bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019–04–28
sixty-four papers selected by
Gavin McStay, Staffordshire University
  1. Nutritional Preconditioning of Apigenin Alleviates Myocardial Ischemia/Reperfusion Injury via the Mitochondrial Pathway Mediated by Notch1/Hes1.
  2. Protective effect of pig brain polypeptides against corticosterone-induced oxidative stress, inflammatory response, and apoptosis in PC12 cells.
  3. Lycopene protects against t-BHP-induced neuronal oxidative damage and apoptosis via activation of the PI3K/Akt pathway.
  4. Chlorogenic acid promotes the Nrf2/HO-1 anti-oxidative pathway by activating p21Waf1/Cip1 to resist dexamethasone-induced apoptosis in osteoblastic cells.
  5. Baicalin attenuates gentamicin-induced cochlear hair cell ototoxicity.
  6. Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway.
  7. Cardamonin Induces Cell Cycle Arrest, Apoptosis and Alters Apoptosis Associated Gene Expression in WEHI-3 Mouse Leukemia Cells.
  8. Mitochondrial protein 18 is a positive apoptotic regulator in cardiomyocytes under oxidative stress.
  9. DHA protects PC12 cells against oxidative stress and apoptotic signals through the activation of the NFE2L2/HO-1 axis.
  10. Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway.
  11. Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells.
  12. Chrysanthemum extract attenuates hepatotoxicity via inhibiting oxidative stress in vivo and in vitro.
  13. Cell death induced by α-terthienyl via reactive oxygen species-mediated mitochondrial dysfunction and oxidative stress in the midgut of Aedes aegypti larvae.
  14. Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation-evoked ischemic injury in neuron by suppressing mTOR-mediated excessive autophagy.
  15. Protective Effect of Phloroglucinol on Oxidative Stress-Induced DNA Damage and Apoptosis through Activation of the Nrf2/HO-1 Signaling Pathway in HaCaT Human Keratinocytes.
  16. (-)-Epigallocatechin-3-gallate suppresses cigarette smoke-induced inflammation in human cardiomyocytes via ROS-mediated MAPK and NF-κB pathways.
  17. Leonurine alleviates LPS-induced myocarditis through suppressing the NF-кB signaling pathway.
  18. Graphene Oxide⁻Platinum Nanoparticle Nanocomposites: A Suitable Biocompatible Therapeutic Agent for Prostate Cancer.
  19. Pre-administration of luteoline attenuates neonatal sevoflurane-induced neurotoxicity in mice.
  20. Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review.
  21. C-phycocyanin from Limnothrix Species KNUA002 Alleviates Cisplatin-Induced Ototoxicity by Blocking the Mitochondrial Apoptotic Pathway in Auditory Cells.
  22. Sapylin inhibits lung cancer cell proliferation and promotes apoptosis by attenuating PI3K/AKT signaling.
  23. Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway.
  24. Ferruginol Diterpenoid Selectively Inhibits Human Thyroid Cancer Growth by Inducing Mitochondrial Dependent Apoptosis, Endogenous Reactive Oxygen Species (ROS) Production, Mitochondrial Membrane Potential Loss and Suppression of Mitogen-Activated Protein Kinase (MAPK) and PI3K/AKT Signaling Pathways.
  25. Sasanquasaponin ΙΙΙ from Schima crenata Korth induces autophagy through Akt/mTOR/p70S6K pathway and promotes apoptosis in human melanoma A375 cells.
  26. PMAP-23 triggers cell death by nitric oxide-induced redox imbalance in Escherichia coli.
  27. Farnesol altered morphogenesis and induced oxidative burst-related responses in Rhizoctonia solani AG1-IA.
  28. Effect of Chitosan-(Poly)Nitroxides on Normal and Tumor Cells under Conditions of Induced Oxidative Stress.
  29. α-Mangostin promotes apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes by reactive oxygen species-dependent activation of ERK1/2 mitogen-activated protein kinase.
  30. Aminated Graphene Oxide as a Potential New Therapy for Colorectal Cancer.
  31. Vaspin prevents myocardial injury in rats model of diabetic cardiomyopathy by enhancing autophagy and inhibiting inflammation.
  32. Effect of metformin on human periodontal ligament stem cells cultured with polydopamine-templated hydroxyapatite.
  33. Emodin inhibits zinc-induced neurotoxicity in neuroblastoma SH-SY5Y cells.
  34. Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury.
  35. Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence.
  36. Amelioration of Radiation Enteropathy by Dietary Supplementation With Reduced Coenzyme Q10.
  37. Targeting non-oncogene ROS pathway by alantolactone in B cell acute lymphoblastic leukemia cells.
  38. Erythrocytes restrict microvesicle-induced production of reactive oxygen species by polymorphonuclear leukocytes.
  39. Conditioned Medium of Human Menstrual Blood-Derived Endometrial Stem Cells Protects Against MPP+-Induced Cytotoxicity in vitro.
  40. Involvement of p38 Activation and Mitochondria in Death of Human Leukemia Cells Induced by an Agonistic Human Monoclonal Antibody Fab Specific to TRAIL Receptor 1.
  41. Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury.
  42. Rosmarinic Acid Attenuates Cadmium-Induced Nephrotoxicity via Inhibition of Oxidative Stress, Apoptosis, Inflammation and Fibrosis.
  43. Ferroptosis as a New Type of Cell Death and its Role in Cancer Treatment.
  44. Involvement of miR-665 in protection effect of dexmedetomidine against Oxidative Stress Injury in myocardial cells via CB2 and CK1.
  45. Selenium-Alleviated Hepatocyte Necrosis and DNA Damage in Cyclophosphamide-Treated Geese by Mitigating Oxidative Stress.
  46. Curcuma raktakanda Induces Apoptosis and Suppresses Migration in Cancer Cells: Role of Reactive Oxygen Species.
  47. Exenatide Protects Against Cardiac Dysfunction by Attenuating Oxidative Stress in the Diabetic Mouse Heart.
  48. Benzophenone-2 Concentration and Its Effect on Oxidative Stress and Apoptosis Markers in Rat Brain.
  49. Low concentration of morphine protects against cell death, oxidative stress and calcium accumulation by nicotine in PC12 cells.
  50. The Role and Study of Mitochondrial Impairment and Oxidative Stress in Cholestasis.
  51. Cholix toxin, an eEF2 ADP-ribosyltransferase, interacts with Prohibitins and induces apoptosis with mitochondrial dysfunction in human hepatocytes.
  52. The Impact of O-Glycosylation on Cyanidin Interaction with RBCs and HMEC-1 Cells-Structure⁻Activity Relationships.
  53. Role of acute-phase protein ORM in a mice model of ischemic stroke.
  54. Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis.
  55. Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway.
  56. 2-D08 as a SUMOylation inhibitor induced ROS accumulation mediates apoptosis of acute myeloid leukemia cells possibly through the deSUMOylation of NOX2.
  57. Chemical composition and cytotoxic screening of Musa cavendish green peels extract: Antiproliferative activity by activation of different cellular death types.
  58. Long non-coding RNA-p21 regulates MPP+-induced neuronal injury by targeting miR-625 and derepressing TRPM2 in SH-SY5Y cells.
  59. Porcine Parvovirus Infection Causes Pig Placenta Tissue Damage Involving Nonstructural Protein 1 (NS1)-Induced Intrinsic ROS/Mitochondria-Mediated Apoptosis.
  60. Fibroblasts rescue oral squamous cancer cell from metformin-induced apoptosis via alleviating metabolic disbalance and inhibiting AMPK pathway.
  61. Heparanase protects the heart against chemical or ischemia/reperfusion injury.
  62. Synthesis and X-ray study of dispiro 8-nitroquinolone analogues and their cytotoxic properties against human cervical cancer HeLa cells.
  63. Environment and Male Fertility: Effects of Benzo-α-Pyrene and Resveratrol on Human Sperm Function In Vitro.
  64. Ameliorative Effect and Mechanism of the Purified Anthraquinone-Glycoside Preparation from Rheum Palmatum L. on Type 2 Diabetes Mellitus.
  1. Oxid Med Cell Longev. 2019 ;2019 7973098
    Nutritional Preconditioning of Apigenin Alleviates Myocardial Ischemia/Reperfusion Injury via the Mitochondrial Pathway Mediated by Notch1/Hes1.
    Huang Huang, Songqing Lai, Yong Luo, Qing Wan, Qicai Wu, Li Wan, Wanghong Qi, Jichun Liu.
      Apigenin (Api), a natural flavone found in high amounts in several herbs, has shown potent cardioprotective effects in clinical studies, although the underlying mechanisms are not clear. We hypothesized that Api protects the myocardium from simulated ischemia/reperfusion (SI/R) injury via nutritional preconditioning (NPC). Rats fed with Api-containing food showed improvement in cardiac functions; lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities; infarct size; apoptosis rates; malondialdehyde (MDA) levels; caspase-3, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities; and ferric reducing antioxidant power (FRAP) compared to those fed standard chow following SI/R injury. In addition, Api pretreatment significantly improved the viability, decreased the LDH activity and intracellular reactive oxygen species (ROS) generation, alleviated the loss of mitochondrial membrane potential (MMP), prevented the opening of the mitochondrial permeability transition pore (mPTP), and decreased the caspase-3 activity, cytochrome c (Cyt C) release, and apoptosis induced by SI/R in primary cardiomyocytes. Mechanistically, Api upregulated Hes1 expression and was functionally neutralized by the Notch1 γ-secretase inhibitor GSI, as well as the mPTP opener atractyloside (Atr). Taken together, Api protected the myocardium against SI/R injury via the mitochondrial pathway mediated by the Notch1/Hes1 signaling pathway.
    DOI:  https://doi.org/10.1155/2019/7973098
  2. Biomed Pharmacother. 2019 Apr 22. pii: S0753-3322(19)30315-4. [Epub ahead of print]115 108890
    Protective effect of pig brain polypeptides against corticosterone-induced oxidative stress, inflammatory response, and apoptosis in PC12 cells.
    Wenqi Jin, Xiaohao Xu, Xuenan Chen, Wenxiu Qi, Jing Lu, Xiuci Yan, Daqing Zhao, Deyu Cong, Xiangyan Li, Liwei Sun.
       OBJECTIVE: Pig brain polypeptides (PBP), active polypeptides hydrolysate extracted from fresh porcine brain tissue, has been shown to have neuroprotective effects in both in vitro and in vivo studies. The present study aimed to explore the molecular mechanisms underlying the neuroprotective effects of PBP in corticosterone (CORT)-induced rat adrenal pheochromocytoma PC12 cells.
    METHODS: Cell viability and lactate dehydrogenase (LDH) release were measured in PC12 cells induced with 200 μM CORT in the presence or absence of various concentrations of PBP for 48 h. Intracellular reactive oxygen species (ROS) generation, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and glutathione (GSH) content were examined to analyze the effect of PBP on CORT-induced oxidative stress. The levels of pro-inflammatory factors, the percentage of apoptotic cells, and apoptosis-related protein expression in PC12 cells were determined.
    RESULTS: PBP is mainly composed of protein subunits with molecular weights ranging from 1000 to 10,000 Da. PBP treatment increased cell viability and decreased the release of LDH in CORT-stimulated PC12 cells. Moreover, PBP reduced the level of CORT-induced oxidative stress by decreasing ROS levels and increasing SOD, GSH-Px activities and GSH content. PBP had an inhibitory effect on the CORT-induced inflammatory response through inhibition of the NF-κB signaling pathway. PBP also inhibited CORT-induced apoptosis by downregulating the mitochondrial apoptotic signaling pathway.
    CONCLUSION: These results suggest that PBP exerts a neuroprotective effect against CORT-induced cell injury by inhibiting oxidative stress, inflammation, and apoptosis. PBP could act as a neuroprotective agent against nerve injury induced by CORT.
    Keywords:  Apoptosis; Inflammation; Neuroprotection; Oxidative stress; PC12; Pig brain polypeptides
    DOI:  https://doi.org/10.1016/j.biopha.2019.108890
  3. Mol Biol Rep. 2019 Apr 20.
    Lycopene protects against t-BHP-induced neuronal oxidative damage and apoptosis via activation of the PI3K/Akt pathway.
    Cuiqin Huang, Caiyan Wen, Mei Yang, Danhui Gan, Chongzhu Fan, An Li, Qin Li, Jiayi Zhao, Lihong Zhu, Daxiang Lu.
      Oxidative stress is a key factor of and closely implicated in the pathogenesis of Alzheimer's disease (AD). We herein used tert-butyl hydroperoxide (t-BHP) to induce oxidative stress and mimic oxidative neurotoxicity in vitro. Lycopene is a natural antioxidant that has a strong ability to eliminate free radicals and shows effective protection in some neurodegenerative disease models. However, the effect of lycopene on t-BHP-induced neuronal damage in primary mouse neurons is unknown. This study aimed to investigate the effects of lycopene on t-BHP-induced neuronal damage and the related mechanisms. We found that lycopene pretreatment effectively enhanced the cell viability, improved the neuron morphology, increased the GSH/GSSG level, restored the mitochondrial membrane potential (ΔΨm) and decreased reactive oxygen species generation. Furthermore, lycopene reduced the ratios of Bax:Bcl-2 and cleaved caspase-3:caspase-3 and the level of cytochrome C, increased the levels of synaptophysin (SYP) and postsynaptic density 95 (PSD95) and activated the PI3K/Akt pathway. In conclusion, lycopene attenuated oxidative stress and reduced t-BHP-induced cell apoptosis, and the mechanism is likely related to activation of the PI3K/Akt pathway. Therefore, lycopene is a potential agent for preventing oxidative stress-mediated AD.
    Keywords:  Alzheimer’s disease; Antioxidant; Apoptosis; Oxidative damage
    DOI:  https://doi.org/10.1007/s11033-019-04801-y
  4. Free Radic Biol Med. 2019 Apr 17. pii: S0891-5849(19)30139-X. [Epub ahead of print]137 1-12
    Chlorogenic acid promotes the Nrf2/HO-1 anti-oxidative pathway by activating p21Waf1/Cip1 to resist dexamethasone-induced apoptosis in osteoblastic cells.
    Dandan Han, Xiaolong Gu, Jian Gao, Zhi Wang, Gang Liu, Herman W Barkema, Bo Han.
      In a previous study, p21Waf1/Cip1 (p21) promoted activation of the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, which has an important role in regulating apoptosis triggered by oxidative stress and inhibiting development of osteoporosis. Chlorogenic acid (CGA) has a strong protective effect on osteoporosis, closely related to activating the Nrf2/HO-1 pathway. However, whether CGA can resist apoptosis by regulating p21 and consequently promote activation of the Nrf2/HO-1 pathway needs further investigation. MC3T3-E1 cells were treated with dexamethasone (Dex), with or without CGA pre-treatment. Cell proliferation and cytotoxicity were measured using MTT assay and LDH release assay, respectively, and apoptosis assessed by flow cytometry. CGA significantly attenuated mitochondrial apoptosis and reversed down-regulation of p21 in osteoblastic MC3T3-E1 cells exposed to Dex. Additionally, CGA decreased Keap1 expression and promoted activation of the Nrf2/HO-1 pathway, quenching intracellular reactive oxygen species (ROS), hydrogen peroxide (H2O2) and mitochondrial superoxide overproduction boosted by Dex. Importantly, depletion of p21 by siRNA blocked activation of the Nrf2/HO-1 pathway, enhanced oxidative stress and increased apoptosis induced by CGA in MC3T3-E1 cells challenged with Dex. Therefore, CGA promoted the Nrf2/HO-1 anti-oxidative pathway by activating p21 to prevent Dex-induced mitochondrial apoptosis in osteoblastic cells. This pathway has potential as a therapeutic target for prevention and treatment of osteoporosis.
    Keywords:  Apoptosis; Chlorogenic acid; Nrf2/HO-1 pathway; Osteoporosis; Oxidative stress; P21(Waf1/Cip1)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.04.014
  5. J Appl Toxicol. 2019 Apr 25.
    Baicalin attenuates gentamicin-induced cochlear hair cell ototoxicity.
    Xianfen Zhang, Jun Yu.
      Gentamicin can lead to cochlear hair cells associated ototoxicity by inducing apoptosis and oxidative stress, which can be alleviated by baicalin, one flavonoid extracted from the root of Scutellaria baicalensis. The role of baicalin in protecting gentamicin-induced hearing loss is unclear. Interference with oxidative stress was investigated in this study using House Ear Institute-Organ of Corti1 (HEI-OC1) cells, which were simultaneously treated with baicalin (0-400 μm) and gentamicin (0.2 or 1 mm). MTT was used to assay cell viability and apoptosis was detected with Annexin V-fluorescein isothiocyanate staining. The production of reactive oxygen species was indicated by 2,7-dichlorofluorescein diacetate fluorescence intensity and mitochondrial depolarization was assayed by JC1-mitochondrial membrane potential assay. Poly(ADP-ribose) polymerase (PARP), cleaved-caspase 3 and cleaved-PARP expression were analyzed with western blot. Baicalin improved the viability of HEI-OC1 cells and significantly reduced the oxidative stress and mitochondrial depolarization compared with the gentamicin treatment group. Gentamicin treatment increased the activation of PARP and caspase-3, while such an increase could be downregulated by baicalin. Baicalin attenuates gentamicin-induced cochlear hair cells ototoxicity, and such inhibition may be mediated by the regulation of reactive oxygen species production, mitochondrial depolarization, and caspase-3 and PARP activation.
    Keywords:  baicalin; cochlear hair cells; gentamicin; ototoxicity; poly(ADP-ribose) polymerase
    DOI:  https://doi.org/10.1002/jat.3806
  6. Chemosphere. 2019 Apr 06. pii: S0045-6535(19)30672-1. [Epub ahead of print]227 541-550
    Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway.
    Zhi-Li Jia, Juan Cen, Jia-Bo Wang, Feng Zhang, Qing Xia, Xue Wang, Xi-Qiang Chen, Rong-Chun Wang, Chung-der Hsiao, Ke-Chun Liu, Yun Zhang.
      Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish. The liver morphology, transaminase level, redox-related enzyme activity, reactive oxygen species (ROS) content and mRNA levels of liver injury-related genes were measured. The results showed that INH (4, 6 mM) significantly caused liver atrophy and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in zebrafish. INH (6 mM) led to decreased catalase (CAT) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) content but increased ROS and malondialdehyde (MDA) levels. Moreover, INH (6 mM) decreased expression levels of miR-122 and pparα but increased mRNA levels of ap-1 and c-jun. Furthermore, mRNA levels of factors related to endoplasmic reticulum stress (ERS) (grp78, atf6, perk, ire1, xbp1s and chop), apoptosis (bax, cyt, caspase-3, caspase-8 and caspase-9) and the Nrf2 signalling pathway (nrf2, ho-1, nqo1, gclm and gclc) were significantly upregulated. INH may act on hepatotoxicity in zebrafish by increasing ROS content, which weakens the antioxidant capacity, leading to ERS, cell apoptosis and liver injury. In addition, the Nrf2 signalling pathway is activated as a stress compensation mechanism during INH-induced liver injury, but it is not sufficient to counteract INH-induced hepatotoxicity.
    Keywords:  Apoptosis; ERS; Hepatotoxicity; Isoniazid; Nrf2; Zebrafish
    DOI:  https://doi.org/10.1016/j.chemosphere.2019.04.026
  7. Am J Chin Med. 2019 Apr 25. 1-22
    Cardamonin Induces Cell Cycle Arrest, Apoptosis and Alters Apoptosis Associated Gene Expression in WEHI-3 Mouse Leukemia Cells.
    Nien-Chieh Liao, Yung-Luen Shih, Jiann-Shang Chou, Kuo-Wei Chen, Yung-Liang Chen, Mei-Hui Lee, Shu-Fen Peng, Sy-Jye Leu, Jing-Gung Chung.
      Cardamonin, the chalcone class, is one of the natural components from the spicy herbaceous plant (Alpinia conchigera Griff) and has anticancer activities in many human cancer cell lines. There is, however, no information to show that cardamonin induces cell apoptosis and alters apoptosis associated gene expressions in mouse leukemia cells. Thus, we investigated the effects of cardamonin on the apoptotic cell death and associated gene expression in mouse leukemia WEHI-3 cells in vitro. Results indicated that cardamonin decreased total viable cell number via induced cell morphological changes and apoptotic cell death in WEHI-3 cells that were assay by contrast-phase microscopy and flow cytometry examinations, respectively. The flow cytometry assay indicated that cardamonin increased reactive oxygen species (ROS) and Ca 2+ production, decreased the levels of mitochondrial membrane potential ( ΔΨm) and increased caspase-3, -8 and -9 activities in WEHI-3 cells. Western blotting was performed to analyze expression of relevant pro- and anti-apoptotic proteins and results showed that cardamonin decreased anti-apoptotic protein of Bcl-2 but increased pro-apoptotic protein of Bax in WEHI-3 cells. Furthermore, cardamonin increased cytochrome c, AIF and Endo G release, increased GRP78, caspase-12 that were associated with ER stress and increased Fas, Fas-Ligand and FADD expression. Furthermore, cardamonin increased the gene expressions of DAP (death-associated protein), TMBIM4 transmembrane (BAX inhibitor motif containing 4), ATG5 (autophagy related 5) but decreased the gene expression of DDIT3 (DNA-damage inducible transcript 3), DDIT4 (DNA-damage-inducible transcript 4), BAG6 (BCL2-associated athanogene 6), BCL2L13 [BCL2-like 13 (apoptosis facilitator)] and BRAT1 (BRCA1-associated ATM activator 1) that are associated with apoptosis pathways. Based on those findings, we may suggest cardamonin induced apoptotic cell death through Fas and Fas-Ligand-, caspase- and mitochondria-dependently pathways and also affects the apoptotic gene expression in WEHI-3 cells in vitro.
    Keywords:  Apoptosis; Cardamonin; Gene Expression; Mouse Leukemia WEHI-3 Cells; cDNA
    DOI:  https://doi.org/10.1142/S0192415X19500332
  8. Clin Sci (Lond). 2019 Apr 23. pii: CS20190125. [Epub ahead of print]
    Mitochondrial protein 18 is a positive apoptotic regulator in cardiomyocytes under oxidative stress.
    Lynn Htet Htet Aung, Yu-Zhen Li, Hua Yu, Xiatian Chen, Zhongjie Yu, Jinning Gao, Peifeng Li.
      Accumulation of reactive oxygen species is a common phenomenon in cardiac stress conditions, for instance, coronary artery disease, aging-related cardiovascular abnormalities, and exposure to cardiac stressors such as hydrogen peroxide (H2O2). Mitochondrial protein 18 (Mtp18) is a novel mitochondrial inner membrane protein, shown to involve in the regulation of mitochondrial dynamics. Although Mtp18 is abundant in cardiac muscles, its role in cardiac apoptosis remains elusive. This study aimed to detect the role of Mtp18 in H2O2-induced mitochondrial fission and apoptosis in cardiomyocytes. We studied the effect of Mtp18 in cardiomyocytes by modulating its expression with lentiviral construct of Mtp18-shRNA and Mtp18 c-DNA, respectively. We then analyzed mitochondrial morphological dynamics with MitoTracker Red staining; apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) and cell death detection assays; and protein expression with immunoblotting. Here, we observed that Mtp18 could regulate oxidative stress-mediated mitochondrial fission and apoptosis in cardiac myocytes. Mechanistically, we found that Mtp8 induced mitochondrial fission and apoptosis by enhancing dynamin-related protein 1 (Drp1) accumulation. Conversely, knockdown of Mtp18 using Mtp18-shRNA interfered with Drp1-associated mitochondrial fission and subsequent activation of apoptosis in both HL-1 cells and primary cardiomyocytes. However, overexpression of Mtp18 alone was not sufficient to execute apoptosis when Drp1 was minimally expressed, suggesting that Mtp18 and Drp1 are inter-dependent in apoptotic cascade. Together, these data highlight the role of Mtp18 in cardiac apoptosis and provide a novel therapeutic insight to minimize cardiomyocyte loss via targeting mitochondrial dynamics.
    Keywords:  Apoptosis; Dynamin-related protein 1; Mitochondrial fission; Mitochondrial protein; Oxidative stress stimulation
    DOI:  https://doi.org/10.1042/CS20190125
  9. Int J Mol Med. 2019 Jun;43(6): 2523-2531
    DHA protects PC12 cells against oxidative stress and apoptotic signals through the activation of the NFE2L2/HO-1 axis.
    Maria Elisabetta Clementi, Giacomo Lazzarino, Beatrice Sampaolese, Anna Brancato, Giuseppe Tringali.
      Docosahexaenoic acid (DHA) is an omega‑3 polyunsaturated fatty acid, derived mainly from fish oil. It is well known that DHA is present in high concentrations in nervous tissue and plays an important role in brain development and neuroprotection. However, the molecular mechanisms underlying its role remain to be fully elucidated. In this study, to enhance our understanding of the pathophysiological role of DHA, we investigated the possible neuroprotective mechanisms of action of DHA against hydrogen peroxide (H2O2)‑induced oxidative damage in a rat pheochromocytoma cell line (PC12). Specifically, we evaluated the viability, oxidation potential, and the expression and production of antioxidant/cytoprotective enzymes, and eventual apoptosis. We found that pre‑treatment with DHA (24 h) protected the cells from H2O2‑induced oxidative damage. In particular, pre‑treatment with DHA: i) Antagonized the consistent decrease in viability observed following exposure to H2O2 for 24 h; ii) reduced the high levels of intracellular reactive oxygen species (ROS) associated with H2O2‑induced oxidative stress; iii) increased the intracellular levels of enzymatic antioxidants [superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px)] both under basal conditions and following H2O2 exposure; iv) augmented the intracellular levels of reduced glutathione (GSH) and ascorbic acid, while it reduced the malondialdehyde (MDA) levels under conditions of oxidative stress; v) upregulated the expression of nuclear factor (erythroid‑derived 2)‑like 2 (NFE2L2) and its downstream target protein, heme‑oxygenase‑1 (HO‑1); and vi) induced an anti‑apoptotic effect by decreasing Bax and increasing Bcl2 expression. These findings provide evidence suggesting that DHA is able to prevent H2O2‑induced oxidative damage to PC12 cells, which is attributed to its antioxidant and anti‑apoptotic effects via the regulation NFE2L2/HO‑1 signaling. Therefore, DHA may play protective role in neurodegenerative diseases associated with oxidative stress.
    DOI:  https://doi.org/10.3892/ijmm.2019.4170
  10. Oxid Med Cell Longev. 2019 ;2019 9675450
    Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway.
    Liubing Hu, Yan Wang, Zui Chen, Liangshun Fu, Sheng Wang, Xinyue Zhang, Pengchao Zhang, Xueping Lu, Huiyang Jie, Manmei Li, Yifei Wang, Zhong Liu.
      Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.
    DOI:  https://doi.org/10.1155/2019/9675450
  11. Medicina (Kaunas). 2019 Apr 22. pii: E114. [Epub ahead of print]55(4):
    Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells.
    Firoozeh Niazvand, Mahmoud Orazizadeh, Layasadat Khorsandi, Mohammadreza Abbaspour, Esrafil Mansouri, Ali Khodadadi.
      : Background and objectives: Previous studies have shown anti-tumor activity of quercetin (QT). However, the low bioavailability of QT has restricted its use. This study aimed to assess the toxic effect of QT encapsulated in solid lipid nanoparticles (QT-SLNs) on the growth of MCF-7 human breast cancer cells. Materials and Methods: MCF-7 and MCF-10A (non-tumorigenic cell line) cell lines treated with 25 µmol/mL of QT or QT-SLNs for 48 h. Cell viability, colony formation, oxidative stress, and apoptosis were evaluated to determine the toxic effects of the QT-SLNs. Results: The QT-SLNs with appropriate characteristics (particle size of 85.5 nm, a zeta potential of -22.5 and encapsulation efficiency of 97.6%) were prepared. The QT-SLNs showed sustained QT release until 48 h. Cytotoxicity assessments indicated that QT-SLNs inhibited MCF-7 cells growth with a low IC50 (50% inhibitory concentration) value, compared to the free QT. QT-SLNs induced a significant decrease in the viability and proliferation of MCF-7 cells, compared to the free QT. QT-SLN significantly increased reactive oxygen species (ROS) level and MDA contents and significantly decreased antioxidant enzyme activity in the MCF-7 cells. Following QT-SLNs treatment, the expression of the Bcl-2 protein significantly decreased, whereas Bx expression showed a significant increase in comparison with free QT-treated cells. Furthermore, The QT-SLNs significantly increased apoptotic and necrotic indexes in MCF-7 cells. Viability, proliferation, oxidative stress and apoptosis of MCF-10A cells were not affected by QT or QT-SLNs. Conclusion: According to the results of this study, SLN significantly enhanced the toxic effect of QT against human breast cancer cells.
    Keywords:  apoptosis; breast cancer; nanomedicine; quercetin; solid lipid nanoparticles; toxicity
    DOI:  https://doi.org/10.3390/medicina55040114
  12. Food Nutr Res. 2019 ;63
    Chrysanthemum extract attenuates hepatotoxicity via inhibiting oxidative stress in vivo and in vitro.
    Zixia Tian, Haiyan Jia, Yuezhen Jin, Minghui Wang, Jiejian Kou, Chunli Wang, Xuli Rong, Xinmei Xie, Guang Han, Xiaobin Pang.
       Background: 'Bianliang ziyu', a famous chrysanthemum variety commonly planted in Kaifeng, China, is often consumed by local residents. However, the hepatoprotective effects of Bianliang ziyu and their underlying mechanisms are not clear.
    Objective: In this study, we investigated the hepatoprotective and antioxidative effects of Bianliang ziyu extract (BZE) on liver injury and explored its molecular mechanisms.
    Design: Sprague-Dawley rats were administered BZE by intragastric administration for 8-9 days, and then alcohol or carbon tetrachloride (CCl4) was administered by gavage to induce acute liver injury. The activities of serum alanine aminotransferase, aspartate aminotransferase, superoxide dismutase, and malondialdehyde in the rats were measured, and the liver of each rat was examined for histopathological changes. In vitro, HL-7702 cells were pretreated with BZE for 24 h and then exposed to 30 mmol•L-1 acetaminophen (APAP) for 12 h. The survival rate of the cells and the alanine aminotransferase and aspartate aminotransferase activities were determined. Then, we investigated the effects of BZE on oxidative stress, apoptosis, and the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling in HL-7702 cells induced by APAP.
    Results: The results showed that BZE prevented alcohol-, CCl4-, and APAP-induced liver injury and suppressed hepatic oxidative stress in vitro and in vivo. BZE was also observed to significantly inhibit the reduction of mitochondrial membrane potential and regulate the expression of Bcl-2, Bax and Caspase-3 in APAP-induced HL-7702 cells. In addition, BZE significantly promoted nuclear translocation and the expression of Nrf2 as well as its downstream gene hemeoxygenase-1 (HO-1) in vitro. Furthermore, the findings showed that Nrf2 siRNA reversed the effects of BZE on cell survival and apoptosis-related protein expression in APAP-induced HL-7702 cells.
    Conclusions: BZE plays an important role in preventing hepatotoxicity by inhibiting oxidative stress and apoptosis through activation of Nrf2 signaling. BZE could be developed as an effective functional food for protecting the liver.
    Keywords:  anti-apoptosis; antioxidative; chrysanthemum extract; liver injury; nuclear factor erythroid-2-related factor 2
    DOI:  https://doi.org/10.29219/fnr.v63.1667
  13. Free Radic Biol Med. 2019 Apr 22. pii: S0891-5849(18)32578-4. [Epub ahead of print]
    Cell death induced by α-terthienyl via reactive oxygen species-mediated mitochondrial dysfunction and oxidative stress in the midgut of Aedes aegypti larvae.
    Jie Zhang, Shakil Ahmad, Lan-Ying Wang, Qian Han, Jian-Chun Zhang, Yan-Ping Luo.
      α-Terthienyl (α-T) is a photosensitizer that produces many reactive oxygen species (ROS) under ultraviolet light. Here, we aimed to evaluate the oxidation mechanism of the 25%, 50%, and 75% lethal concentrations in Aedes aegypti larvae; the lethal concentration of α-T was used as the test value. The effects on mitochondria, oxidative stress, and cell death patterns caused by ROS were evaluated. The results showed that α-T mainly produced large amounts of ROS in the midgut of larvae. Moreover, mitochondrial ROS were increased in midgut cells, and the production of ROS sites, such as complex enzymes, was inhibited, resulting in enhanced production of ROS. Ultrastructural analysis of mitochondria revealed significant vacuolation, decreased activity of tricarboxylic acid cycle enzymes, and reduced ATP content and mitochondrial membrane potential in the high concentration group compared with those in the control group. Additionally, mitochondrial biosynthesis was blocked in the high concentration group. Thus, exposure to α-T disrupted mitochondrial function, although the mitochondrial DNA content may have increased because of mitochondrial self-protection mechanisms against oxidative stress. Furthermore, high concentrations of α-T aggravated oxidative stress and increased the number of intracellular oxidative damage products. Reverse transcription polymerase chain reaction and fluorescence staining showed that ROS induced by low α-T concentrations upregulated apoptotic genes, including Dronc (P < 0.05), thereby promoting apoptosis. Moderate concentrations of α-T promoted autophagy through induction of ROS, inhibited apoptosis, and induced necrosis. In contrast, high α-T concentrations induced high levels of ROS, which caused mitochondrial dysfunction and increased cytoplasmic Ca2+ concentration, directly inducing cell necrosis. We also found that α-T may disrupt the permeability of the peritrophic membrane, leading to intestinal barrier dysfunction. These results provided insights into the mode of action of α-T in Aedes aegypti.
    Keywords:  Aedes aegypti; Alpha-terthienyl; Apoptosis; Autophagy; Mitochondrial dysfunction; Necrosis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.04.021
  14. J Cell Biochem. 2019 Apr 25.
    Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation-evoked ischemic injury in neuron by suppressing mTOR-mediated excessive autophagy.
    Juguang Sun, Fenglei Yue.
      Cerebral ischemia/reperfusion (I/R) typically occurs after mechanical thrombectomy to treat ischemic stroke, generation of reactive oxygen species (ROS) after reperfusion may result in neuronal insult, ultimately leading to disability and death. Regulated in development and DNA damage responses 1 (REDD1) is a conserved stress response protein under various pathogenic conditions. Recent research confirms the controversial role of REDD1 in injury processes. Nevertheless, the role of REDD1 in cerebral I/R remains poorly defined. In the current study, increased expression of REDD1 was observed in neurons exposed to simulated I/R via oxygen glucose deprivation/reoxygenation (OGD/R) treatment. Knockdown of REDD1 enhanced OGD/R-inhibited cell viability, but suppressed lactate dehydrogenase (LDH) release in neurons upon OGD/R. Simultaneously, suppression of REDD1 also antagonized OGD/R-evoked cell apoptosis, Bax expression, and caspase-3 activity. Intriguingly, REDD1 depression abrogated neuronal oxidative stress under OGD/R condition by suppressing ROS, MDA generation, and increasing antioxidant SOD levels. Further mechanism analysis corroborated the excessive activation of autophagy in neurons upon OGD/R with increased expression of autophagy-related LC3 and Beclin-1, but decreased autophagy substrate p62 expression. Notably, REDD1 inhibition reversed OGD/R-triggered excessive neuronal autophagy. More importantly, depression of REDD1 also elevated the expression of p-mTOR. Preconditioning with mTOR inhibitor rapamycin engendered not only a reduction in mTOR activation, but also a reactivation of autophagy in REDD1 knockdown-neurons upon OGD/R. In addition, blocking the mTOR pathway muted the protective roles of REDD1 inhibition against OGD/R-induced neuron injury and oxidative stress. Together these data suggested that REDD1 may regulate I/R-induced oxidative stress injury in neurons by mediating mTOR-autophagy signaling, supporting a promising therapeutic strategy against brain ischemic diseases.
    Keywords:  REDD1; cerebral ischemia/reperfusion; mTOR-autophagy pathway; neuron injury; oxidative stress
    DOI:  https://doi.org/10.1002/jcb.28737
  15. Mar Drugs. 2019 Apr 13. pii: E225. [Epub ahead of print]17(4):
    Protective Effect of Phloroglucinol on Oxidative Stress-Induced DNA Damage and Apoptosis through Activation of the Nrf2/HO-1 Signaling Pathway in HaCaT Human Keratinocytes.
    Cheol Park, Hee-Jae Cha, Su Hyun Hong, Gi-Young Kim, Suhkmann Kim, Heui-Soo Kim, Byung Woo Kim, You-Jin Jeon, Yung Hyun Choi.
      Phloroglucinol (PG) is a component of phlorotannins, which are abundant in marine brown alga species. Recent studies have shown that PG is beneficial in protecting cells from oxidative stress. In this study, we evaluated the protective efficacy of PG in HaCaT human skin keratinocytes stimulated with oxidative stress (hydrogen peroxide, H2O2). The results showed that PG significantly inhibited the H2O2-induced growth inhibition in HaCaT cells, which was associated with increased expression of heme oxygenase-1 (HO-1) by the activation of nuclear factor erythroid 2-related factor-2 (Nrf2). PG remarkably reversed H2O2-induced excessive ROS production, DNA damage, and apoptosis. Additionally, H2O2-induced mitochondrial dysfunction was related to a decrease in ATP levels, and in the presence of PG, these changes were significantly impaired. Furthermore, the increases of cytosolic release of cytochrome c and ratio of Bax to Bcl-2, and the activation of caspase-9 and caspase-3 by the H2O2 were markedly abolished under the condition of PG pretreatment. However, the inhibition of HO-1 function using zinc protoporphyrin, a HO-1 inhibitor, markedly attenuated these protective effects of PG against H2O2. Overall, our results suggest that PG is able to protect HaCaT keratinocytes against oxidative stress-induced DNA damage and apoptosis through activating the Nrf2/HO-1 signaling pathway.
    Keywords:  Nrf2/HO-1; ROS; keratinocytes; oxidative stress; phloroglucinol
    DOI:  https://doi.org/10.3390/md17040225
  16. Phytomedicine. 2018 Nov 20. pii: S0944-7113(18)30584-1. [Epub ahead of print]58 152768
    (-)-Epigallocatechin-3-gallate suppresses cigarette smoke-induced inflammation in human cardiomyocytes via ROS-mediated MAPK and NF-κB pathways.
    Yingmin Liang, Mary Sau Man Ip, Judith Choi Wo Mak.
       BACKGROUND: Cigarette smoking is the leading cause for the initiation and development of cardiovascular disease (CVD). Oxidative stress and inflammatory responses play important roles in the pathophysiological processes of smoking-induced cardiac injury. (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, which is made from Camellia sinensis leaves, has been reported to possess potent anti-oxidant property.
    PURPOSE: This study aims to investigate whether the antioxidant EGCG could alleviate cigarette smoke medium (CSM)-induced inflammation in human AC16 cardiomyocytes in vitro.
    METHODS: Human AC16 cardiomyocytes were pre-treated with EGCG, N-acetyl-L-cysteine (NAC), or specific inhibitors for 30 min before 4% CSM was added. Supernatant was collected for determination of interleukin (IL)-8 by ELISA and cells were collected for flow cytometry, biochemical assays and Western blot analysis.
    RESULTS: EGCG treatment significantly attenuated CSM-induced oxidative stress as evidenced by reducing intracellular and mitochondrial reactive oxygen species (ROS) generations and preventing antioxidant depletion. EGCG treatment reduced CSM-induced inflammatory chemokine interleukin (IL)-8 productions in the supernatant via the inhibition of ERK1/2, p38 MAPK and NF-κB pathways. EGCG treatment further inhibited CSM-induced cell apoptosis.
    CONCLUSION: Taken together, EGCG protected against CSM-induced inflammation and cell apoptosis by attenuating oxidative stress via inhibiting ERK1/2, p38 MAPK, and NF-κB activation in AC16 cardiomyocytes. These findings suggest that EGCG with its antioxidant, anti-inflammatory and anti-apoptotic properties may act as a promising cardioprotective agent against ROS-mediated cardiac injury.
    Keywords:  (-)-epigallocatechin-3-gallate; Cardiomyocytes; Cigarette smoke; Inflammation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.phymed.2018.11.028
  17. Toxicology. 2019 Apr 18. pii: S0300-483X(18)30706-6. [Epub ahead of print]422 1-13
    Leonurine alleviates LPS-induced myocarditis through suppressing the NF-кB signaling pathway.
    Ruiyu Wang, Dan Li, Jing Ouyang, Xiaocui Tian, Yongpeng Zhao, Xin Peng, Siyu Li, Guiquan Yu, Jiadan Yang.
      Myocarditis is a serious hazard to human life and is difficult to treat due to the proliferation of inflammatory lesions in the myocardium. Leonurine (LE) is a plant phenolic alkaloid extracted from Herba leonuri that has demonstrated cardioprotective effects in many preclinical experiments. However, whether LE can be used for myocarditis therapy has not been reported. We aimed to investigate the cardioprotective effects of LE on lipopolysaccharide (LPS)-induced myocarditis in vivo and vitro. The possible mechanism involved was also further elucidated. In vivo, C57BL/6 mice were exposed to LPS with or without LE. We found out that LE effectively improved cardiac function and attenuated cardiomyocyte apoptosis in mice with myocarditis. In addition, LPS-induced inflammatory and oxidative injuries in the myocardium were also reduced by LE administration. In vitro, LPS simultaneously induced apoptosis and reduced the H9c2 cells viability, followed by elevation of intracellular reactive oxygen species (ROS) generation. However, the abnormalities mentioned were preventable by LE pretreatment in a dose-dependent manner. Both in vivo and in vitro, LPS activated the nuclear factor kappa B (NF-кB) signaling pathway in myocarditis, and LE inhibited the increased expression of phosphorylated iκBα and p65 (p-iκBα, p-p65). Furthermore, the nuclear translocalization and nuclear protein expression of p65 in LPS-injured H9c2 cells were also suppressed by LE. Our results demonstrated that LE exerts potent cardioprotective effects against myocarditis via anti-inflammatory and antioxidative mechanisms, possibly through blocking the activation of NF-кB pathway.
    Keywords:  Inflammation; Leonurine; NF-кB; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tox.2019.04.011
  18. Polymers (Basel). 2019 Apr 23. pii: E733. [Epub ahead of print]11(4):
    Graphene Oxide⁻Platinum Nanoparticle Nanocomposites: A Suitable Biocompatible Therapeutic Agent for Prostate Cancer.
    Sangiliyandi Gurunathan, Muniyandi Jeyaraj, Min-Hee Kang, Jin-Hoi Kim.
      Metal nanoparticles and the combination of metal nanoparticles with graphene oxide are widely used in environmental, agriculture, textile, and therapeutic applications. The effect of graphene oxide-green platinum nanoparticles (GO-PtNPs) on human prostate cancer cells (LNCaP) is unclear. Therefore, this study aimed to synthesize a nanocomposite of GO-PtNPs and evaluate their effect on prostate cancer cells. Herein, we synthesized GO-PtNPs using vanillin and characterized GO-PtNPs. GO-PtNP cytotoxicity in LNCaP cells was demonstrated by measuring cell viability and proliferation. Both decreased in a dose-dependent manner compared to that by GO or PtNPs alone. GO-PtNP cytotoxicity was confirmed by increased lactate dehydrogenase release and membrane integrity loss. Oxidative stress induced by GO-PtNPs increased malondialdehyde, nitric oxide, and protein carbonyl contents. The effective reactive oxygen species generation impaired the cellular redox balance and eventually impaired mitochondria by decreasing the membrane potential and ATP level. The cytotoxicity to LNCaP cells was correlated with increased expression of proapoptotic genes (p53, p21, Bax, Bak, caspase 9, and caspase 3) and decreased levels of antiapoptotic genes (Bcl2 and Bcl-xl). Activation of the key regulators p53 and p21 inhibited the cyclin-dependent kinases Cdk2 and Cdk4, suggesting that p53 and p21 activation in GO-PtNP-treated cells caused genotoxic stress and apoptosis. The increased expression of genes involved in cell cycle arrest and DNA damage and repair, and increased levels of 8-oxo-deoxyguanosine and 8-oxoguanine suggested that GO-PtNPs potentially induce oxidative damage to DNA. Thus, GO-PtNPs are both cytotoxic and genotoxic. LNCaP cells appear to be more susceptible to GO-PtNPs than to GO or PtNPs. Therefore, GO-PtNPs have potential as an alternate and effective cancer therapeutic agent. Finally, this work shows that the combination of graphene oxide with platinum nanoparticles opens new perspectives in cancer therapy. However further detailed mechanistic studies are required to elucidate the molecular mechanism of GO-PtNPs induced cytotoxicity in prostate cancer.
    Keywords:  DNA damage; cytotoxicity; graphene oxide–platinum nanoparticles nanocomposites; mitochondrial membrane potential; oxidative stress; prostate cancer
    DOI:  https://doi.org/10.3390/polym11040733
  19. Acta Histochem. 2019 Apr 18. pii: S0065-1281(18)30371-4. [Epub ahead of print]
    Pre-administration of luteoline attenuates neonatal sevoflurane-induced neurotoxicity in mice.
    Yang Wang, Chun Wang, Yue Zhang, Guan Wang, Haitao Yang.
      Sevoflurane is a widely used inhaled anesthetic, which triggers neuroapoptosis and oxidative damage in the developing central nervous system and cognitive dysfunction later in life. However, no effective therapeutic strategy for sevoflurane-induced deleterious effects is well developed. The purpose of the present study was to explore whether luteoline could attenuate neonatal sevoflurane exposure-triggered neurotoxicity. In this study, six-day-old C57BL/6 mice were pretreated with luteoline (30, 60 mg/kg) intraperitoneally for 30 min before exposed to 3% sevoflurane 6 h consecutively. We first examined the effects of luteoline on hippocampal neuron apoptosis, inflammation and oxidative stress 18 h post anesthesia. The spatial learning and memory performance was measured using Morris water maze test from postnatal day 31 to 38. The results showed that luteoline ameliorated neuronal apoptosis as evidenced by decrease of apoptotic cells, downregulation of the cleavage levels of caspase-3 and PRAP, and inactivation of caspase-3. Moreover, luteoline significantly decreased protein expressions of inflammatory cytokines (IL-1β, IL-18 and TNF-α), inhibited NF-кB/NLRP3 pathway (NF-кB, NLRP3, ASC and caspase-1) and suppressed NF-кB activity. Our analyses indicated that luteoline had a significant effect on decreasing the contents of ROS and MDA, elevating the activity of SOD, and ultimately improving spatial learning and memory deficits of mice. In summary, our findings confirm that the attenuation of luteoline on sevoflurane-induced spatial learning and memory impairment later is associated with inhibition of hippocampal neuron apoptosis, inflammation and oxidative stress early. Luteoline might be a potential therapeutic for sevoflurane anesthesia-induced neurobehavioral dysfunction.
    Keywords:  Luteoline; Neurotoxicity; Sevoflurane; Spatial learning
    DOI:  https://doi.org/10.1016/j.acthis.2019.04.004
  20. Antioxidants (Basel). 2019 Apr 24. pii: E109. [Epub ahead of print]8(4):
    Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review.
    Chisato Fujimoto, Tatsuya Yamasoba.
      Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients.
    Keywords:  antioxidants; hearing loss; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox8040109
  21. Mar Drugs. 2019 Apr 19. pii: E235. [Epub ahead of print]17(4):
    C-phycocyanin from Limnothrix Species KNUA002 Alleviates Cisplatin-Induced Ototoxicity by Blocking the Mitochondrial Apoptotic Pathway in Auditory Cells.
    Ye-Ri Kim, Jeong-Mi Do, Kyung Hee Kim, Alexandra R Stoica, Seung-Woo Jo, Un-Kyung Kim, Ho-Sung Yoon.
      Ototoxicity, or adverse pharmacological effects on the inner ear or auditory nerve, is a common side effect of cisplatin, a platinum-based drug widely used in anticancer chemotherapy. Although the incidence of ototoxicity is high among patients that receive cisplatin therapy, there is currently no effective treatment for it. The generation of excessive reactive oxygen species (ROS) is considered to be the major cause of cisplatin-induced ototoxicity. C-phycocyanin (C-PC), a blue phycobiliprotein found in cyanobacteria and red algae, has antioxidant and anticancer activities in different experimental models in vitro and in vivo. Thus, we tested the ability of C-PC from Limnothrix sp. KNUA002 to protect auditory cells from cisplatin-induced ototoxicity in vitro. Pretreatment with C-PC from Limnothrix sp. KNUA002 inhibited apoptosis and protected mitochondrial function by preventing ROS accumulation in cisplatin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, a mouse auditory cell line. Cisplatin increased the expression of Bax and reduced the expression of Bcl-2, which activate and inhibit, respectively, the mitochondrial apoptotic pathway in response to oxidative stress. Pretreatment with C-PC prior to cisplatin treatment caused the Bax and Bcl-2 levels to stay close to the levels in untreated control cells. Our results suggest that C-PC from Limnothrix sp. KNUA002 protects cells against cisplatin-induced cytotoxicity by inhibiting the mitochondrial apoptotic pathway.
    Keywords:  C-phycocyanin; HEI-OC1; Limnothrix; cisplatin; ototoxicity
    DOI:  https://doi.org/10.3390/md17040235
  22. J Cell Biochem. 2019 Apr 22.
    Sapylin inhibits lung cancer cell proliferation and promotes apoptosis by attenuating PI3K/AKT signaling.
    Lin Zhang, Benhong Liu.
      Sapylin (OK-432) revealed biological properties in cancers. In this study, the effect of sapylin on lung cancer cell A549 was investigated. A549 cell lines were treated with sapylin (0.1, 0.5, and 1 KE/mL) for different time intervals. A549 cell proliferation and apoptosis was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide/Ki67 assay and flow cytometry, respectively. Western blot was used to determine the expressions of proteins involved in proliferation, apoptosis, and phosphoinositide 3-kinase/serine/threonine kinase (PI3K/AKT), Wnt3a/β-catenin signaling pathway. Level of intracellular reactive oxygen species (ROS) was insured by using the ROS kit. Sapylin inhibited A549 cell viability and the expressions of proliferation-related proteins (cyclin E1 and D1) in dose- and time-dependent manners. Sapylin promoted apoptosis in a dose- and time-dependent manners. Sapylin also promoted the expressions of apoptotic proteins (cleaved caspase-3 and 8) in dose- and time-dependent manners. Furthermore, sapylin increased the intracellular concentration of ROS in a dose-dependent manner. Besides, the high expression of ROS level might induce inhibition of cell viability and increase cell apoptosis. The mechanistic study revealed that sapylin inactivated the PI3K/AKT and Wnt3a/β-catenin signaling pathways. Our findings suggest that sapylin inhibits proliferation and promotes apoptosis in lung cancer cells, thus providing a new theoretical basis for the treatment of lung cancer.
    Keywords:  PI3K/AKT; apoptosis; cell proliferation; lung cancer; sapylin
    DOI:  https://doi.org/10.1002/jcb.28729
  23. Cancer Cell Int. 2019 ;19 97
    Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway.
    Weilong Yao, Shengtao Zhu, Peng Li, Shutian Zhang.
       Background: 5-Fluorouracil (5-FU) is a standard treatment for colorectal cancer, but most patients develop 5-FU resistance. Here, we conducted experiments to identify an effective approach to augment 5-FU-based treatment in colorectal cancer in vitro.
    Methods: SW480 cells were in the present study and treated with 5-FU. Besides, LATS2 adenovirus vectors were infected into SW480 cells. Western blotting, immunofluorescence and ELISA were used to evaluate cell death and mitochondrial function. Pathway blocker was used to verify the role of MAPK-JNK pathway in SW480 cell death.
    Results: An obvious drop in large tumor suppressor kinase 2 (LATS2) expression was observed in SW480 cells after treatment with 5-FU. In addition, upregulation of LATS2 expression through infection with LATS2 adenovirus further increased the reduction of SW480 cell viability induced by 5-FU. Functional exploration showed that 5-FU treatment suppressed mitochondrial membrane potential, enhanced cyt-c release into the nucleus, induced an oxidative injury environment by promoting ROS production, and eventually upregulated Bax-related mitochondrial apoptosis. Besides, LATS2 overexpression in combination with 5-FU treatment further perturbed mitochondrial homeostasis, and this effect was achieved by elevating mitochondrial division. Mechanistically, LATS2 overexpression and 5-FU co-treatment amplified mitochondrial division by upregulating MIEF1 expression in a manner dependent on MAPK-JNK axis. Knockdown of MIEF1 using an siRNA-mediated loss of function assay and/or inhibition of the MAPK-JNK pathway using the specific inhibitor SP600125 abolished LATS2/5-FU-mediated deleterious effects on mitochondrial performance and SW480 cell viability.
    Conclusions: In light of the above findings, LATS2 downregulation could be a potential mechanism of low response to 5-FU treatment. Overexpression of LATS2 to further disrupt mitochondrial function via the JNK-MIEF1 signalling pathway might be a method to optimize 5-FU-based chemotherapy.
    Keywords:  5-FU; Apoptosis; Colorectal cancer; LATS2; MIEF1; Mitochondrial fission
    DOI:  https://doi.org/10.1186/s12935-019-0812-3
  24. Med Sci Monit. 2019 Apr 21. 25 2935-2942
    Ferruginol Diterpenoid Selectively Inhibits Human Thyroid Cancer Growth by Inducing Mitochondrial Dependent Apoptosis, Endogenous Reactive Oxygen Species (ROS) Production, Mitochondrial Membrane Potential Loss and Suppression of Mitogen-Activated Protein Kinase (MAPK) and PI3K/AKT Signaling Pathways.
    Guoqing Luo, Jingjing Zhou, Guanjie Li, Ningdong Hu, Xu Xia, Haibo Zhou.
      BACKGROUND Thyroid cancer causes considerable mortality and morbidity across the globe. Owing to the unavailability of biomarkers and the adverse effects of existing drugs, there is an urgent need to develop efficient chemotherapy for the treatment of thyroid cancers. Plants have served as exceptional source of drugs for the treatment of lethal diseases. The purpose of this study was to evaluate the anticancer effects of ferruginol against thyroid cancer cells. MATERIAL AND METHODS We monitored the cell proliferation rate using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected using 4',6-diamidino-2-phenylindole (DAPI), acridine orange/ethidium bromide (AO/EB), and annexin V/propidium iodide (PI) staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were examined by fluorescence microscopy. Protein expressed was examined by western blotting. RESULTS We found that ferruginol exerted potent antiproliferative action against thyroid cancer cells, and an IC₅₀ of 12 µM was observed for ferruginol against the MDA-T32 cell line. The toxic effects of ferruginol were less pronounced against normal cells. The anticancer effects of ferruginol were likely due to the induction of apoptosis which was also associated with upregulation of Bax and downregulation of Bcl-2. Ferruginol also caused ROS mediated alterations in the MMP of MDA-T32 cells. In MDA-T32 cells, ferruginol might also block the MAPK and PI3K/AKT signaling pathway, which is believed to be an important therapeutic target of anticancer drugs. CONCLUSIONS In conclusion, in view of the results of this study, it might be suggested that ferruginol might serve as an essential lead molecule for the treatment of thyroid cancer provided further in-depth studies especially studying ferruginol toxicological as well as in vivo studies are needed.
    DOI:  https://doi.org/10.12659/MSM.914348
  25. Phytomedicine. 2018 Nov 20. pii: S0944-7113(18)30585-3. [Epub ahead of print]58 152769
    Sasanquasaponin ΙΙΙ from Schima crenata Korth induces autophagy through Akt/mTOR/p70S6K pathway and promotes apoptosis in human melanoma A375 cells.
    Qiu-Ping Liang, Tian-Qi Xu, Bai-Lian Liu, Xue-Ping Lei, Jacob R Hambrook, Dong-Mei Zhang, Guang-Xiong Zhou.
       BACKGROUND: Melanoma is a high fatality skin cancer which lacks effective drugs. Sasanquasaponin, an important sort of constituents in theaceae, has been demonstrated to have potent anti-tumor effect in breast cancer and hepatocellular carcinoma. As a sasanquasaponin, we speculate that Sasanquasaponin III (SQS III) isolated from Schima crenata Korth may also have anti-tumor activity.
    PURPOSE: This study aims to investigate whether SQS III has anti-melanoma activity and examine the underlying mechanisms of SQS III against melanoma.
    METHODS/STUDY DESIGNS: The anti-proliferative effect of SQS III was assessed by cells viability assay. Annexin V-FITC/PI double staining assay was utilized for detection of apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) production were detected using JC-1 and DCFH-DA assay, respectively. Autophagy was monitored using transmission electron microscopy (TEM) and GFP-LC3 transfection fluorescence analysis. Autophagosome-lysosome fusion and lysosomal degradation were determined using a GFP-LC3 & LAMP1 co-localization assay and DQ-BSA staining. Proteins related to apoptosis and autophagy were analyzed by Western blotting.
    RESULTS: Our results demonstrated that the SQS III exhibited potent anti-cancer activity in A375 cells by inducing both apoptosis and autophagy. In melanoma cells treated with SQS III, caspases were activated and PARP was cleaved, proving the occurrence of apoptosis. Mechanistic studies indicated that the pro-apoptosis activity of SQS III was mediated by death receptor pathway and mitochondrial dysfunction which was induced by ROS accumulation and reversed by the ROS inhibitor N-acetyl-cysteine (NAC). In addition to triggering apoptosis, SQS III may also cause autophagy in melanoma cells. Our results demonstrated that SQS III induced up-regulated expression of GFP-LC3, autophagosome-lysosomal fusion and lysosomal degradation. Additionally, the ROS accumulation was also involved in the activation of autophagy. Meanwhile, it was also found that after SQS III treatment, the expression of LC3-II was up-regulated and the AKT/mTOR signaling pathway was inhibited. The autophagy inhibitor 3-MA converted cytotoxicity and apoptosis of SQS III in A375 cells, which indicated that autophagy promoted the SQS III-induced apoptosis.
    CONCLUSION: SQS III showed potent anti-cancer activity by inducing apoptosis and autophagy, which provides insights into its possible use as a therapy for melanoma.
    Keywords:  Akt/mTOR/p70S6K pathway; Apoptosis; Autophagy; ROS; Sasanquasaponin III
    DOI:  https://doi.org/10.1016/j.phymed.2018.11.029
  26. Biochim Biophys Acta Gen Subj. 2019 Apr 23. pii: S0304-4165(19)30097-2. [Epub ahead of print]
    PMAP-23 triggers cell death by nitric oxide-induced redox imbalance in Escherichia coli.
    Suhyun Kim, Dong Gun Lee.
       BACKGROUND: Antibiotic resistance is a global problem and there is an urgent need to augment the arsenal against pathogenic bacteria. The emergence of different drug resistant bacteria is threatening human lives to be pushed toward the pre-antibiotic era. Antimicrobial peptides (AMPs) are a host defense component against infectious pathogens in response to innate immunity. PMAP-23, an AMP derived from porcine myeloid, possesses antibacterial activity. It is currently not clear how the antibacterial activity of PMAP-23 is manifested.
    METHODS: The disruptive effect of nitric oxide (NO) on the catalase activity, reactive oxygen species (ROS) production, DNA oxidation and apoptosis-like death were evaluated using the nitric oxide synthase (NOS) inhibitor.
    RESULTS: In this investigation, PMAP-23 generates NO in a dose dependent manner. NO deactivated catalase and this antioxidant could not protect Escherichia coli against reactive oxygen species (ROS), especially hydroxyl radical. This redox imbalance was shown to induce oxidative stress, thus leading to DNA strand break. Consequently, PMAP-23 treated E. coli cells resulted in apoptosis-like death. These physiological changes were inhibited when NOS were inhibited. In the ΔdinF mutant, the levels of DNA strand break sharply increased and the cells were more sensitive to PMAP-23 than wild type.
    CONCLUSION: Our data strongly indicates that PMAP-23 mediates apoptosis-like cell death through affecting intracellular NO homeostasis. Furthermore, our results demonstrate that DinF functioned in protection from oxidative DNA damage.
    GENERAL SIGNIFICANCE: The identification of PMAP-23 antibacterial activity and mechanism provides a promising antibacterial agent, supporting the role of NO in cell death regulation.
    Keywords:  Antimicrobial peptide; Apoptosis-like death; DinF; Nitric oxide; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbagen.2019.04.014
  27. Mycologia. 2019 Apr 25. 1-12
    Farnesol altered morphogenesis and induced oxidative burst-related responses in Rhizoctonia solani AG1-IA.
    Zohreh Nassimi, Parissa Taheri, Saeed Tarighi.
      Farnesol induces morphological changes characteristic of apoptosis in filamentous fungi. Growth-inhibitory effect and induced features of apoptosis on Rhizoctonia solani AG1-IA were observed in our study by addition of exogenous farnesol to the culture. The obtained results implied that farnesol triggered apoptosis-like features, such as production of reactive oxygen species (ROS), in R. solani AG1-IA and that there was increased superoxide dismutase (SOD) activity in the presence of farnesol, as well as decreased fungal biomass. Light microscopic analysis showed that farnesol disrupted the cytoplasm and deformed the hyphae of R. solani AG1-IA. The diameter of the hyphal cross-section in the fungus treated with farnesol decreased compared with control. Transmission electron microscopy (TEM) showed marked alternations in the cell wall, cell membrane, parenthesome, septum, and septal pore of the fungal cells. The findings of this work suggest that farnesol is deleterious to R. solani and has potential for use as an antifungal compound against this destructive phytopathogenic fungus.
    Keywords:  ; Cell death; electron microscopy; quorum sensing molecule; reactive oxygen species; superoxide dismutase
    DOI:  https://doi.org/10.1080/00275514.2019.1600315
  28. Bull Exp Biol Med. 2019 Apr 26.
    Effect of Chitosan-(Poly)Nitroxides on Normal and Tumor Cells under Conditions of Induced Oxidative Stress.
    V A Mumyatova, A A Balakina, V D Sen', E M Pliss, A A Terent'ev.
      The cytotoxicity and antioxidant effects of chitosan-(poly)nitoxides of different molecular weights containing a nitroxide radical of the piperidine structure were studied on tumor (HeLa, A172, and HepG2) and normal (Vero) cell lines. The chitosan-(poly)nitroxides exhibited low cytotoxicity. Under conditions of oxidative stress induced with tert-butyl hydroperoxide, the most pronounced decrease in ROS levels in the presence of chitosan-(poly)nitroxides was observed in normal cells. In cell homogenates, the decrease in malondialdehyde levels was observed only in the presence of low-molecular-weight chitosan-(poly)nitroxide irrespective of the cell line. Our data demonstrate that the cell-specific antioxidant properties of chitosan-(poly)nitroxides are related to their penetration into cells and interaction with intracellular membranes.
    Keywords:  chitosan; cytotoxicity; malondialdehyde; nitroxide radical; reactive oxygen species
    DOI:  https://doi.org/10.1007/s10517-019-04439-7
  29. J Cell Biochem. 2019 Apr 26.
    α-Mangostin promotes apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes by reactive oxygen species-dependent activation of ERK1/2 mitogen-activated protein kinase.
    Xiaoyun Sheng, Jun Li, Chao Zhang, Lianggong Zhao, Laiwei Guo, Tianen Xu, Jiaxin Jin, Meng Wu, Yayi Xia.
      α-Mangostin (α-M) is a commonly used traditional medicine with various biological and pharmacological activities. Our study aimed to explore the effects and mechanism of α-M in regulating apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). α-M of 10 to 100 μM was used to treat RA-FLS for 24 hours, followed by measuring cell viability and apoptosis. The involvement of reactive oxygen species (ROS) and mitogen-activated protein kinases was detected. Treatment of α-M promoted apoptosis and reduced viability of RA-FLS in a dose-dependent manner. The mitochondrial membrane potential in RA-FLS was remarkably reduced by α-M treatment, accompanied by the cytochrome c accumulation in the cytosol and increased activities of caspase-3 and caspase-9. Moreover, we found that α-M treatment promoted ROS production and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. The proapoptotic activity of α-M in RA-FLS was markedly reversed by the co-induction with the ERK1/2 inhibitor LY3214996 or ROS scavenger N-acetyl-l-cysteine. In conclusion, our studies found that α-M had remarkable proapoptotic activities in RA-FLS, which is regulated by the induction of ROS accumulation and ERK1/2 phosphorylation. α-M may thus have potential therapeutic effects for rheumatoid arthritis.
    Keywords:  apoptosis; extracellular signal-regulated kinase 1/2; rheumatoid arthritis; rheumatoid arthritis fibroblast-like synoviocytes, α-mangostin
    DOI:  https://doi.org/10.1002/jcb.28760
  30. Oxid Med Cell Longev. 2019 ;2019 3738980
    Aminated Graphene Oxide as a Potential New Therapy for Colorectal Cancer.
    Natalia Krasteva, Milena Keremidarska-Markova, Kamelia Hristova-Panusheva, Tonya Andreeva, Giorgio Speranza, Dayong Wang, Milena Draganova-Filipova, George Miloshev, Milena Georgieva.
      Nanotechnology-based drug delivery systems for cancer therapy are the topic of interest for many researchers and scientists. Graphene oxide (GO) and its derivates are among the most extensively studied delivery systems of this type. The increased surface area, elevated loading capacity, and aptitude for surface functionalization together with the ability to induce reactive oxygen species make GO a promising tool for the development of novel anticancer therapies. Moreover, GO nanoparticles not only function as effective drug carriers but also have the potential to exert their own inhibitory effects on tumour cells. Recent results show that the functionalization of GO with different functional groups, namely, with amine groups, leads to increased reactivity of the nanoparticles. The last steers different hypotheses for the mechanisms through which this functionalization of GO could potentially lead to improved anticancer capacity. In this research, we have evaluated the potential of amine-functionalized graphene oxide nanoparticles (GO-NH2) as new molecules for colorectal cancer therapy. For the purpose, we have assessed the impact of aminated graphene oxide (GO) sheets on the viability of colon cancer cells, their potential to generate ROS, and their potential to influence cellular proliferation and survival. In order to elucidate their mechanism of action on the cellular systems, we have probed their genotoxic and cytostatic properties and compared them to pristine GO. Our results revealed that both GO samples (pristine and aminated) were composed of few-layer sheets with different particle sizes, zeta potential, and surface characteristics. Furthermore, we have detected increased cyto- and genotoxicity of the aminated GO nanoparticles following 24-hour exposure on Colon 26 cells. The last leads us to conclude that exposure of cancer cells to GO, namely, aminated GO, can significantly contribute to cancer cell killing by enhancing the cytotoxicity effect exerted through the induction of ROS, subsequent DNA damage, and apoptosis.
    DOI:  https://doi.org/10.1155/2019/3738980
  31. Biochem Biophys Res Commun. 2019 Apr 20. pii: S0006-291X(19)30752-1. [Epub ahead of print]
    Vaspin prevents myocardial injury in rats model of diabetic cardiomyopathy by enhancing autophagy and inhibiting inflammation.
    Xuelian Li, Xuan Ke, Zhiyang Li, Bingong Li.
      NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM). It is known that autophagy is related to the activation of inflammasomes during oxidative stress. Visceral adipose tissue-derived serine protease inhibitor (Vaspin), is an adipocytokine that has been shown to exert a protective effect on autophagic activity, but whether and how Vaspin improves myocardial damage in DCM remain unclear. In this study, we explored the role of Vaspin in DCM using a streptozotocin (STZ)-induced diabetes model. Cardiac function, cardiomyocyte apoptosis, myocardial tissue morphology, and mitochondrial morphology in diabetic rats were improved after eight weeks of Vaspin treatment. Vaspin treatment augmented autophagy activation in diabetic rat hearts. Moreover, the activation of NLRP3 inflammasome was inhibited by Vaspin, followed by a decrease in the cleavage of caspase-1 and maturation of IL-1β and TNF-ɑ. In vitro studies found that the mitochondrial reactive oxygen species (ROS) generation as well as the depolarization of the mitochondrial membrane in H9C2cells induced by high glucose were attenuated by Vaspin. This inhibitory effect of Vaspin on NLRP3 inflammasome activation was due to the protection of autophagy activity and was abolished after the treatment of autophagy inhibitor (3-MA). These results demonstrate that Vaspin alleviates STZ-induced myocardial injury and renders a cardioprotective effect by suppressing NLRP3 inflammasome activation and promoting autophagy.
    Keywords:  Autophagy; Diabetic cardiomyopathy; NLRP3 inflammasome; ROS; Vaspin
    DOI:  https://doi.org/10.1016/j.bbrc.2019.04.110
  32. Eur J Oral Sci. 2019 Apr 24.
    Effect of metformin on human periodontal ligament stem cells cultured with polydopamine-templated hydroxyapatite.
    Zun Yang, Xiang Gao, Mengjiao Zhou, Yunchun Kuang, Mingli Xiang, Jie Li, Jinlin Song.
      Polydopamine-templated hydroxyapatite (tHA) is a type of nano-biomaterial that can promote osteogenesis in bone tissue engineering. However, high concentrations of tHA stimulate production of reactive oxygen species (ROS), resulting in cell injury and apoptosis. Metformin has been demonstrated to activate the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, which induces autophagy and decreases ROS production to prevent apoptosis. The present study was performed to investigate the potential application of tHA in combination with metformin in periodontal bone tissue engineering. Human periodontal ligament stem cells (hPDLSCs) were exposed to tHA in the presence or absence of metformin, and cytocompatibility and osteogenesis were detected by related assays. Additionally, the autophagy signaling pathway was analyzed by western blotting. Polydopamine-templated hydroxyapatite, in combination with metformin, substantially reduced ROS production and apoptosis, and enhanced proliferation and osteogenic differentiation of hPDLSCs. Enhanced levels of microtubule-associated protein 1 light chain 3 II and Beclin-1 were observed after exposure to tHA plus metformin. Expression of phosphorylated AMPK was increased and that of phosphorylated mammalian target of rapamycin (mTOR) was decreased after exposure to tHA plus metformin. Taken together, our results demonstrate that tHA, combined with metformin, increases the viability of hPDLSCs via the AMPK/mTOR signaling pathway by regulating autophagy and further improving the osteogenic effect.
    Keywords:  adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway; autophagy; biocompatibility; osteogenic differentiation; reactive oxygen species
    DOI:  https://doi.org/10.1111/eos.12616
  33. Biosci Rep. 2019 Apr 25. pii: BSR20182378. [Epub ahead of print]
    Emodin inhibits zinc-induced neurotoxicity in neuroblastoma SH-SY5Y cells.
    Wenzhou Liu, Zhen Fan, Feng Gao, Li Ou, Min Li, Xin Zhou, Wenjia Luo, Peifeng Wei, Feng Miao.
      Emodin is a natural anthraquinone derivative with numerous beneficial effects, including antioxidant properties, anti-tumor activities, and protecting the nerves. Zinc-induced neurotoxicity plays a crucial role in the pathogenesis of vascular dementia (VD) and Parkinson's disease (PD). Here, the protective activity of emodin inhibiting zinc-induced neurotoxicity and its molecular mechanisms such as cellular Zn2+ influx and zinc-induced gene expression were examined using human neuroblastoma cells (SH-SY5Y cells). Our findings showed that emodin obviously enhanced cell viability and reduced cell apoptosis and LDH release. Bedsides, we detected a decrease of intracellular Zn2+ concentration after SH-SY5Y cells were pretreated with emodin. Simultaneously, the expression of zinc transporter-1 (ZnT-1), metallothionein-1 (MT1) and metallothionein-2 (MT2) were weakened in emodin-pretreated SH-SY5Y cells. In addition, emodin prevented the depletion of NAD+ and ATP induced by zinc. Emodin also reduced intracellular reactive oxygen species (ROS) and endoplasmic reticulum (ER)-stress levels. Strikingly, emodin elevated SH-SY5Y cell viability and inhibited cell apoptosis caused by AMP-activated protein kinase (AMPK) signaling pathway activation. Thus, emodin could protect against neurotoxicity induced by Zn2+ in neuroblastoma SH-SY5Y cells. It is expected to have future therapeutic potential for VD or PD and other neurodegenerative diseases.
    Keywords:  AMPK; ER-stress; Emodin; Zinc; senile dementia
    DOI:  https://doi.org/10.1042/BSR20182378
  34. Front Physiol. 2019 ;10 411
    Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury.
    Wenjun Xiong, Zhuang Ma, Dongqi An, Zuheng Liu, Wanqiang Cai, Yujia Bai, Qiong Zhan, Wenyan Lai, Qingchun Zeng, Hao Ren, Dingli Xu.
       Background: Mitochondrial dynamics play a critical role in mitochondrial function. The mitofusin 2 (MFN2) gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion to maintain and operate the mitochondrial network. Moreover, MFN2 is essential for mitophagy. In Ang II-induced cardiac remodeling, the combined effects of MFN2-mediated mitochondrial fusion and mitophagy are unclear. This study was designed to explore a novel strategy for preventing cardiomyocyte injury via modulation of mitochondrial dynamics.
    Methods: We studied the function of MFN2 in mitochondrial fusion and mitophagy in Ang II-stimulated cardiomyocyte injury. Cardiomyocyte injury experiments, including reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and apoptosis rate of cardiomyocytes were performed. The mitochondrial morphology in cardiomyocytes was examined via transmission electron microscopy (TEM) and confocal microscopy. Autophagic levels in response to Ang II were examined by immunoblotting of autophagy-related proteins. Moreover, PINK1/MFN2/Parkin pathway-related proteins were examined.
    Results: With stimulation by Ang II, MFN2 expression was progressively reduced. MFN2 deficiency impaired mitochondrial quality, resulting in exacerbated mitochondrial damage induced by Ang II. The Ang II-induced increases in ROS production and apoptosis rate were alleviated by MFN2 overexpression. Moreover, MFN2 alleviated the Ang II-induced reduction in MMP. MFN2 promoted mitochondrial fusion, and MFN2 promoted Parkin translocation and phosphorylation, leading to mitochondrial autophagy. The effects of MFN2 overexpression were reversed by autophagy inhibitors.
    Conclusion: Mitofusin 2 promotes Parkin translocation and phosphorylation, leading to mitophagy to clear damaged mitochondria. However, the beneficial effects of MFN2 were reversed by autophagy inhibitors. Additionally, MFN2 participates in mitochondrial fusion to maintain mitochondrial quality. Thus, MFN2 participated in mitophagy and mitochondrial fusion against Ang II-induced cardiomyocyte injury.
    Keywords:  MFN2; ROS; angiotensin II; autophagy; mitochondria
    DOI:  https://doi.org/10.3389/fphys.2019.00411
  35. Oxid Med Cell Longev. 2019 ;2019 3640753
    Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence.
    Youngmun Lee, Sunyoung Kim, Yeonsoo Oh, Young-Mi Kim, Young-Won Chin, Jungsook Cho.
      Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer's disease.
    DOI:  https://doi.org/10.1155/2019/3640753
  36. Adv Radiat Oncol. 2019 Apr-Jun;4(2):4(2): 237-245
    Amelioration of Radiation Enteropathy by Dietary Supplementation With Reduced Coenzyme Q10.
    Yasuyuki Shimizu, Naritoshi Mukumoto, Nelly Idrus, Hiroaki Akasaka, Sachiko Inubushi, Kenji Yoshida, Daisuke Miyawaki, Takeaki Ishihara, Yoshiaki Okamoto, Takahiro Yasuda, Makiko Nakahana, Ryohei Sasaki.
       Purpose: Effective methods to ameliorate radiation enteropathy have not been developed. To address this issue, we investigated the reduced form of coenzyme Q10 (rCoQ10) as a potential radioprotector in a mouse model.
    Methods and Materials: rCoQ10 was added to a standard laboratory mouse diet at a final concentration of 1.0% 9 days before irradiation and 30 days thereafter or dissolved in corn oil and administered transorally. Accumulated amounts of coenzyme Q10 (CoQ10) or coenzyme Q9 in the intestine were measured by high-performance liquid chromatography. Reactive oxygen species (ROS), apoptosis, and morphologic changes in the intestine were assessed by immunohistochemistry after administration of 13 Gy of x-ray to the mouse abdomen. Body weight and survival were monitored for 30 days after irradiation. Cytotoxicity using 3 human cancer cell lines and the tumor growth-inhibiting effect in a xenograft were investigated to determine whether rCoQ10 interferes with radiation-specific cytotoxic effects on tumor growth.
    Results: CoQ10 was greatly accumulated in all sections of the intestine after both massive transoral dosing and dietary administration, whereas coenzyme Q9 was not. Administration of rCoQ10 suppressed ROS production and inhibited apoptosis in the crypts, resulting in preservation of villi structures after irradiation. Notably, 92% of mice fed the rCoQ10-supplemented diet were healthy and alive 30 days after irradiation, whereas 50% of control mice died (P < .05). Moreover, rCoQ10 did not interfere with radiation-specific cytotoxic effects on tumors either in vitro or in vivo.
    Conclusions: Administration of rCoQ10 led to its accumulation in the intestine and induced radioprotective effects by inhibiting ROS-mediated apoptosis, thereby preserving intestinal structures. Our results indicated that rCoQ10 supplementation effectively ameliorated radiation enteropathy.
    DOI:  https://doi.org/10.1016/j.adro.2019.01.006
  37. Life Sci. 2019 Apr 17. pii: S0024-3205(19)30290-5. [Epub ahead of print]
    Targeting non-oncogene ROS pathway by alantolactone in B cell acute lymphoblastic leukemia cells.
    Xiaoguang Xu, Lei Huang, Zilu Zhang, Jia Tong, Jianqing Mi, Yingli Wu, Chenli Zhang, Hua Yan.
       AIMS: Alantolactone (ALT) is active component of natural product Inula helenium with a lot of pharmacological effects, including anti-tumor effect. The present work aimed to explore the antitumor effect of ALT in B cell acute lymphoblastic leukemia (B-ALL).
    MAIN METHODS: B-ALL cells were treated with various concentrations of ALT, and then trypan blue assay, Annexin V/PI staining assay, PI staining assay, western blot analysis were employed to measure the effect of ALT on viability, apoptosis and cell cycle in B-ALL cells. In addition, a synthetic bioinformatics method was used to predict the underlying mechanism of antitumor effect of ALT. Then Reactive Oxygen Species (ROS) probe Dihydroethidium (DHE) and 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) were used to detect accumulation of cellular ROS. Meanwhile, DNA damage was identified by 8-oxoG, p-ATM1987, γ-H2AX and comet assay. In addition, activity of glutathione reductase (GR), thioredoxin reductase (TrxR) and catalase were measured and overexpressed in SEM and RS4;11 cells to study the inhibition on these enzymes. Finally, B-ALL NOD-SCID mouse model was used to test its performance in vivo.
    KEY FINDINGS: ALT showed good antitumor effect in B-ALL in vivo and in vitro through inducing ROS overload, which led to DNA damage. In addition, we found ROS overload caused by ALT was due to its direct inhibition on reductase.
    SIGNIFICANCE: We found that ALT, a natural product, showing a promising tactic in the therapy of B-ALL by targeting ROS pathway.
    Keywords:  Alantolactone; Apoptosis; B cell acute lymphoblastic leukemia; Bioinformatics analysis; DNA damage; ROS
    DOI:  https://doi.org/10.1016/j.lfs.2019.04.034
  38. APMIS. 2019 Apr 22.
    Erythrocytes restrict microvesicle-induced production of reactive oxygen species by polymorphonuclear leukocytes.
    Line Kjaer Winberg, Niclas Stefan Rasmussen, Claus Henrik Nielsen, Søren Jacobsen.
      Microvesicles (MVs) are extracellular vesicles released by several cell types upon activation or apoptosis. MVs have the potential to activate complement, which has been suggested to mediate their clearance. However, it is not clear how complement-opsonized MVs are prevented from activating circulating polymorphonuclear leukocytes (PMNs) with release of reactive oxygen species (ROS) and potential damage of endothelium and other bystander cells as consequence. We hypothesized that binding of opsonized MVs to erythrocytes (Es) attenuates MV-induced PMN activation. To test this, normal PMNs were exposed to MVs in presence and absence of Es from allogenic healthy donors. As analysed by flow cytometry, the presence of Es restricted the PMN binding of MVs by about 85% (p=0.002) and mediated a 60-70% inhibition of the PMN production of the reactive oxygen species (ROS) H2 O2 , induced by MVs, when lipopolysaccharide was used as primer (p=0.002). The competitive binding of MVs to Es was partly dependent on complement, since EDTA inhibited MV-binding to Es by 75%. These data suggest that Es, through competitive binding, may restrict MV-induced activation of circulating PMNs and thereby serve a role as a regulator of PMN activation. This article is protected by copyright. All rights reserved.
    Keywords:  Microvesicles; immunology; inflammation; pathology; reactive oxygen species
    DOI:  https://doi.org/10.1111/apm.12954
  39. Front Mol Neurosci. 2019 ;12 80
    Conditioned Medium of Human Menstrual Blood-Derived Endometrial Stem Cells Protects Against MPP+-Induced Cytotoxicity in vitro.
    Han Li, Badrul Hisham Yahaya, Wai Hoe Ng, Narazah Mohd Yusoff, Juntang Lin.
      Mesenchymal stem cells (MSCs) showed the potential to treat Parkinson's disease (PD). However, it is unknown whether the conditioned medium of human menstrual blood-derived endometrial stem cells (MenSCs-CM) has the function to alleviate syndromes of PD. In this study, human neuroblastoma SH-SY5Y cells were exposed to neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) for inducing a range of response characteristics of PD. After culturing this cell model with 24 h/48 h collected MenSCs-CM for different days, cell viability, pro-inflammation cytokines, mitochondrial membrane potential (ΔΨm), oxidative stress, and cell apoptosis were detected. Finally, protein assay was performed to detect 12 kinds of neurotrophic factors inside MenSCs-CM. Our results showed that MPP+ caused SH-SY5Y cell viability reduction as an increasing dose and time dependent manner. MPP+ treatment resulted in inflammation, mitochondrial dysfunction, reactive oxygen species (ROS) production accumulation, and apoptosis of SH-SY5Y at its IC50 concentration. Forty-eight hours-collected MenSCs-CM and culturing with the MPP+-treated SH-SY5Y for 2 days are the optimized condition to increase cell viability. Besides, MenSCs-CM was efficacious against MPP+ induced inflammation, ΔΨm loss, ROS generation, and it could significantly decrease cells numbers in late apoptosis stage. What's more, protein assay showed that MenSCs-CM contained various neuroprotective factors. Our study provided the first evidence that MenSCs-CM has a protective effect on MPP+-induced cytotoxicity in various aspects, and firstly showed that MenSCs can release at least 12 kinds of neurotrophic factors to medium, which may contribute to the protective function of MenSCs-CM to treat PD. This research enlightening that MenSCs-CM is beneficial in the therapy for PD and probably also for other neurodegenerative diseases.
    Keywords:  MPP+; MSCs; Parkinson’s disease; ROS; SH-SY5Y; conditioned medium; inflammation
    DOI:  https://doi.org/10.3389/fnmol.2019.00080
  40. Int J Mol Sci. 2019 Apr 22. pii: E1967. [Epub ahead of print]20(8):
    Involvement of p38 Activation and Mitochondria in Death of Human Leukemia Cells Induced by an Agonistic Human Monoclonal Antibody Fab Specific to TRAIL Receptor 1.
    You-Ri Lee, Eunjoo Hwang, Young-Ju Jang.
      The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death with minimal damage to normal cells; however, some cancer cells are resistant to TRAIL. TRAIL resistance may be overcome by agonistic antibodies to TRAIL receptors. In this study, we report the toxic effects of a novel recombinant agonistic human anti-TRAIL receptor 1 (DR4) monoclonal antibody Fab fragment, DR4-4, on various TRAIL-resistant and -sensitive cancer cell lines. The mechanisms of DR4-4 Fab-induced cell death in a human T cell leukemia cell line (Jurkat) were investigated using cell viability testing, immunoblotting, immunoassays, flow cytometry, and morphological observation. DR4-4 Fab-induced caspase-independent necrosis was observed to occur in Jurkat cells in association with p38 mitogen-activated protein kinase activation, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein degradation, decreased mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production. Increased cytotoxic effects of DR4-4 Fab were observed in combination with TRAIL or γ-irradiation. Our results indicate that the novel DR4-4 Fab might overcome TRAIL-resistance and induce death in leukemia cells via cellular mechanisms different from those activated by TRAIL. DR4-4 Fab may have application as a potential therapeutic antibody fragment in single or combination therapy for cancer.
    Keywords:  DR4; Fab; TRAIL; TRAIL receptor 1; TRAIL-resistance; agonistic human antibody; cancer cells; mitochondria; p38
    DOI:  https://doi.org/10.3390/ijms20081967
  41. Int Urol Nephrol. 2019 Apr 24.
    Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury.
    Yunwen Yang, Yu Fu, Peipei Wang, Suwen Liu, Yugen Sha, Yue Zhang, Aihua Zhang, Zhanjun Jia, Guixia Ding, Songming Huang.
       OBJECTIVES: The dysfunction of mitochondrial respiratory chain induced by cisplatin results in overproduction of reactive oxygen species (ROS) which contributes to kidney injury. The current study aimed to evaluate the effect of a mitochondrial electron transport inhibitors of rotenone (mitochondrial complex I inhibitor) and azoxystrobin (mitochondrial complex III inhibitor), in cisplatin-induced kidney injury.
    METHODS: In vivo, cisplatin was administered to male C57BL/6J mice by a single intraperitoneal (i.p.) injection (20 mg/kg). Then the mice were treated with or without 200 ppm rotenone in food. Mice were sacrificed after cisplatin administration for 72 h. The serum and the kidney tissues were collected for further analysis. In vitro, mouse proximal tubular cells (mPTCs) were treated with cisplatin (5 µg/mL) and rotenone/azoxystrobin for 24 h. Flow cytometry, Western blotting, and TUNEL staining were used to evaluate the cell injury.
    RESULTS: In vivo, rotenone treatment obviously ameliorated cisplatin-induced renal tubular injury evidenced by the improved histology and blocked NGAL upregulation. Meanwhile, cisplatin-induced renal dysfunction shown by the increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C were significantly reduced by rotenone treatment. Moreover, the increments of cleaved caspase-3 and transferase dUTP nick-end labeling (TUNEL)-positive cells were markedly decreased in line with the attenuated mitochondrial dysfunction and oxidative stress after rotenone administration. In vitro, rotenone and azoxystrobin protected against mitochondrial dysfunction, oxidative stress, and renal tubular cell apoptosis induced by cisplatin.
    CONCLUSIONS: Our results demonstrated that inhibition of mitochondrial activity significantly attenuated cisplatin nephrotoxicity possibly by inhibiting mitochondrial oxidative stress.
    Keywords:  AKI; Cisplatin; Mitochondrial activity; Oxidative stress
    DOI:  https://doi.org/10.1007/s11255-019-02113-5
  42. Int J Mol Sci. 2019 Apr 24. pii: E2027. [Epub ahead of print]20(8):
    Rosmarinic Acid Attenuates Cadmium-Induced Nephrotoxicity via Inhibition of Oxidative Stress, Apoptosis, Inflammation and Fibrosis.
    Swarnalata Joardar, Saikat Dewanjee, Shovonlal Bhowmick, Tarun K Dua, Sonjit Das, Achintya Saha, Vincenzo De Feo.
      The present investigation was executed to reveal the protective mechanism of rosmarinic acid (RA) against cadmium (Cd)-induced nephrotoxicity. RA exhibited a concentration-dependent anti-apoptotic effect against CdCl2 in isolated mouse proximal tubular epithelial cells. Cd treatment significantly (p < 0.01) imparted oxidative stress to the renal cells via excessive ROS production, triggering NO level, NADPH oxidase activation, and impairment of cellular redox defense system. Cd-mediated oxidative stress significantly (p < 0.01) endorsed apoptosis to the murine kidney cells by triggering NF-κB/PKC-δ/TNFR2 activation. In addition, CdCl2 induced renal fibrosis by triggering TGF-β1/SMAD3/α-SMA/collagen signaling within renal cells. On the other hand, RA significantly (p < 0.05-0.01) attenuated Cd-provoked oxidative stress and associated pathological signal transduction in murine renal cells. RA treatment also could significantly (p < 0.05-0.01) reciprocate Cd-mediated pathological changes in blood and urine parameters in mice. In addition, histological data supported the pharmacological findings. In silico chemometric analyses predicted the possible interactions between RA and different signal proteins and anticipated drug-likeness characteristics of RA. Hence, RA can potentially be applied as a therapeutic agent to treat Cd-mediated nephrotoxicity in future.
    Keywords:  antioxidant; apoptosis; cadmium; oxidative stress; rosmarinic acid
    DOI:  https://doi.org/10.3390/ijms20082027
  43. Klin Onkol. 2018 ;31(Supplementum 2): 21-26
    Ferroptosis as a New Type of Cell Death and its Role in Cancer Treatment.
    Skoupilová Hana, Michalová Eva, Hrstka Roman.
       BACKGROUND: Ferroptosis is a recently discovered type of cell death. It is genetically, morphologically, and biochemically distinct from other types of programmed cell death, such as necrosis, apoptosis, and autophagy. The level of intracellular free iron and reactive oxygen species formation are important for ferroptosis activation, which can occur through either of two key inhibitory processes. The first one involves inhibition of cystine transfer into cells by the cystine/glutamate antiporter system (Xc-). Cystine serves as a precursor for the synthesis of glutathione, a major cellular antioxidant. The second one involves the inhibition of glutathione peroxidase 4, which protects cells from lipid peroxidation. Ferroptosis is associated with many metabolic disorders, including neurological diseases and cancer. Molecules involved in the activation of ferroptotic pathways are involved in protecting cells against stress conditions, and in the maintenance of nicotinamide adenine dinucleotide phosphate and glutathione levels, as well as iron homeostasis. Also important is the connection with autophagy, so called ferritinophagy, in which iron is released from lysosomes into the cytosol. Cascade reactions of free unstable iron atoms with other molecules result in the production of reactive oxygen species that initiate the cellular stress that triggers ferroptosis. In diseases such as cancer where cell death inducing mechanisms, including apoptosis, are usually suppressed by genetic changes, the induction of alternative pathways leading to cell death could provide an attractive treatment strategy.
    CONCLUSION: In recent years, research into new antimetastatic drugs has focused on the activation of alternative cell death pathways that might overcome disturbed metabolic processes inside cancer cells or the chemotherapy resistance acquired in the course of routine treatment. A number of molecules have been found to induce ferroptosis in tumor cells, suggesting that they may offer new alternatives for anticancer treatment. Key words: cell death - cancer - autophagy - ferroptosis - ferritinophagy - cellular stress - ROS This work was supported by the projects GA&#268;R 17-05838S, MEYS - NPS I - LO1413 and MH CZ- -DRO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 31. 8. 2018.
    Keywords:  00209805). The authors declare they have no potential conflicts of interest concerning drugs; MEYS - NPS I - LO1413 and MH CZ- -DRO (MMCI; cell death - cancer - autophagy - ferroptosis - ferritinophagy - cellular stress - ROS This work was supported by the projects GA&#268;R 17-05838S; or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 31. 8. 2018; products
    DOI:  https://doi.org/10.14735/amko20182S21
  44. Biomed Pharmacother. 2019 Apr 23. pii: S0753-3322(19)30802-9. [Epub ahead of print]115 108894
    Involvement of miR-665 in protection effect of dexmedetomidine against Oxidative Stress Injury in myocardial cells via CB2 and CK1.
    Juan Yu, Wei Yang, Wei Wang, Zhuoran Wang, Yuju Pu, Hongmei Chen, Fei Wang, Jinqiao Qian.
       BACKGROUND: Dexmedetomidine (Dex) can confer cardioprotective effects against ischemia/reperfusion (I/R) injury. While there are no studies addressing cardioprotection of Dex via regulation of microRNAs. The purpose of this study was to examine the roles and mechanisms of microRNA in cardioprotection of dexmedetomidine.
    METHODS: Rat heart Langendorff preparation was established. We assayed expression profiling of miRNAs in perfused rat hearts and predicted Target genes using MiRanda, MiRDB, and TargetScan. Oxide stress (H2O2) was employed to simulate I/R injury. miR-665 mimic, inhibitor, and siRNA of AK1 and Cnr2 were transfected to H9C2. The real-time quantitative polymerase chain reaction was used to quantify miR-665 and Ak1 and Cnr2 mRNA. The apoptosis of the cells was examined. The expression levels of cleaved caspase-3, Bcl-2, Bax, AK1, and Cnr2 were detected by Western blot. The combination between miR-665 and the 3'-untranslated region of AK1 and Cnr2 was validated by a luciferase reporter assay.
    RESULTS: Dex precondition down-regulated miR-665 expression in hearts compared to I/R group. Dex reduced miR-665 expression and apoptosis increased by oxide stress. However, up-regulation of miR-665 exacerbated the changes caused by oxide stress and inhibited the effects of Dex. Down-regulation of miR-665 also reduced apoptosis, but inhibition of AK1 and Cnr2 aggravated apoptosis. The luciferase reporter assay indicated that miR-665 could down-regulate expression levels of AK1 and Cnr2.
    CONCLUSIONS: Dex precondition confers hearts protective effect against I/R injury by down-regulating expression of miR-665 and up-regulating expression of AK1 and Cnr2.
    Keywords:  AK1; Cardioprotection; Cnr2; Dexmedetomidine; Oxidative stress; microRNAs
    DOI:  https://doi.org/10.1016/j.biopha.2019.108894
  45. Biol Trace Elem Res. 2019 Apr 25.
    Selenium-Alleviated Hepatocyte Necrosis and DNA Damage in Cyclophosphamide-Treated Geese by Mitigating Oxidative Stress.
    Bingxin Li, Wanyan Li, Yunbo Tian, Sixuan Guo, Long Qian, Danning Xu, Nan Cao.
      Selenium (Se) has been well recognized as an immune-enhancing agent with antioxidant and anti-tumor properties. The commonly used chemotherapy drug, cyclophosphamide (CTX), induces liver injury by increasing the reactive oxygen species (ROS) level. However, little is known about how Se alleviates CTX-induced liver injury in geese. In this study, 90 male Magang geese (3 days old) were randomly allocated into three groups (control, CTX, and Se + CTX group) with three replicates per group and ten geese per replicate. The control and CTX groups were fed a basal diet (Se content was 0.03 mg/kg). The Se + CTX group was fed a basal diet containing 0.44 mg/kg sodium selenite (Se content was 0.2 + 0.03 mg/kg). The control group was injected with 0.5 mL saline, while the CTX and Se + CTX groups were injected with CTX at 40 mg/kg body weight per day on days 21-23. The liver index, liver histology, and ultra-micromorphology detected antioxidant enzyme activity in the liver and serum. In addition, we detected the liver marker enzymes and protein levels in serum, and hepatocyte DNA damage. Se could alleviate liver development dysregulation, hepatocyte structural damage, the disturbances in antioxidant enzyme (GPx, CAT, and SOD) activity, and malondialdehyde (MDA) levels in the serum and liver. Besides, Se could alleviate the dysregulation of liver marker enzyme (ALT and AST) activity and protein (ALB and TP) levels in the serum, and DNA migration induced by CTX. In conclusion, Se may inhibit hepatocyte necrosis and DNA damage by inhibiting CTX-induced oxidative stress.
    Keywords:  Cyclophosphamide; DNA damage; Liver; Oxidative stress; Selenium
    DOI:  https://doi.org/10.1007/s12011-019-01717-3
  46. Biomolecules. 2019 Apr 23. pii: E159. [Epub ahead of print]9(4):
    Curcuma raktakanda Induces Apoptosis and Suppresses Migration in Cancer Cells: Role of Reactive Oxygen Species.
    Shruti Mishra, Sumit Singh Verma, Vipin Rai, Nikee Awasthee, Jayadev S Arya, Kaustabh K Maiti, Subash C Gupta.
      Although over 100 species of Curcuma are reported, only Curcuma longa is extensively studied. Curcuma raktakanda, a poorly studied species, is most commonly distributed in the Kerala state of India. For the first time, we examined the efficacy of different fractions (acetone, hexane, and ethyl acetate) of C. raktakanda against glioma, cervical, and breast cancer cell lines. As determined by mitochondrial reductase activity assay, the viability of cancer cells was decreased in a concentration-dependent manner by the three fractions. The half maximal inhibitory concentration (IC-50) values after the treatment of C-6 glioma cells for 48 h was found to be 32.97 µg/mL (acetone extract), 40.63 µg/mL (hexane extract), and 51.65 µg/mL (ethyl acetate extract). Of the three fractions, the acetone fraction was more effective. The long-term colony formation of cancer cells was significantly suppressed by the acetone fraction. Analyses using DAPI (4',6-diamidino-2-phenylindole) staining, AO/PI (acridine orange/propidium iodide) staining, DNA laddering, and sub-G1 population revealed that the acetone extract induced apoptosis in glioma cells. The extract induced reactive oxygen species generation and suppressed the expression of cell survival proteins. The migration of cancer cells was also suppressed by the acetone extract. The gas chromatography-mass spectrometry (GC-MS) analysis indicated that tetracontane, dotriacontane, hexatriacontane, pentacosane, hexacosane, and eicosane are the major components in the acetone extract. Collectively, the extract from C. raktakanda exhibited anti-carcinogenic activities in cancer cells. We are exploring whether the phytoconstituents, individually, or collectively contribute to the anti-cancer activities of C. raktakanda.
    Keywords:  cancer; curcuma; glioblastoma; inflammation; reactive oxygen species
    DOI:  https://doi.org/10.3390/biom9040159
  47. Front Endocrinol (Lausanne). 2019 ;10 202
    Exenatide Protects Against Cardiac Dysfunction by Attenuating Oxidative Stress in the Diabetic Mouse Heart.
    Wei Ding, Wen-Guang Chang, Xiao-Ci Guo, Ying Liu, Dan-Dan Xiao, Dan Ding, Jian-Xun Wang, Xue-Juan Zhang.
      Cardiovascular disease is the major cause of death in patients with diabetes. Current treatment strategies for diabetes rely on lifestyle changes and glucose control to prevent angiopathy and organ failure. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used as an add-on therapy to insulin treatment. Exenatide also has multiple beneficial effects in addition to its hypoglycemic effects, such as preventing hepatic steatosis and protecting against cardiac injury from doxorubicin-induced cardiotoxicity or ischemic reperfusion. However, the mechanisms underlying the cardioprotective effects of exenatide in diabetes have not been fully clarified. To address this issue, we investigated the cardioprotective effects of exenatide in type 1 and type 2 diabetic mice. We found that exenatide simultaneously attenuated reactive oxidative species (ROS) production through increases in the antioxidant enzymes manganese dependent superoxide dismutase (MnSOD) and catalase. Moreover, exenatide decreased tumor protein P53 (p53) expression and prevented cell apoptosis in H9c2 cells. The presence of the catalase inhibitor 3-AT attenuated the effects of exenatide. Overall, the results strongly indicate that exenatide treatment may be protective against the development of diabetic cardiomyopathy.
    Keywords:  ROS; apoptosis; cardiac function; diabetes; exenatide
    DOI:  https://doi.org/10.3389/fendo.2019.00202
  48. Neurotox Res. 2019 Apr 22.
    Benzophenone-2 Concentration and Its Effect on Oxidative Stress and Apoptosis Markers in Rat Brain.
    Żaneta Broniowska, Beata Bystrowska, Beata Starek-Świechowicz, Bartosz Pomierny, Weronika Krzyżanowska, Maria Walczak, Bogusława Budziszewska.
      Benzophenones, frequently used as UV chemical filters, are absorbed through the skin and can exert systemic adverse effects. So far, most of the data are related to their action on sex hormone receptors whereas potential neurotoxic effect is expected mainly on the basis of in vitro studies. The aim of the present study was to determine concentrations of BP-2, oxidative stress and apoptosis markers in the rat brain after topical administration of this compound. Male Wistar rats were treated dermally with BP-2 (100 mg/kg, 4 weeks), and next, blood and tissue BP-2 concentrations and oxidative stress and apoptotic markers in the frontal cortex and hippocampus were determined. After dermal BP-2 administration, blood level of this compound was about 300 ng/ml while in the liver and adipose tissue 1354 and 823 ng/g wt tissue, respectively. In the studied brain structures, the levels of the test compound were from 5 to 19 ng/g tissue. In the hippocampus, where BP-2 level was about 3.5-fold lower than in the frontal cortex, no significant changes in either oxidative stress and apoptosis markers were observed. There was also no change in apoptosis markers in the frontal cortex but unexpectedly the oxidative stress markers were reduced. The research showed that BP-2 passes through the blood-brain barrier but its concentration in the brain structures are much lower than in the blood. This compound did not exacerbate oxidative stress and apoptosis markers in the hippocampus and frontal cortex, and even lowered oxidative stress in the frontal cortex.
    Keywords:  Benzophenone-2; Brain concentration; Oxidative stress; UV filters
    DOI:  https://doi.org/10.1007/s12640-019-0011-y
  49. Bratisl Lek Listy. 2019 ;120(4): 256-262
    Low concentration of morphine protects against cell death, oxidative stress and calcium accumulation by nicotine in PC12 cells.
    K Amini, H Zhaleh, R Tahvilian, V Farnia.
       OBJECTIVE: Nicotine causes cell death in many cell lines. Morphine at low concentrations has protective effects against cell death. We investigated the effects of low concentration of morphine on nicotine-induced cell death in PC12 cells.
    MATERIALS AND METHODS: PC12 are cells that grow in DMEM culture medium. Cell viability was detected by MTT test and cells cytotoxicity was measured by LDH test. The activity of caspase-3 was diagnosed by the caspase activity colorimetric assay kit, and detection of mitochondrial membrane potential was confirmed by rhodamine 123 and TUNEL test was performed for DNA fragmentation detection. The fura-2 AM and also rhod 2-AM was used for measurement of intracellular calcium (Ca2+) ic and mitochondrial calcium (Ca2+) m and finally, measurement of antioxidant enzyme activities was assessed.
    RESULTS: The low concentration of morphine increased cell viability and suppressed cell cytotoxicity, cell death and the formation of mitochondrial membrane potential compared to nicotine treated cells.  It also reduced the intracellular calcium (Ca2+) ic and mitochondrial calcium (Ca2+)m concentration, respectively.
    CONCLUSION: Morphine as a pain reducer drug, in low concentrations, can protect PC12 cells from nicotine-induced cell death (Fig. 7, Ref. 59).
    Keywords:  apoptosis cell death.; morphine; nicotine
    DOI:  https://doi.org/10.4149/BLL_2019_042
  50. Methods Mol Biol. 2019 ;1981 117-132
    The Role and Study of Mitochondrial Impairment and Oxidative Stress in Cholestasis.
    Reza Heidari, Hossein Niknahad.
      The blockage of bile flow, cholestasis, could lead to serious clinical outcomes, including severe liver injury. Accumulation of the cytotoxic molecules, such as bile acids, during cholestasis, not only impairs liver function, but also affects other organs, including the kidneys. Although the precise mechanisms of cytotoxicity and organ injury in cholestasis are far from clear, oxidative stress and its subsequent events seem to play a central role in this complication. Oxidative stress acts as a signaling path which could finally lead to cell death and organ injury. At the cellular level, mitochondria are major targets affected by cytotoxic molecules. Mitochondrial impairment could lead to severe outcomes, including cellular energy crisis and release of cell death mediators from this organelle. Therefore, targeting oxidative stress and mitochondrial dysfunction might serve as a therapeutic point of intervention against cholestasis-associated organ injury. In this protocol, an animal model of cholestasis is described, and the techniques for liver mitochondria isolation, evaluating mitochondrial indices of functionality, and assessing biomarkers of oxidative stress in the liver tissue are outlined.
    Keywords:  Apoptosis; Bile acids; Bioenergetics; Cellular energy crisis; Cholestasis; Mitochondria-mediated cell death
    DOI:  https://doi.org/10.1007/978-1-4939-9420-5_8
  51. Cell Microbiol. 2019 Apr 22. e13033
    Cholix toxin, an eEF2 ADP-ribosyltransferase, interacts with Prohibitins and induces apoptosis with mitochondrial dysfunction in human hepatocytes.
    Kinnosuke Yahiro, Kohei Ogura, Yasuhiro Terasaki, Mamoru Satoh, Satoru Miyagi, Mika Terasaki, Eiki Yamasaki, Joel Moss.
      Vibrio cholerae produced-Cholix toxin (Cholix) is a cytotoxin that ADP-ribosylates eukaryotic elongation factor 2, inhibiting protein synthesis, and inducing apoptosis. Here, we identified prohibitin (PHB) 1 and 2 as novel Cholix-interacting membrane proteins in immortalized human hepatocytes and HepG2 cells by Cholix immunoprecipitation assays. The expression level of PHB1 was decreased by Cholix after a 12 h incubation. Cholix-induced poly (ADP-ribose) polymerase (PARP) cleavage was significantly enhanced in PHB (PHB1 or PHB2) knockdown cells. In contrast, transiently overexpressed PHB in hepatocytes attenuated Cholix-induced Bax/Bak conformational changes and PARP cleavage. In addition, Cholix-induced reactive oxygen species (ROS) production and accumulation of fragmented mitochondria were enhanced in PHB-knockdown cells. Furthermore, Cholix induced activation of Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which was enhanced in PHB-knockdown cells, followed by actin filament depolymerization and accumulation of tubulin in the blebbing cells. Inhibition of ROCK1 by siRNA or its inhibitor suppressed Cholix-induced PARP cleavage and ROS generation. Our findings identify PHB as a new protein that interacts with Cholix and is involved in Cholix-induced mitochondrial dysfunction and cytoskeletal rearrangement by ROCK1 activation during apoptosis.
    Keywords:  Cholix; ROS generation; cell death; mitochondria; prohibitin
    DOI:  https://doi.org/10.1111/cmi.13033
  52. Int J Mol Sci. 2019 Apr 19. pii: E1928. [Epub ahead of print]20(8):
    The Impact of O-Glycosylation on Cyanidin Interaction with RBCs and HMEC-1 Cells-Structure⁻Activity Relationships.
    Sylwia Cyboran-Mikołajczyk, Katarzyna Solarska-Ściuk, Katarzyna Mieszała, Natalia Glatzel-Plucińska, Karolina Matczak, Halina Kleszczyńska.
      With the aim of contributing to the knowledge about their potential therapeutic activity, we determined the biological activities of cyanidin and its selected O-glycosides in relation to erythrocytes (RBCs) and human dermal vascular endothelial cells (HMEC-1). Furthermore, on the basis of changes in the physical/functional properties of the cells, the structure-activity relationships of the compounds were determined. Concerning erythrocytes, we analyzed the antioxidant activity of the compounds and their impact on the RBCs' shape and transmembrane potential. The compounds' cytotoxic activity, ability to modulate apoptosis, cell cycle, and intracellular ROS generation, as well as inhibitory activity against AAPH-inducted oxidative stress, were determined in relation to HMEC-1 cells. We demonstrated that biological activity of cyanidin and its O-glycosides strongly depends on the number and type of sugar substituents, and varies depending on the extracellular environment and type of cells. The compounds are practically non-cytotoxic, and do not induce apoptosis or disturb the progression of the cell cycle. Additionally, the compounds alter the shape of RBCs, but they do not affect their transmembrane potential. They effectively protect erythrocytes against free radicals and affect intracellular reactive oxygen spices (ROS) generation under physiological and AAPH-induced oxidative stress conditions. Our results suggest a potential beneficial effect of cyanidin on the cardiovascular system.
    Keywords:  HMEC-1; RBCs; SARs; anthocyanins; apoptosis; intracellular ROS; toxicity
    DOI:  https://doi.org/10.3390/ijms20081928
  53. J Cell Physiol. 2019 Apr 26.
    Role of acute-phase protein ORM in a mice model of ischemic stroke.
    Jing-Jing Wan, Peng-Yuan Wang, Yu Zhang, Zhen Qin, Yang Sun, Bo-Han Hu, Ding-Feng Su, Dong-Ping Xu, Xia Liu.
      The only Food and Drug Administration-approved treatment for acute ischemic stroke is tissue plasminogen activator, and the discovery of novel therapeutic targets is critical. Here, we found orosomucoid (ORM), an acute-phase protein mainly produced by the liver, might act as a treatment candidate for an ischemic stroke. The results showed that ORM2 is the dominant subtype in mice normal brain tissue. After middle cerebral artery occlusion (MCAO), the level of ORM2 is significantly increased in the ischemic penumbra compared with the contralateral normal brain tissue, whereas ORM1 knockout did not affect the infarct size. Exogenous ORM could significantly decrease infarct size and neurological deficit score. Inspiringly, the best administration time point was at 4.5 and 6 hr after MCAO. ORM could markedly decrease the Evans blue extravasation, and improve blood-brain barrier-associated proteins expression in the ischemic penumbra of MACO mice and oxygen-glucose deprivation (OGD)-treated bEnd3 cells. Meanwhile, ORM could significantly alleviate inflammation by inhibiting the production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α), reduce oxidative stress by improving the balance of malondialdehyde (MDA) and superoxide dismutase (SOD), inhibit apoptosis by decreasing caspase-3 activity in ischemic penumbra of MCAO mice and OGD-treated bEnd.3 cells. Because of its protective role at multiple levels, ORM might be a promising therapeutic target for ischemic stroke.
    Keywords:  ORM; apoptosis; blood-brain barrier; inflammation; ischemic stroke; oxidative stress
    DOI:  https://doi.org/10.1002/jcp.28653
  54. J Mol Med (Berl). 2019 Apr 25.
    Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis.
    Yan Ma, Michael Baltezor, Lian Rajewski, Jennifer Crow, Glenson Samuel, Vincent S Staggs, Katherine M Chastain, Jeffrey A Toretsky, Scott J Weir, Andrew K Godwin.
      Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, respectively. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clinical development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES. KEY MESSAGES: • Entinostat potently inhibits ES both in vitro and in vivo. • EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment. • Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling. • HDAC3 is a transcriptional target of EWS-FLI1. • HDAC3 is essential for ES cell viability and genomic stability maintenance.
    Keywords:  EWS-FLI1; Entinostat; Ewing sarcoma; HDAC3; Histone deacetylase inhibitor
    DOI:  https://doi.org/10.1007/s00109-019-01782-0
  55. J Cell Physiol. 2019 Apr 25.
    Melatonin attenuates TNF-α-mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt-Sirt3 signaling pathway.
    Jie Song, Chang Lu, Wei Zhao, Xue Shao.
      The role of mitochondrial dysfunction and its molecular mechanism in inflammation-induced acute liver failure (ALF) remain unknown. Despite the numerous studies performed to date, very few therapies are available for inflammation-induced ALF. Therefore, our study is aimed to explore the regulatory effects of mitochondrial stress and the Akt-Sirt3 pathway on the development of TNF-α-induced hepatocyte death and assess the therapeutic effects of melatonin on the damaged liver. Our results exhibited that TNF-α treatment induced hepatocyte damage in vitro; the effect of which was dose-dependently inhibited by melatonin. At the molecular level, TNF-α-treated hepatocytes expressed lower levels of Sirt3 and subsequently exhibited mitochondrial stress. Interestingly, melatonin treatment improved mitochondrial bioenergetics, reduced mitochondrial oxidative stress, reversed mitochondrial dynamics, and repressed mitochondrial apoptosis by reversing the decrease in Sirt3 expression after TNF-α challenge. In addition, we found that melatonin-regulated Sirt3 expression in a manner dependent on the Akt pathway. Blockade of the Akt pathway abolished the protective exerted by melatonin on mitochondria and hepatocyte under TNF-α treatment. In conclusion, TNF-α promotes hepatocyte apoptosis by inducing mitochondrial stress. However, melatonin significantly increases the activity of the Akt/Sirt3 axis and consequently maintains mitochondrial homeostasis, restoring hepatocyte viability in an inflammatory environment. Thus, the information compiled here might provide important perspectives for the use of melatonin in the clinic for preventive and therapeutic applications in patients with ALF based on its anti-inflammatory and mitochondria-protective effects.
    Keywords:  Akt pathway; Sirt3; acute liver failure; hepatocyte death; melatonin; mitochondria
    DOI:  https://doi.org/10.1002/jcp.28701
  56. Biochem Biophys Res Commun. 2019 Apr 19. pii: S0006-291X(19)30713-2. [Epub ahead of print]
    2-D08 as a SUMOylation inhibitor induced ROS accumulation mediates apoptosis of acute myeloid leukemia cells possibly through the deSUMOylation of NOX2.
    Pan Zhou, Xing Chen, Mengke Li, Jiaqi Tan, Yicheng Zhang, Weiping Yuan, Jianfeng Zhou, Gaoxiang Wang.
      Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic malignancy with poor survival and frequent relapse. Recently, a posttranslational modification of proteins with small ubiquitin-like modifiers (SUMO) has been notably implicated in a wide spectrum of diseases, especially cancers. Ubc9, as the sole E2-conjugating enzyme in SUMOylation cascade, particularly has been associated with adverse clinical outcomes. 2-D08, a small molecular agent, functions by blocking the transfer of SUMO from the Ubc9 thioester to SUMO substrates without any effects on other individual steps in this process. However, both the effects and mechanisms of 2-D08 on AML cells are still unknown. In this study, we found that 2-D08 significantly suppressed cell viability and colony formation ability. Additionally, it induced mitochondrial-mediated apoptosis with dramatic accumulation of the reactive oxygen species (ROS), which could be almost completely rescued by the ROS scavenger N-acetylcysteine (NAC). Furthermore, we confirmed that the fatal accumulation of ROS was due to its aberrant generation instead of defective scavenging. In summary, our results suggest that 2-D08, as a specific SUMOylation inhibitor, induces ROS accumulation-mediated intrinsic apoptosis of AML cells possibly through deSUMOylation of NOX2. Therefore, 2-D08 might be a promising therapeutic agent for the treatment of AML in the future.
    Keywords:  2-D08; Acute myeloid leukemia; Apoptosis; NOX2; ROS; SUMOylation
    DOI:  https://doi.org/10.1016/j.bbrc.2019.04.079
  57. Toxicol In Vitro. 2019 Apr 21. pii: S0887-2333(19)30026-8. [Epub ahead of print]
    Chemical composition and cytotoxic screening of Musa cavendish green peels extract: Antiproliferative activity by activation of different cellular death types.
    Wermerson Assunção Barroso, Iracelle Carvalho Abreu, Larissa Sousa Ribeiro, Cláudia Quintino da Rocha, Heraldo Possolo de Souza, Thais Martins de Lima.
      Musa cavendish, commonly known as banana, is a fruit with nutritional and therapeutic properties. We investigated the chemical composition and in vitro cytotoxic effect of M. cavendish green peel extract (MHE) on cancer cells for the first time. The compounds characterization was performed by HPLC-UV/Vis and FIA-ESI-IT-MSn. We investigated in vitro cytotoxic effect of Musa cavendish green peels extract (MHE) in HepG2, A-375, MCF-7 and Caco-2 cancer cells. We evaluated the effect of MHE on proliferation of different cell lines through apoptosis, necrosis, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) content determination. We identified 12 compounds from different classes in the extract, including derivatives of phenolic acids, aglycone flavonoids, glycoside flavonoids and catecholamines. Our results indicate that MHE exerts, after 48 h treatment, an accentuated antiproliferative effect from the dose of 100 μg/mL in all cell lines tested. In HepG2 cells, these effects were related to the induction of cell death, both necrotic and apoptotic, and remarkable changes in cell morphology. Depolarization of MMP and high ROS content were also observed in the cells in a dose-dependent manner. Our results show that MHE may be used as a source of new drugs with anticancer activity.
    Keywords:  Antiproliferative activity; Cell death; Chemical composition; Green peel; Musa cavendish
    DOI:  https://doi.org/10.1016/j.tiv.2019.04.020
  58. Chem Biol Interact. 2019 Apr 17. pii: S0009-2797(18)31804-0. [Epub ahead of print]
    Long non-coding RNA-p21 regulates MPP+-induced neuronal injury by targeting miR-625 and derepressing TRPM2 in SH-SY5Y cells.
    Xiu-Ming Ding, Lian-Jiang Zhao, Han-Yong Qiao, Shao-Lan Wu, Xi-Hui Wang.
      Parkinson's disease (PD), the second most prevalent age-related neurodegenerative disease, occurs as a result of the loss of dopaminergic neurons in the substantia nigra. Long non-coding RNA-p21 (lnc-p21) has been demonstrated to be upregulated in PD. However, its role in PD is unknown. Here, the results showed that lnc-p21 was highly expressed in human neuroblastoma SH-SY5Y cells treated with MPP+. Knockdown of lnc-p21 attenuated the cytotoxicity and cell apoptosis induced by MPP+ as shown by enhanced cell viability, decreased LDH release and cell apoptosis rate, accompanying with reduction of caspase-3 activity and Bax expression, and enhancement of Bcl-2 expression. Furthermore, knockdown of lnc-p21 mitigated MPP+-induced oxidative stress and neuroinflammation, as evidenced by the decrease in ROS generation, increase in SOD activity and decline in TNF-α, IL-1β and IL-6 levels. Conversely, overexpression of lnc-p21 resulted in the opposite effect. miR-625 was identified as a target of lnc-p21. lnc-p21 overturned the inhibitory effect of miR-625 on MPP+-induced neuronal injury in SH-SY5Y cells. Additionally, lnc-p21 positively regulated TRPM2 expression by targeting miR-625, and knockdown of TRPM2 inhibited MPP+-induced neuronal injury. Overall, our study identified a new lnc-p21-miR-625-TRPM2 regulatory network that lnc-p21 regulated MPP + -induced neuronal injury by sponging miR-625 and upregulating TRPM2 in SH-SY5Y cells, which provide a better understanding for the pathogenesis of PD.
    Keywords:  MPP(+); Parkinson's disease; TRPM2; lncRNA-p21; miR-625
    DOI:  https://doi.org/10.1016/j.cbi.2019.04.017
  59. Viruses. 2019 Apr 25. pii: E389. [Epub ahead of print]11(4):
    Porcine Parvovirus Infection Causes Pig Placenta Tissue Damage Involving Nonstructural Protein 1 (NS1)-Induced Intrinsic ROS/Mitochondria-Mediated Apoptosis.
    Jianlou Zhang, Jinghui Fan, Yan Li, Shuang Liang, Shanshan Huo, Xing Wang, Yuzhu Zuo, Dan Cui, Wenyan Li, Zhenyu Zhong, Fei Zhong.
      Porcine parvovirus (PPV) is an important pathogen causing reproductive failure in pigs. PPV-induced cell apoptosis has been recently identified as being involved in PPV-induced placental tissue damages resulting in reproductive failure. However, the molecular mechanism was not fully elucidated. Here we demonstrate that PPV nonstructural protein 1 (NS1) can induce host cell apoptosis and death, thereby indicating the NS1 may play a crucial role in PPV-induced placental tissue damages and reproductive failure. We have found that NS1-induced apoptosis was significantly inhibited by caspase 9 inhibitor, but not caspase 8 inhibitor, and transfection of NS1 gene into PK-15 cells significantly inhibited mitochondria-associated antiapoptotic molecules Bcl-2 and Mcl-1 expressions and enhanced proapoptotic molecules Bax, P21, and P53 expressions, suggesting that NS1-induced apoptosis is mainly through the mitochondria-mediated intrinsic apoptosis pathway. We also found that both PPV infection and NS1 vector transfection could cause host DNA damage resulting in cell cycle arrest at the G1 and G2 phases, trigger mitochondrial ROS accumulation resulting in mitochondria damage, and therefore, induce the host cell apoptosis. This study provides a molecular basis for elucidating PPV-induced cell apoptosis and reproductive failure.
    Keywords:  NS1 protein; Porcine parvovirus; apoptosis reactive oxygen species; intrinsic pathway; mitochondria damage
    DOI:  https://doi.org/10.3390/v11040389
  60. Cell Cycle. 2019 Apr 23. 1-14
    Fibroblasts rescue oral squamous cancer cell from metformin-induced apoptosis via alleviating metabolic disbalance and inhibiting AMPK pathway.
    Zhuoyuan Zhang, Xiao Liang, Yaping Fan, Zhenjie Gao, Laurence A Bindoff, Daniela Elena Costea, Longjiang Li.
      Metformin is an antidiabetic drug widely used for the treatment of type 2 diabetes. Growing evidence suggests that it may exert antitumor effects in vivo and in vitro. However, even with the promising potency on defeating cancer cells, the pre-clinical and epidemiological studies of metformin on various kinds of cancers are not satisfactory, and the reasons and underlying mechanisms remain unknown. Since cancer is a complex system, dependent on a promoting microenvironment, we hypothesize that the interactions between cancer cells and their neighborhood fibroblasts are essential for metformin resistance. To test this, we used a cell co-culture model closely mimicking the in vivo interactions and metabolic exchanges between normal stromal cells (NOFs) and oral squamous cancer cells (OSCC). Here we show that while metformin can significantly inhibit cell growth and induce apoptosis of OSCC cultured alone in a dose-dependent manner through activating p-AMPKT172 and modulating Bcl-2, Bax, and cleaved PARP. However, when OSCC are co-cultured with NOFs the metformin effects on OSCC cells are annihilated. NOFs are rescuing OSCC from metformin - induced apoptosis, at least partially, through inhibiting the activity of AMPK and PARP, maintaining mitochondrial membrane potential and increasing the oxidative stress. Our results indicate that metformin effects on oral cancer cells are modulated by the microenvironment and that this has to be taken into consideration in the context of developing a new combination of drugs for oral cancer treatment.
    Keywords:  Metabolic reprogramming; Metformin; ROS; apoptosis; autophagy; co-culture
    DOI:  https://doi.org/10.1080/15384101.2019.1598727
  61. J Mol Cell Cardiol. 2019 Apr 17. pii: S0022-2828(18)31283-5. [Epub ahead of print]131 29-40
    Heparanase protects the heart against chemical or ischemia/reperfusion injury.
    Fulong Wang, Thomas Pulinilkunnil, Stephane Flibotte, Corey Nislow, Israel Vlodavsky, Bahira Hussein, Brian Rodrigues.
      Although cancer cells use heparanase for tumor metastasis, favourable effects of heparanase have been reported in the management of Alzheimer's disease and diabetes. Indeed, we previously established a protective function for heparanase in the acutely diabetic heart, where it conferred cardiomyocyte resistance to oxidative stress and apoptosis by provoking changes in gene expression. In this study, we tested if overexpression of heparanase can protect the heart against chemically induced or ischemia/reperfusion (I/R) injury. Transcriptomic analysis of Hep-tg hearts reveal that 240 genes related to the stress response, immune response, cell death, and development were altered in a pro-survival direction encompassing genes promoting the unfolded protein response (UPR) and autophagy, as well as those protecting against oxidative stress. The observed UPR activation was adaptive and not apoptotic, was mediated by activation of ATF6α, and when combined with mTOR inhibition, induced autophagy. Subjecting wild type (WT) mice to increasing concentrations of the ER stress inducer thapsigargin evoked a transition from adaptive to apoptotic UPR, an effect that was attenuated in Hep-tg mouse hearts. Consistent with these observations, when exposed to I/R, the infarct size and markers of apoptosis were significantly lower in the Hep-tg heart compared to WT. Finally, UPR and autophagy inhibitors reduced the protective effects of heparanase overexpression during I/R. Our data suggest that the mechanisms that underlie the role of heparanase in promoting cell survival could be uniquely beneficial to the heart by providing protection against cellular stresses, and could be useful for exploitation as a therapeutic target for the treatment of heart disease.
    Keywords:  Autophagy; Cardioprotection; Energy balance; Heparanase; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.yjmcc.2019.04.008
  62. Medchemcomm. 2019 Mar 01. 10(3): 439-449
    Synthesis and X-ray study of dispiro 8-nitroquinolone analogues and their cytotoxic properties against human cervical cancer HeLa cells.
    Selvaraj Shyamsivappan, Raju Vivek, Arjunan Saravanan, Thangaraj Arasakumar, Gopalan Subashini, Thangaraj Suresh, Ramasamy Shankar, Palathurai Subramaniam Mohan.
      A series of unique dispiro analogues containing an oxindole pyrrolidine 8-nitroquinolone hybrid has been obtained through a one-pot three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the condensation of isatins and benzylamine with (E)-3-arylidene-2,3-dihydro-8-nitro-4-quinolones. The structures of the newly synthesized compounds were characterized by using different spectroscopic techniques and by X-ray diffraction studies of their regio- and stereochemistry. All the synthesized compounds were screened for in vitro cytotoxic activity against the human cervical cancer cell line HeLa. The compounds have exhibited potent inhibition against human cervical cancer cells and insignificant toxicity to normal cells. The compounds 6d, 6a, 6h, 6b, and 6e induced apoptosis of HeLa cells, through ROS influx. The expression levels of proteins involved in the mitochondrion-related pathways were detected, and Western blot analysis showed that apoptosis occurred via activation of caspase-3.
    DOI:  https://doi.org/10.1039/c8md00482j
  63. J Clin Med. 2019 Apr 25. pii: E561. [Epub ahead of print]8(4):
    Environment and Male Fertility: Effects of Benzo-α-Pyrene and Resveratrol on Human Sperm Function In Vitro.
    Angela Alamo, Rosita A Condorelli, Laura M Mongioì, Rossella Cannarella, Filippo Giacone, Vittorio Calabrese, Sandro La Vignera, Aldo E Calogero.
      Lifestyle, cigarette smoking and environmental pollution have a negative impact on male fertility. Therefore, the aim of this study was to evaluate the in-vitro effects of benzo-α-pyrene (BaP) and aryl hydrocarbon receptor (AHR) agonists on motility and bio-functional sperm parameters. We further assessed whether resveratrol (RES), an AHR antagonist and antioxidant molecule, had any protective effect. To accomplish this, 30 normozoospermic, healthy, non-smoker men not exposed to BaP were enrolled. Spermatozoa of 15 men were incubated with increasing concentrations of BaP to evaluate its effect and to establish its dose response. Then, spermatozoa of the 15 other men were incubated with BaP (15 µM/mL), chosen according to the dose-response and/or RES to evaluate its antagonistic effects. The effects of both substances were evaluated after 3 h of incubation on total and progressive sperm motility and on the following bio-functional sperm parameters evaluated by flow cytometry: Degree of chromatin compactness, viability, phosphatidylserine externalization (PS), late apoptosis, mitochondrial membrane potential (MMP), DNA fragmentation, degree of lipoperoxidation (LP), and concentrations of mitochondrial superoxide anion. Benzo-α-pyrene decreased total and progressive sperm motility, impaired chromatin compactness, and increased sperm lipoperoxidation and mitochondrial superoxide anion levels. All these effects were statistically significant at the lowest concentration tested (15 µM/mL) and they were confirmed at the concentration of 45 µM/mL. In turn, RES was able to counteract the detrimental effects of BaP on sperm motility, abnormal chromatin compactness, lipid peroxidation, and mitochondrial superoxide. This study showed that BaP alters sperm motility and bio-functional sperm parameters and that RES exerts a protective effect on BaP-induced sperm damage.
    Keywords:  DNA integrity; benzo-α-pyrene; bio-functional sperm parameters; oxidative stress; resveratrol; sperm motility
    DOI:  https://doi.org/10.3390/jcm8040561
  64. Molecules. 2019 Apr 12. pii: E1454. [Epub ahead of print]24(8):
    Ameliorative Effect and Mechanism of the Purified Anthraquinone-Glycoside Preparation from Rheum Palmatum L. on Type 2 Diabetes Mellitus.
    Fang-Rong Cheng, Hong-Xin Cui, Ji-Li Fang, Ke Yuan, Ying Guo.
      Rheum palmatum L. is a traditional Chinese medicine with various pharmacological properties, including anti-inflammatory, antibacterial, and detoxification effects. In this study, the mechanism of the hypoglycemic effect of purified anthraquinone-Glycoside from Rheum palmatum L. (PAGR) in streptozotocin (STZ) and high-fat diet induced type 2 diabetes mellitus (T2DM) in rats was investigated. The rats were randomly divided into normal (NC), T2DM, metformin (Met), low, middle (Mid), and high (Hig) does of PAGR groups. After six weeks of continuous administration of PAGR, the serum indices and tissue protein expression were determined, and the pathological changes in liver, kidney, and pancreas tissues were observed. The results showed that compared with the type 2 diabetes mellitus group, the fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) levels in the serum of rats in the PAGR treatment groups were significantly decreased, while superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels were noticeably increased. The expression of Fas ligand (FasL), cytochrome C (Cyt-c), and caspase-3 in pancreatic tissue was obviously decreased, and the pathological damage to the liver, kidney, and pancreas was improved. These indicate that PAGR can reduce oxidative stress in rats with diabetes mellitus by improving blood lipid metabolism and enhancing their antioxidant capacity, thereby regulating the mitochondrial apoptotic pathway to inhibitβ-cell apoptosis and improve β-cell function. Furthermore, it can regulate Fas/FasL-mediated apoptosis signaling pathway to inhibit β-cell apoptosis, thereby lowering blood glucose levels and improving T2DM.
    Keywords:  Rheum palmatum L.; apoptosis; oxidative stress; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/molecules24081454
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