB on oxygen glucose deprivation/reoxygenation (OGD/R)-damaged SH-SY5Y cells and cerebral ischemia/reperfusion (I/R) injury rats, as well as its mechanisms involved. Cell experiments demonstrated that TAB (10, 20 and 40 μg/mL) protected OGD/R-induced SH-SY5Y cell injury by promoting cell proliferation and suppressing LDH leakage; Meanwhile, the results in vivo showed that TAB (20, 40 and 80 mg/kg) might significantly ameliorate the neurological deficit score, cerebral edema, neuronal cell loss and apoptosis, suppress cerebral infarction volume of the cerebral I/R injury rats. Further studies in vitro and in vivo indicated TAB could efficiently reduce OGD/R-damaged SH-SY5Y cell and cerebral I/R rat serum ROS, LDH and MDA levels, elevate SOD, GSH-Px and CAT activities, downregulate miR-10a mRNA and Bax, cytochrome C, cleaved-caspase-3 and cleaved-caspase-9 protein expressions, upregulate p-PIK3CA, p-Akt, p-mTOR, Bcl-2, pro-caspase-9 and pro-caspase-3 protein expressions and p-PIK3CA/PIK3CA, p-Akt/Akt, p-mTOR/mTOR ratios (P < 0.05 or P < 0.01, respectively). Our present study indicated that TAB possessed neuroprotective property against ODG/R and I/R injury by suppressing miR-10a expression, activating PI3K/Akt/mTOR signaling pathway, thereby reducing mitochondrial-mediated apoptosis, which provided a new insight for interpreting the underlying mechanisms of TAB' neuroprotective effect and a candidate agent to treat cerebral I/R injury.
    Keywords:  Cerebral ischemia and reperfusion injury; MicroRNA-10a; Oxidative stress; PI3K/Akt/mTOR and mitochondrial apoptotic pathways; Trametenolic acid B
    DOI:  https://doi.org/10.1016/j.biopha.2019.108692
  43. Sleep Breath. 2019 Mar 01.
    Mechanisms of vascular endothelial cell injury in response to intermittent and/or continuous hypoxia exposure and protective effects of anti-inflammatory and anti-oxidant agents.
    Fan Xiao, Xin Li, Juan Wang, Jie Cao.
       BACKGROUND: Hypoxia induces vascular endothelial injuries; however, the mechanisms involved and effects of interventions remain unclear.
    OBJECTIVE: Investigate the inflammatory response and oxidative stress in co-cultured neutrophils and vascular endothelial cells, apoptotic changes in endothelial cells, and effects of the antioxidant, Tempol, or the NF-êB inflammatory channel blocker, pyrrolidine dithiocarbamate (PDTC), upon endothelial cells under conditions of intermittent and/or continuous hypoxic exposure.
    METHODS: Polymorphonuclear neutrophils co-cultured with human umbilical vein endothelial cells were subjected to the following conditions: intermittent normoxia (IN), intermittent hypoxia (IH), continuous hypoxia (CH), intermittent with continuous hypoxia (OS), OS+Tempol (OS+T), or OS+PDTC (OS+P) for 2, 5, or 8 h. Inflammatory factors, TNF-α and IL-6, the adhesion molecule, ICAM-1, CAT activity, and MDA concentrations in supernatants from the co-culture as well as pro- (Bak) and anti- (Bcl-xl) apoptotic gene expression levels in the endothelial cells were determined.
    RESULTS: Inflammatory factors, adhesion molecules, oxidative stress, and apoptosis genes in all groups showed significant, time-dependent increases as compared with the IN group. TNF-α, IL-6, ICAM-1, and MDA levels in the OS group were increased, while CAT was decreased as compared with that observed in the IH, CH, OS+T, and OS+P groups. Bcl-x1 expression and Bcl-x1/BAK ratios were decreased and BAX increased in the OS versus IH, CH, OS+T, or OS+P groups. Both pro- and anti-apoptotic proteins showed time-dependent increases, while the Bcl-x1/BAK ratio decreased over these times. Tempol and PDTC partially prevented these effects.
    CONCLUSION: Inflammation, oxidative stress, and apoptosis are all involved in vascular endothelial injury induced by OS. Anti-inflammatory and anti-oxidative interventions can partially improve effects of OS.
    Keywords:  Apoptosis; Hypoxia; Inflammation; Interaction; Neutrophils; Oxidative stress; Vascular endothelial cells
    DOI:  https://doi.org/10.1007/s11325-019-01803-9
  44. Cell Biol Toxicol. 2019 Mar 01.
    A new pyridazinone exhibits potent cytotoxicity on human cancer cells via apoptosis and poly-ubiquitinated protein accumulation.
    Denisse A Gutierrez, Rebecca E DeJesus, Lisett Contreras, Isela A Rodriguez-Palomares, Paulina J Villanueva, Karol S Balderrama, Lenore Monterroza, Manuel Larragoity, Armando Varela-Ramirez, Renato J Aguilera.
      In the last 15 years, pyridazinone derivatives have acquired extensive attention due to their widespread biological activities and pharmacological applications. Pyridazinones are well known for their anti-microbial, anti-viral, anti-inflammatory, anti-cancer, and cardiovascular activities, among others. In this study, we evaluated the anti-cancer activity of a new pyridazinone derivative and propose it as a potential anti-neoplastic agent in acute promyelocytic leukemia cells. Pyr-1 cytotoxicity was assessed on several human cancer and two non-cancerous cell lines by the DNS assay. Pyr-1 demonstrated potent cytotoxicity against 22 human cancer cell lines, exhibiting the most favorable selective cytotoxicity on leukemia (CEM and HL-60), breast (MDA-MB-231 and MDA-MB-468), and lung (A-549) cancer cell lines, when compared with non-cancerous breast epithelial MCF-10A cells. Analyses of apoptosis/necrosis pathways, reactive oxygen species (ROS) production, mitochondria health, caspase-3 activation, and cell cycle profile were performed via flow cytometry. Both hmox-1 RNA and protein expression levels were evaluated by quantitative real-time PCR and Western blotting assays, respectively. Pyr-1 induced apoptosis in acute promyelocytic leukemia cells as confirmed by phosphatidylserine externalization, mitochondrial depolarization, caspase-3 activation, DNA fragmentation, and disrupted cell cycle progression. Additionally, it was determined that Pyr-1 generates oxidative and proteotoxic stress by provoking the accumulation of ROS, resulting in the overexpression of the stress-related hmox-1 mRNA transcripts and protein and a marked increase in poly-ubiquitinated proteins. Our data demonstrate that Pyr-1 induces cell death via the intrinsic apoptosis pathway by accumulating ROS and by impairing proteasome activity.
    Keywords:  Anti-cancer; Apoptosis; Proteasome inhibition; Pyridazinone; ROS; hmox-1
    DOI:  https://doi.org/10.1007/s10565-019-09466-8
  45. Toxicology. 2019 Feb 25. pii: S0300-483X(18)30603-6. [Epub ahead of print]
    Inhibition of double-stranded RNA-dependent protein kinase prevents oxytosis and ferroptosis in mouse hippocampal HT22 cells.
    Yoko Hirata, Takuya Iwasaki, Yukimi Makimura, Sayaka Okajima, Kentaro Oh-Hashi, Hiroshi Takemori.
      Double-stranded RNA-dependent protein kinase (PKR) is a component of signal transduction pathways mediating various stress signals including oxidative stress and endoplasmic reticulum (ER) stress and is suggested to be implicated in several neurodegenerative diseases. Cell death in neurodegenerative conditions has been linked to oxidative stress; however, the involvement of PKR in endogenous oxidative stress such as oxytosis and ferroptosis which is quite distinct from classical apoptosis remains unknown. We investigated here the effect of a PKR inhibitor C16 (an imidazole-oxindole derivative) on oxytosis and ferroptosis in cultured HT22 mouse hippocampal cells. C16 prevented glutamate- and erastin-induced cell death, reactive oxygen species accumulation, Ca2+ influx, phosphorylation of inositol-requiring enzyme 1 (IRE1), one of the three branches of ER stress signaling and its downstream signaling components. On the other hand, C16 did not prevent oxidative stress-induced heme oxygenase-1 expression; instead, C16 activated the extracellular signal-regulated kinase pathway. The protective effect of C16 is diminished in PKR knockout HT22 cells. Real time measurements of the oxygen consumption rate and extracellular acidification rate over a long period of time leading to cell death showed that C16 partially prevented erastin-induced mitochondrial and glycolytic dysfunction. These results suggest that PKR is an important component of oxytosis and ferroptosis and the inhibition of PKR is neuroprotective against endogenous oxidative stress-induced cell death and provide an effective strategy for neuroprotection.
    Keywords:  Ferroptosis; IRE1; JNK; Key words; Oxytosis; PKR
    DOI:  https://doi.org/10.1016/j.tox.2019.02.012
  46. Ann Neurosci. 2019 Jan;25(3): 160-165
    Altered Micro-RNA Regulation and Neuroprotection Activity of Eremostachys labiosiformis in Alzheimer's Disease Model.
    Mohammad Rasoul Samandari-Bahraseman, Mehrdad Jahanshahi, Sara Asadi Barbariha, Leila Elyasi.
       Background: Amyloid-β peptide (Aβ) is involved in the formation of senile plaques in Alzheimer's disease (AD), and causes neuronal cell death by inducing oxidative stress.
    Objective: We investigated the protective effect of Eremostachys labiosiformis extract against the Aβ-induced toxicity in SH-SY5Y cells.
    Methods: Methanolic extract from the aerial parts of E. labiosiformis was prepared by percolation method at room temperature. SH-SY5Y cells were treated and incubated with different concentrations of the extract for 1 h, before addition of Aβ. Cytotoxicity was measured 24 h after the addition of Aβ to the medium using MTT and reactive oxygen species (ROS) assays. Effective doses were evaluated using real-time polymerase chain reaction to evaluate expression of miR-212 and miR-132. The results were analyzed using SPSS software (16).
    Results: Exposure of -SH-SY5Y cells to Aβ significantly affected the viability of cells and increased ROS levels. The results revealed that 1.2 and 2.5 μg/mL of the E. labiosiformis extract reduced Aβ-induced deterioration. Only 2.5 μg/mL of the extract could reduce ROS levels. In addition, 5 μg/mL of the extract increased the expression of the miRNAs, which was reduced after exposure to Aβ.
    Conclusion: Based on the antioxidant and protective effects of the E. labiosiformis extract on expression of miR-132 and miR-212 and ROS level, this herb could be used as a suitable candidate for future studies on neurodegenerative diseases including AD.
    Keywords:  Alzheimer's disease; Amyloid beta; Apoptosis; Eremostachys labiosiformis
    DOI:  https://doi.org/10.1159/000489551
  47. Food Chem Toxicol. 2019 Feb 22. pii: S0278-6915(19)30080-8. [Epub ahead of print]
    Combination of carnosine and asiatic acid provided greater anti-inflammatory protection for HUVE cells and diabetic mice than individual treatments of carnosine or asiatic acid alone.
    Sheng-Lei Yan, Zhi-Hong Wang, Mei-Chin Mong, Ya-Chen Yang, Mei-Chin Yin.
      The purpose of present HUVE cells and mice study was to investigate the combined effects of carnosine and asiatic acid (AA) against diabetic progression. In HUVE cells, high glucose decreased cell viability, reduced Bcl-2 mRNA expression and increased Bax mRNA expression. The co-treatment of 0.5 μM carnosine plus 0.5 μM AA led to greater cell viability and Bcl-2 mRNA expression than 1 μM carnosine or 1 μM AA treatment alone. This combination more significantly decreased the production of DNA fragmentation, tumor necrosis factor (TNF)-alpha, reactive oxygen species (ROS), and nuclear factor kappa B binding activity than carnosine or AA treatment alone. In diabetic mice, the combination of 0.25% carnosine plus 0.25% AA in diet resulted in higher final body weight, and lower levels of plasma glucose and triglyceride than 0.5% carnosine or 0.5% AA treatment alone. Carnosine and AA combination caused more reduction in renal levels of leukin-6, TNF-alpha and ROS than carnosine or AA treatment alone. This combination also more significantly limited renal cyclooxygenase-2 activity and p-p38 phosphorylation than carnosine or AA treatment alone. These novel findings support that this combination is a more powerful remedy for diabetic control.
    Keywords:  Apoptosis; Asiatic acid; Carnosine; Diabetes; HUVE cell; p38MPAK
    DOI:  https://doi.org/10.1016/j.fct.2019.02.027
  48. Sci Total Environ. 2019 Feb 18. pii: S0048-9697(19)30770-3. [Epub ahead of print]666 390-398
    Isoliquiritigenin as an antioxidant phytochemical ameliorates the developmental anomalies of zebrafish induced by 2,2',4,4'-tetrabromodiphenyl ether.
    Chao Wang, Lu Yang, Yuhuan Hu, Jiansheng Zhu, Rong Xia, Yongquan Yu, Jiemiao Shen, Zhan Zhang, Shou-Lin Wang.
      2,2',4,4'-Tetrabromodiphenyl ether (BDE47) is the most abundant PBDE congeners in biological samples. It has strong tendencies to bioaccumulate and potentially endangers development of mammals through oxidative stress. Isoliquiritigenin (ISL), an emerging natural chalcone-type flavonoid, possesses various biological and pharmacological properties, including antioxidant, anti-allergic, anti-inflammatory, anti-tumor and estrogenic activities. The purpose of the study is to explore the antioxidant effect of ISL on the amelioration of developmental anomalies induced by BDE47. Zebrafish (Danio rerio) embryos were exposed to BDE47 (1 and 10 μM) and/or ISL (4 μM) for 4 to 120 hours post fertilization (hpf), and the morphology, development, behavior, oxidative stress status and related genes expression were assessed. The results showed that BDE47 contributed to dose-dependent growth retardation and deformities, including delayed hatching, spinal curvature, reduced body length, increased death rate, aberrant behaviors and impaired dark-adapted vision, which were significantly mitigated by ISL. Besides, ISL ameliorated excessive ROS accumulation, and exaggerated the expressions of apoptosis-related genes p53, Bcl-2, caspase 3 and caspase 9 induced by BDE47, suggesting that ISL protected zebrafish from the developmental toxicity of BDE47 by inactivation of programmed apoptosis and activation of antioxidant signaling pathways. Taken together, developing ISL as a dietary supplement might be a promising preventive strategy for the amelioration of developmental toxicity induced by environmental pollutants.
    Keywords:  2,2′,4,4′-Tetrabromodiphenyl ether; Antioxidant phytochemicals; Dysplasia; Isoliquiritigenin; Oxidative stress; Zebrafish
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.02.272
  49. J Enzyme Inhib Med Chem. 2019 Dec;34(1): 703-711
    Evaluation of the anticancer potential of a sulphonamide carbonic anhydrase IX inhibitor on cervical cancer cells.
    Ismail Koyuncu, Yasin Tülüce, Hewa Slahaddin Qadir, Mustafa Durgun, Claudiu T Supuran.
      Cervical cancer is a common type of cancer. Carbonic anhydrase IX (CA IX) is an attractive target for tumour therapy, being overexpressed in many cancers. We investigated the anticancer properties of the aromatic sulphonamide S-1 as a CA IX inhibitor on cervical cancer cells (HeLa) positive for CA IX expression and normal prostate epithelial cell line (PNT1-A) negative for CA IX. We examined the cytotoxic, apoptosis, genotoxic, and oxidative stress activity of S-1 on HeLa and PNT1-A cell lines. S-1 induced significant reduction of cell viability, caused apoptosis, and up-regulated ROS production. This decrease in cell survival rate can be attributed to the high level of ROS and apoptosis, which has also been shown to arrest the cell cycle. Our findings indicated that S-1 is more effective on HeLa than PNT1-A. S-1 was able to induce apoptosis of cervical cancer cells and is a possible candidate for future anticancer studies.
    Keywords:  Apoptosis; carbonic anhydrase-IX inhibitor; cervical cancer; cytotoxicity; oxidative stress
    DOI:  https://doi.org/10.1080/14756366.2019.1579805
  50. Mol Med Rep. 2019 Feb 15.
    Neuroprotection of hydroxysafflor yellow A in experimental cerebral ischemia/reperfusion injury via metabolic inhibition of phenylalanine and mitochondrial biogenesis.
    Suning Chen, Mao Sun, Xianghui Zhao, Zhifu Yang, Wenxing Liu, Jinyi Cao, Yi Qiao, Xiaoxing Luo, Aidong Wen.
      Stroke is the second most frequent cause of mortality, resulting in a huge societal burden worldwide. Timely reperfusion is the most effective therapy; however, it is difficult to prevent ischemia/reperfusion (I/R) injury. In traditional Chinese medicine, hydroxysafflor yellow A (HSYA) has been widely used for the treatment of cerebrovascular disease and as a protective therapy against I/R injury. Evidence has demonstrated that HSYA could reduce the levels of reactive oxygen species and suppress cellular apoptosis; however, whether HSYA alters the metabolic profile as its underlying mechanism for neuroprotection remains unknown. In the present study, using a metabolomic screening, phenylalanine was identified to significantly increase in an experimental model of mouse cerebral I/R injury. Notably, western blotting and qPCR analysis were conducted to test the expression level of apoptosis‑associated factors, and HSYA was identified to be able to protect neuronal cells by reducing phenylalanine level associated with I/R injury. Additionally, these findings were confirmed in primary mouse neurons and PC12 cells exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) stress. Of note, HSYA was observed to regulate the mRNA expression of key metabolic enzymes, phenylalanine hydroxylase, tyrosine aminotransferase and aspartate aminotransferase, which are responsible for phenylalanine metabolism. Furthermore, by performing mitochondrial labeling and JC‑1 fluorescence assay, HSYA was identified to promote mitochondrial function and biogenesis suppressed by OGD/R. The findings of the present study demonstrated that I/R injury could increase the levels of phenylalanine, and HSYA may inhibit phenylalanine synthesis to enhance mitochondrial function and biogenesis for neuroprotection. The present study proposed a novel metabolite biomarker for cerebral I/R injury and the evaluated the efficacy of HSYA as a potential therapeutic treatment I/R injury.
    DOI:  https://doi.org/10.3892/mmr.2019.9959
  51. Oncol Rep. 2019 Feb 14.
    Chlorophyllin e6‑mediated photodynamic therapy inhibits proliferation and induces apoptosis in human bladder cancer cells.
    Zhiyuan Zhuo, Zhenyu Song, Zhe Ma, Yuanfang Zhang, Guoxiong Xu, Gang Chen.
      Patients with non‑muscle invasive bladder cancer (NMIBC) frequently relapse following surgery due to incomplete resection and chemoresistance, highlighting the importance of developing novel therapeutic strategies that mechanistically assist in eradicating the residual tumor. The aim of the present study was to evaluate the anticancer effect of chlorophyllin e6‑mediated photodynamic therapy (e6‑PDT) and its potential mechanisms by using monolayer cells or multicellular tumor spheroid models of human bladder cancer cells (T24 and 5637). The results revealed that e6‑PDT exhibited significant cytotoxicity in the T24 and 5637 cells of these two models as detected by the Water‑Soluble Tetrazolium Salts‑1 and CellTiter‑Glo Luminescent Cell Viability assays, respectively. Cell migration and invasion capacities decreased markedly following e6‑PDT. In addition, the cells following e6‑PDT exhibited typical morphological changes of apoptosis as detected by fluorescence microscopy with 4',6‑diamidino‑2‑phenylindole staining and transmission electron microscopy. A greater number of apoptotic cells were observed post‑e6‑PDT by flow cytometry. The expression levels of poly(adenosine diphosphate‑ribose) polymerase (PARP) and B‑cell lymphoma 2 protein were decreased, while cleaved PARP was increased, significantly following e6‑PDT as determined by western blotting. The level of intracellular reactive oxygen species (ROS) was increased, while the activity of superoxide dismutase (SOD) was decreased, significantly in e6‑PDT‑treated cells. Thus, the novel e6‑PDT exhibits prominent photo‑cytotoxicity effect and the induction of apoptosis was probably due to the inhibition of SOD activity and the generation of ROS. These results indicate that chlorophyllin e6 is an effective photosensitizer and that e6‑PDT may have a therapeutic application for the treatment of bladder cancer.
    DOI:  https://doi.org/10.3892/or.2019.7013
  52. Stem Cell Reports. 2019 Feb 05. pii: S2213-6711(19)30021-9. [Epub ahead of print]
    Anti-apoptotic Regulation Contributes to the Successful Nuclear Reprogramming Using Cryopreserved Oocytes.
    Ah Reum Lee, Kwonho Hong, Seo Hye Choi, Chanhyeok Park, Jae Kyun Park, Jin Il Lee, Jae Il Bang, Dong-Won Seol, Jeoung Eun Lee, Dong Ryul Lee.
      Cryopreservation has a negative effect on the quality of oocytes and may be closely associated with increased levels of reactive oxygen species (ROS) and apoptotic events. The purpose of the present study was to evaluate the detrimental effects on the developmental competence of somatic cell nuclear transferred (SCNT) mouse embryos using vitrified (cryopreserved) oocytes and to evaluate the recovery effects of melatonin on cryo-damage in cloned embryos. Development of SCNT embryos using cryopreserved oocyte cytoplasm (SCNT-CROC) was inferior to those using fresh cytoplasm (SCNT-FOC). Using RNA-sequencing analysis, we found upregulation of eight pro-apoptotic-related genes (Cyct, Dapk2, Dffb, Gadd45g, Hint2, Mien1, P2rx7, and Pmaip) in the SCNT-CROC group. Furthermore, the addition of melatonin, an agent that reduces apoptosis and ROS production, enhanced blastocyst formation rates in the SCNT-CROP group when compared with the melatonin-untreated group. Additionally, melatonin treatment increased the derivation efficiency of pluripotent stem cells from cloned embryos using cryopreserved oocyte.
    Keywords:  cryo-damage; cryopreserved oocytes; embryonic development; melatonin; somatic cell nuclear transfer
    DOI:  https://doi.org/10.1016/j.stemcr.2019.01.019
  53. Reprod Fertil Dev. 2019 Mar 01.
    Baicalin improves IVM of pig oocytes and subsequent preimplantation embryo development by inhibiting apoptosis.
    Qing Guo, Mei-Fu Xuan, Zhao-Bo Luo, Jun-Xia Wang, Song-Shan Jin, Xi-Jun Yin, Jin-Dan Kang.
      Baicalin, a monomer of flavonoids extracted from dried roots of Scutellaria baicalensis, is used to treat female infertility. However, the effect of baicalin on oocyte maturation is unknown. In this study we investigated the effects of baicalin on the IVM of pig oocytes and subsequent embryo development following parthenogenetic activation (PA). We found that 0.1µgmL-1 baicalin significantly (P<0.05) increased the IVM rate of oocytes compared with the non-treatment (control) group by reducing levels of reactive oxygen species (ROS). In addition, the mRNA expression of genes related to nuclear maturation and cumulus cell expansion, mitochondrial membrane potential and ATP content was significantly (P<0.05) higher in baicalin-treated than control oocytes. To determine whether baicalin treatment during IVM of pig oocytes improves subsequent development of PA embryos, we measured the cleavage and blastocyst formation rates, as well as the number of cells per blastocyst. All these parameters were significantly (P<0.05) higher in the baicalin-treated than control group. In conclusion, this study demonstrates that baicalin improves pig oocyte maturation and subsequent embryo development invitro by inhibiting production of ROS and reducing apoptosis in oocytes.
    DOI:  https://doi.org/10.1071/RD18333
  54. Cells. 2019 Feb 24. pii: E198. [Epub ahead of print]8(2):
    Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice.
    Lin-Bo Li, Rui Chai, Shuai Zhang, Shuang-Feng Xu, Yan-Hui Zhang, Hai-Long Li, Yong-Gang Fan, Chuang Guo.
      Although the causal relationship between Alzheimer's disease (AD) and iron overload remains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead to the accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areas related to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS) and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn) expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmed that there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice given HDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increased ROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis, and autophagy signaling, especially in pathological conditions, these data clearly indicate that chronic iron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasing the risk for developing AD.
    Keywords:  Alzheimer’s disease; apoptosis; autophagy; ferroptosis; iron; neuron loss
    DOI:  https://doi.org/10.3390/cells8020198
  55. Phytomedicine. 2018 Dec 31. pii: S0944-7113(18)30630-5. [Epub ahead of print]57 262-270
    Caffeic acid has antipromastigote activity by apoptosis-like process; and anti-amastigote by TNF-α/ROS/NO production and decreased of iron availability.
    Bruna Taciane da Silva Bortoleti, Fernanda Tomiotto-Pellissier, Manoela Daiele Gonçalves, Milena Menegazzo Miranda-Sapla, João Paulo Assolini, Amanda Cristina Carloto, Débora Messagi Lima, Guilherme Ferreira Silveira, Ricardo Sergio Almeida, Idessania Nazareth Costa, Ivete Conchon-Costa, Wander Rogério Pavanelli.
       BACKGROUND: Leishmaniasis is a disease caused by protozoan parasites of the Leishmania genus whose current treatment has high cost, highly toxic, and difficult administration, which makes it very important to find alternative natural compounds of high efficiency and low cost.
    PURPOSE: This study assessed the in vitro effect of caffeic acid (CA) on promastigotes and L. amazonensis-infected macrophages.
    METHODS: Evaluation of the in vitro leishmanicidal activity of CA against promastigotes and L. amazonensis infected peritoneal macrophages, as well its microbicide mechanisms.
    RESULTS: CA 12.5-100 µg/ml were able to inhibit promastigotes proliferation at all tested periods. The IC50, 12.5 µg/ml, also altered promastigote cell morphology and cell volume accompanied by loss of mitochondrial integrity, increase in reactive oxygen species (ROS) production, phosphatidylserine exposure, and loss of plasma membrane integrity - characterizing the apoptosis-like process. Moreover, CA reduced the percentage of infected macrophages and the number of amastigotes per macrophages increasing TNF-α, ROS, NO and reducing IL-10 levels as well as iron availability.
    CONCLUSION: CA showed in vitro antipromastigote and antiamostigote by increasing oxidant and inflammatory response important to eliminate the parasite.
    Keywords:  Apoptosis-like; Caffeic acid (CA); Cytotoxity; Iron; Phenolic compound; TNF-α
    DOI:  https://doi.org/10.1016/j.phymed.2018.12.035
  56. 3 Biotech. 2019 Mar;9(3): 88
    Astaxanthin supplementation reduces dichlorvos-induced cytotoxicity in Saccharomyces cerevisiae.
    S J Sudharshan, Subasri Subramaniyan, Greeshma Satheeshan, Madhu Dyavaiah.
      This study evaluates the protective effect of astaxanthin against dichlorvos cytotoxicity in yeast Saccharomyces cerevisiae. Dichlorvos induce a dose-dependent cytotoxicity in yeast cells, which is mediated by oxidative stress. Our experimental results showed pre-treatment with astaxanthin enhances cell viability by 20-30% in yeast cells exposed to dichlorvos. A decrease in DCF fluorescence intensity and lipid peroxidation, increased SOD activity, and glutathione levels in astaxanthin-treated cells indicate that astaxanthin protected the cells against dichlorvos-induced oxidative stress. Reduced chromatin condensation and nuclear fragmentation in astaxanthin pre-treated cells also indicate that astaxanthin rescued the cells from dichlorvos-induced apoptosis. Our overall results suggest that dichlorvos induces oxidative stress-mediated cytotoxicity in yeast cells, and that was rescued by astaxanthin pre-treatment.
    Keywords:  Apoptosis; Astaxanthin; Cytotoxicity; Dichlorvos; ROS; Yeast
    DOI:  https://doi.org/10.1007/s13205-019-1634-7
  57. Viruses. 2019 Feb 24. pii: E196. [Epub ahead of print]11(2):
    Duck Plague Virus Promotes DEF Cell Apoptosis by Activating Caspases, Increasing Intracellular ROS Levels and Inducing Cell Cycle S-Phase Arrest.
    Chuankuo Zhao, Mingshu Wang, Anchun Cheng, Qiao Yang, Ying Wu, Renyong Jia, Dekang Zhu, Shun Chen, Mafeng Liu, XinXin Zhao, Shaqiu Zhang, Yunya Liu, Yanling Yu, Ling Zhang, Bin Tian, Mujeeb Ur Rehman, Leichang Pan, Xiaoyue Chen.
       BACKGROUND: Duck plague virus (DPV) can induce apoptosis in duck embryo fibroblasts (DEFs) and in infected ducks, but the molecular mechanism of DPV-induced apoptosis remains unknown.
    METHODS: We first used qRT-PCR and a Caspase-Glo assay to determine whether the caspase protein family plays an important role in DPV-induced apoptosis. Then, we used an intracellular ROS detection kit and the mitochondrial probe JC-1 to respectively detect ROS levels and mitochondrial membrane potential (MMP). Finally, flow cytometry was used to detect apoptosis and cell cycle progression.
    RESULTS: In this study, the mRNA levels and enzymatic activities of caspase-3, caspase-7, caspase-8, and caspase-9 were significantly increased during DPV-induced apoptosis. The caspase inhibitors Z-DEVD-FMK, Z-LEHD-FMK, and Q-VD-OphA could inhibit DPV-induced apoptosis and promote viral replication. Subsequently, a significant decrease in MMP and an increase in the intracellular ROS levels were observed. Further study showed that pretreating infected cells with NAC (a ROS scavenger) decreased the intracellular ROS levels, increased the MMP, inhibited apoptosis, and promoted viral replication. Finally, we showed that DPV infection can cause cell cycle S-phase arrest.
    CONCLUSIONS: This study shows that DPV causes cell cycle S-phase arrest and leads to apoptosis through caspase activation and increased intracellular ROS levels. These findings may be useful for gaining an understanding of the pathogenesis of DPV and the apoptotic pathways induced by α-herpesviruses.
    Keywords:  ROS; apoptosis; cell cycle; duck embryo fibroblast; duck plague virus
    DOI:  https://doi.org/10.3390/v11020196
  58. Sci Rep. 2019 Feb 28. 9(1): 3062
    Treatment with maresin 1, a docosahexaenoic acid-derived pro-resolution lipid, protects skin from inflammation and oxidative stress caused by UVB irradiation.
    Talita L C Cezar, Renata M Martinez, Camila da Rocha, Cristina P B Melo, David L Vale, Sergio M Borghi, Victor Fattori, Josiane A Vignoli, Doumit Camilios-Neto, Marcela M Baracat, Sandra R Georgetti, Waldiceu A Verri, Rubia Casagrande.
      Acute exposure to UVB irradiation causes skin inflammation and oxidative stress, and long-term exposure to UVB irradiation may lead to carcinogenesis. Our organism has endogenous mechanisms to actively limit inflammation. Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid) is a pro-resolution lipid mediator derived from the docosahexaenoic acid, which presents anti-inflammatory and pro-resolution effects. However, it remains to be determined if treatment with MaR1 can inhibit inflammatory and oxidative alterations in the skin triggered by UVB. The treatment with MaR1 (0.1-10 ng/mice at -10 min relative to the UVB irradiation protocol) reduced UVB-induced skin edema, neutrophil recruitment (MPO; myeloperoxidase activity, and migration of LysM-eGFP+ cells), cytokine production, matrix metalloproteinase-9 activity, keratinocyte apoptosis, epidermal thickening, mast cells counts and degradation of skin collagen in hairless mice. UVB irradiation caused a decrease of GSH (reduced glutathione) levels, activity of the enzyme catalase, ferric reducing ability (FRAP), and ABTS radical scavenging capacity as well as induced lipid hydroperoxide, superoxide anion production, and gp91phox mRNA expression. These parameters that indicate oxidative stress were inhibited by MaR1 treatment. Therefore, these data suggest MaR1 as a promising pharmacological tool in controlling the deleterious effects related to UVB irradiation.
    DOI:  https://doi.org/10.1038/s41598-019-39584-6
  59. Phytomedicine. 2018 Dec 31. pii: S0944-7113(18)30637-8. [Epub ahead of print]57 245-254
    F3, a novel active fraction of Valeriana jatamansi Jones induces cell death via DNA damage in human breast cancer cells.
    Zhihui Zhu, Weifeng Shen, Shasha Tian, Bo Yang, Huajun Zhao.
       BACKGROUND: F3 is a novel fraction, for the first time isolated from Valeriana jatamansi Jones, which is a traditional Chinese folk medicine. Its anti-cancer potential and the underlying molecular mechanisms have not been well elucidated.
    PURPOSE: This study aims to investigate the anti-cancer effects of F3 on human breast cancer cell lines and its underlying mechanisms.
    METHODS: MTT assay was first performed to detect the effect of F3 on cell viability in human breast cancer cell lines and human mammary epithelial MCF-10A cells. Cell apoptosis, mitochondrial membrane potential and ROS level were detected by flow cytometry. Comet and immunofluorescence assays were utilized to assess DNA damage and expression of γ-H2AX. Autophagy were observed by AO staining and fluorescence microscopy. The expression of relative proteins was detected by western blotting. The xenograft model in nude mice was used to elucidate the effect of F3 on tumor growth and DNA damage in vivo.
    RESULTS: F3 could significantly inhibit the growth of breast cancer cells in concentration-dependent manner by inducing apoptosis and has no obvious inhibitory effect of the growth on MCF-10A cells. Mechanistic studies demonstrated that F3-induced apoptosis was mediated by DNA damage as presented by DNA strand breaks and γ-H2AX activation that might be attacked by ROS accumulation. This triggered several key molecular events involving activation of MAPKs pathway. Further study showed that F3 induced autophagy with the autophagosome formation and increased LC3-II levels. Finally, in vivo study, F3 exhibited a potential antitumor effect and induced DNA damage in MDA-MB-231 xenografts.
    CONCLUSION: The antitumorigenic activity of F3 was found in vitro and in vivo. These data suggest that F3 may be a potential natural active fraction for the treatment of human breast cancer.
    Keywords:  Breast cancer; Cell death; DNA damage; F3
    DOI:  https://doi.org/10.1016/j.phymed.2018.12.041
  60. World J Surg Oncol. 2019 Feb 27. 17(1): 44
    Effects of bradykinin on the survival of multiterritory perforator flaps in rats.
    Jieke Wang, Encheng Ji, Chen Lin, Long Wang, Li Dai, Weiyang Gao.
       BACKGROUND: Bradykinin, a vasoactive peptide, has many biological functions. For example, it accelerates angiogenesis. Thus, we studied the effects of bradykinin on the survival of perforator flaps.
    METHODS: Averagely, 50 male Sprague-Dawley rats were divided into control and bradykinin groups and underwent procedures to the multiterritory perforator flap. Areas of flap survival were tested 7 days later. Flap perfusion was evaluated by laser Doppler imaging. We assessed the extent of autophagy by determining LC3-II/I, Beclin 1, and p62. Flap angiogenesis was assessed by immunohistochemistry and H&E staining. We measured the level of vascular endothelial growth factor (VEGF) protein using western blot. We assessed oxidative stress by measuring the activity of superoxide dismutase (SOD) and malondialdehyde (MDA) levels. The apoptotic index was also evaluated by western blot, and we determined nitric oxide (NO) production using an NO assay kit.
    RESULTS: The bradykinin group exhibited significantly larger areas of flap survival, higher blood supply, and more neovascularization. The bradykinin group also had higher SOD activity, higher VEGF expression and NO content, and reduced MDA compared to the control group. Rats treated with bradykinin also had lower levels of apoptosis and autophagy relative to the control group.
    CONCLUSION: Our results suggest that bradykinin promotes the survival of multiterritory perforator flaps by increasing angiogenesis, promoting the release of NO, suppressing apoptosis, reducing oxidative stress, and inhibiting autophagy.
    Keywords:  Angiogenesis; Apoptosis; Autophagy; Bradykinin; Perforator flap
    DOI:  https://doi.org/10.1186/s12957-019-1570-3
  61. Redox Biol. 2019 Feb 21. pii: S2213-2317(19)30022-9. [Epub ahead of print] 101141
    Mitochondrial superoxide disrupts the metabolic and epigenetic landscape of CD4+ and CD8+ T-lymphocytes.
    C M Moshfegh, C W Collins, V Gunda, A Vasanthakumar, J Z Cao, P K Singh, L A Godley, Adam J Case.
      While the role of mitochondrial metabolism in controlling T-lymphocyte activation and function is becoming more clear, the specifics of how mitochondrial redox signaling contributes to T-lymphocyte regulation remains elusive. Here, we examined the global effects of elevated mitochondrial superoxide (O2-) on T-lymphocyte activation using a novel model of inducible manganese superoxide dismutase (MnSOD) knock-out. Loss of MnSOD led to specific increases in mitochondrial O2- with no evident changes in hydrogen peroxide (H2O2), peroxynitrite (ONOO-), or copper/zinc superoxide dismutase (CuZnSOD) levels. Unexpectedly, both mitochondrial and glycolytic metabolism showed significant reductions in baseline, maximal capacities, and ATP production with increased mitochondrial O2- levels. MnSOD knock-out T-lymphocytes demonstrated aberrant activation including widespread dysregulation in cytokine production and increased cellular apoptosis. Interestingly, an elevated proliferative signature defined by significant upregulation of cell cycle regulatory genes was also evident in MnSOD knock-out T-lymphocytes, but these cells did not show accelerated proliferative rates. Global disruption in T-lymphocyte DNA methylation and hydroxymethylation was also observed with increased mitochondrial O2-, which was correlated to alterations in intracellular metabolite pools linked to the methionine cycle. Together, these results demonstrate a mitochondrial redox and metabolic couple that when disrupted may alter cellular processes necessary for proper T-lymphocyte activation.
    Keywords:  Adaptive immunity; Apoptosis; Cytokines; Hydroxymethylation; Immune; Manganese superoxide dismutase; Metabolism; Methylation; Oxidative stress; Proliferation; Redox
    DOI:  https://doi.org/10.1016/j.redox.2019.101141
  62. Braz J Cardiovasc Surg. 2019 Jan-Feb;34(1):pii: S0102-76382019000100120. [Epub ahead of print]34(1): 120
    ERRATUM.
      [This corrects the article doi: 10.21470/1678-9741-2018-0036].
    DOI:  https://doi.org/10.21470/1678-9741-2018-0036e
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:11.