bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019‒02‒03
fifty-nine papers selected by
Gavin McStay
Staffordshire University
  1. Toxic effects and possible mechanisms of deoxynivalenol exposure on sperm and testicular damages in BALB/c mice.
  2. Synthesis and antitumor activity of 2-isocamphanyl thiosemicarbazone derivatives via ROS-enhanced mitochondria damage.
  3. Hydrogen peroxide in the reactions of cancer cells to cisplatin.
  4. Resveratrol provides neuroprotective effects through modulation of mitochondrial dynamics and ERK1/2 regulated autophagy.
  5. Synergistic Effects of The Enhancements to Mitochondrial ROS, p53 Activation and Apoptosis Generated by Aspartame and Potassium Sorbate in HepG2 Cells.
  6. Tanshinone IIA protects lens epithelial cells from H2 O 2 -induced injury by upregulation of lncRNA ANRIL.
  7. The Dual Neuroprotective-Neurotoxic Effects of Sevoflurane After Hemorrhagic Shock Injury.
  8. The effect of melatonin on digoxin‑induced cardiac damage in cardiomyocytes.
  9. Biological effects of whole Z.Officinale extract on chronic myeloid leukemia cell line K562.
  10. Fucoxanthin induces apoptosis in human glioma cells by triggering ROS-mediated oxidative damage and regulating MAPKs and PI3K/AKT pathways.
  11. HIF-1α protects against oxidative stress by directly targeting mitochondria.
  12. Astragaloside IV Alleviates Ammonia-Induced Apoptosis and Oxidative Stress in Bovine Mammary Epithelial Cells.
  13. Oxyresveratrol protects human lens epithelial cells against hydrogen peroxide-induced oxidative stress and apoptosis by activation of Akt/HO-1 pathway.
  14. Mechanisms underlying isoliquiritigenin-induced apoptosis and cell cycle arrest via ROS-mediated MAPK/STAT3/NF-κB pathways in human hepatocellular carcinoma cells.
  15. Stilbene glycoside protects osteoblasts against oxidative damage via Nrf2/HO-1 and NF-κB signaling pathways.
  16. Influence of total polar compounds on lipid metabolism, oxidative stress and cytotoxicity in HepG2 cells.
  17. Sulforaphane Attenuates H₂O₂-induced Oxidant Stress in Human Trabecular Meshwork Cells (HTMCs) via the Phosphatidylinositol 3-Kinase (PI3K)/Serine/Threonine Kinase (Akt)-Mediated Factor-E2-Related Factor 2 (Nrf2) Signaling Activation.
  18. Renin-angiotensin system inhibitor attenuates oxidative stress induced human coronary artery endothelial cell dysfunction via the PI3K/AKT/mTOR pathway.
  19. The photocytotoxicity effect of cationic sulfonated corrole towards lung cancer cells: in vitro and in vivo study.
  20. Prevention of ochratoxin A-induced oxidative stress-mediated apoptotic processes and impairment of embryonic development in mouse blastocysts by liquiritigenin.
  21. Dexmedetomidine Promotes SH-SY5Y Cell Resistance Against Impairment of Iron Overload by Inhibiting NF-κB Pathways.
  22. RASGRP2 Suppresses Apoptosis via Inhibition of ROS Production in Vascular Endothelial Cells.
  23. Identification of 3-(benzazol-2-yl)quinoxaline derivatives as potent anticancer compounds: Privileged structure-based design, synthesis, and bioactive evaluation in vitro and in vivo.
  24. The anticancer activity of visnagin, isolated from Ammi visnaga L., against the human malignant melanoma cell lines, HT 144.
  25. Kai Xin San ameliorates scopolamine-induced cognitive dysfunction.
  26. Effect of magnesium on reducing the UV-induced oxidative damage in marrow mesenchymal stem cells.
  27. Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer's disease.
  28. Lycium barbarum polysaccharide enhances development of previously-cryopreserved murine two-cell embryos via restoration of mitochondrial function and down-regulated generation of reactive oxygen species.
  29. Icariin Attenuates High Glucose-Induced Apoptosis, Oxidative Stress, and Inflammation in Human Umbilical Venous Endothelial Cells.
  30. RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer.
  31. The protective effects of vernicilignan A, a new flavonolignan isolated from Toxicodendron vernicifluum on SH-SY5Y cells against oxidative stress-induced injury.
  32. Mitochondrial translocation of estrogen receptor β affords resistance to oxidative insult-induced apoptosis and contributes to the pathogenesis of endometriosis.
  33. Selenium-Containing Protein From Selenium-Enriched Spirulina platensis Attenuates Cisplatin-Induced Apoptosis in MC3T3-E1 Mouse Preosteoblast by Inhibiting Mitochondrial Dysfunction and ROS-Mediated Oxidative Damage.
  34. CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma.
  35. The Effect of Overexpression of the Enhancer of Zeste Homolog 1 (EZH1) Gene on Aristolochic Acid-Induced Injury in HK-2 Human Kidney Proximal Tubule Cells In Vitro.
  36. Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease.
  37. Neuroprotection by urate on the Mutant hSOD1-related Cellular and Drosophila Models of Amyotrophic Lateral Sclerosis: Implication for GSH synthesis via Activating Akt/GSK3β/Nrf2/GCLC Pathways.
  38. Aspirin eugenol ester attenuates oxidative injury of vascular endothelial cells by regulating NOS and Nrf2 signaling pathways.
  39. MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells.
  40. Cytotoxicity of the crude extract and constituents of the bark of Fagara tessmannii towards multi-factorial drug resistant cancer cells.
  41. Ferroptosis Contributes to Isoflurane Neurotoxicity.
  42. The Effect of Fucoidan on Cellular Oxidative Stress and the CatD-Bax Signaling Axis in MN9D Cells Damaged by 1-Methyl-4-Phenypyridinium.
  43. Silence of lncRNA CHRF protects H9c2 cells against lipopolysaccharide-induced injury via up-regulating microRNA-221.
  44. Astragaloside IV Protects Primary Cerebral Cortical Neurons from Oxygen and Glucose Deprivation/Reoxygenation by Activating the PKA/CREB Pathway.
  45. Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5.
  46. Dietary pomegranate supplement alleviates murine pancreatitis by modulating Nrf2-p21 interaction and controlling apoptosis to survival switch.
  47. M1 macrophage mediated increased reactive oxygen species (ROS) influence wound healing via the MAPK signaling in vitro and in vivo.
  48. Aspirin Inhibits Natural Killer/T-Cell Lymphoma by Modulation of VEGF Expression and Mitochondrial Function.
  49. Characterization and Regulation of Carrier Proteins of Mitochondrial Glutathione Uptake in Human Retinal Pigment Epithelium Cells.
  50. Sinensetin induces apoptosis and autophagy in the treatment of human T-cell lymphoma.
  51. Programmed Cell Death and Aerenchyma Formation in Water-Logged Sunflower Stems and Its Promotion by Ethylene and ROS.
  52. Modulation Of Caspase-3 Gene Expression And Protective Effects Of Garlic And Spirulina Against CNS Neurotoxicity Induced By Lead Exposure In Male Rats.
  53. FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway.
  54. MicroRNA-128 confers protection against cardiac microvascular endothelial cell injury in coronary heart disease via negative regulation of IRS1.
  55. Restraining Cancer Cells by Dual-Metabolic Inhibitions with a Mitochondrion-Targeted Platinum(II) Complex.
  56. Dietary protocatechuic acid abrogates male reproductive dysfunction in streptozotocin-induced diabetic rats via suppression of oxidative damage, inflammation and caspase-3 activity.
  57. Protective effects of Camellia japonica flower extract against urban air pollutants.
  58. Royal Jelly Alleviates Cognitive Deficits and β-Amyloid Accumulation in APP/PS1 Mouse Model Via Activation of the cAMP/PKA/CREB/BDNF Pathway and Inhibition of Neuronal Apoptosis.
  59. TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model.
  1. J Agric Food Chem. 2019 Feb 01.
    Toxic effects and possible mechanisms of deoxynivalenol exposure on sperm and testicular damages in BALB/c mice.
    Junhua Yang, Jianhua Wang, Wenbo Guo, A-Ru Ling, Ai-Qiong Luo, Dan Liu, Xianli Yang, Zhihui Zhao.
      Deoxynivalenol (DON, vomitoxin) is the most common mycotoxin in cereals and grains. DON contamination can cause a serious health threat to humans and farm animals. DON has been reported to exert significant toxicity effects on male reproductive system. However, the causes and mechanisms underlying efforts of DON on sperm and testicular damage remain largely unclear. In the present study, we deeply investigated into this issue. Eighty male BALB/c mice were randomly divided into control group (n=40) and DON treatment group (2.4 mg/kg bw, n=40). The ratio of testes and seminal vesicle to body, sperm survival and motility, and morphology of sperm and testis were observed in DON-treated and control mice. In addition, the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and glutathione (GSH), as well as the expression levels of JNK/c-Jun signaling and apoptotic factors such as caspase-3, caspase-8, caspase-9, Bim and Bid were analyzed and compared between the two groups. The results demonstrated that a single topical application of DON significantly increased the percentage of abnormal sperm and decreased the motility of sperm, indicating the sperms are damaged by DON. Additionally, the reduced relative body weight of testis and severe destruction of testicular morphology were observed. Moreover, the increased levels of ROS and MDA levels and decreased activities of SOD and GSH were found in testicular tissues, suggesting that oxidative stress is induced by DON treatment. Furthermore, DON upregulated the expression of stress-induced JNK/c-Jun signaling pathway proteins as well as JNK/c-Jun phosphorylation proteins. Besides, DON could enhanced testicular apoptosis by increasing expression levels of apoptotic genes including Bim, cytochrome c, caspase 3, caspase 8 and caspase 9. These results suggest that DON exposure can cause sperm damage, oxidative stress, testicular apoptosis and phosphorylation of JNK/c-Jun signaling pathway. The underlying mechanisms may be that DON induces sperm damage by exacerbating oxidative stress-mediated testicular apoptosis via JNK/c-Jun signaling pathway.
    DOI:  https://doi.org/10.1021/acs.jafc.8b04783
  2. Chem Biol Drug Des. 2019 Jan 28.
    Synthesis and antitumor activity of 2-isocamphanyl thiosemicarbazone derivatives via ROS-enhanced mitochondria damage.
    Yunyun Wang, Zhonglong Wang, Hongbo Kuang, Yan Zhang, Wen Gu, Yongqiang Zhu, Shifa Wang.
      A series of novel 2-isocamphanyl thiosemicarbazone derivatives were synthesized and characterized by 1 H NMR, 13 C NMR and HRMS. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against four cancer cell lines (RPMI-8226, A549, MDA-MB-231 and HepG2 cancer cells) and showed low toxicity against human gastric mucosal cells (GES-1). Among them, compound 4h exhibited excellent antitumor activity against the tested cancer cells with IC50 values of 0.4, 1.1, 1.6, and 1.7 μM for MDA-MB-231, RPMI-8226, A549 and HepG2, respectively. Further mechanism studies indicated that compound 4h induced apoptosis in MDA-MB-231 cells through enhancing the reactive oxygen species level, inducing mitochondrial membrane potential decrease and influencing the expression of Bax, Bcl-2, caspase-3 and caspase-9. This article is protected by copyright. All rights reserved.
    Keywords:  2-isocamphanyl thiosemicarbazone derivatives; antitumor activity; cell apoptosis; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1111/cbdd.13492
  3. Biochim Biophys Acta Gen Subj. 2019 Jan 25. pii: S0304-4165(19)30019-4. [Epub ahead of print]1863(4): 692-702
    Hydrogen peroxide in the reactions of cancer cells to cisplatin.
    A S Nerush, K M Shсhukina, I V Balalaeva, A G Orlova.
      BACKGROUND: Hydrogen peroxide (H2O2) is thought to be one of the key components involved in the responses of tumor cells to chemotherapy. The aim of this study was to reveal the pathways and the phases of cisplatin-induced cell death that are characterized by changes of H2O2 level.METHODS: The genetically encoded cytosolic fluorescent sensor HyPer2 was used for flow cytometric analysis of the cisplatin-induced changes in H2O2 level in HeLa Kyoto cells. Using a vital dye and the apoptotic markers PE Annexin V or TMRE the pathways and stages of cell death were investigated simultaneously with HyPer2 response. The H2O2 level was studied separately in viable and early apoptotic cells after 12, 18, 24 h's incubation with cisplatin at several concentrations with or without the scavenger of reactive oxygen species NAC.
    RESULTS: Cisplatin causes dose- and time-dependent increase of H2O2 level in TMRE-positive and PE Annexin V-negative cancer cells. The scavenging of ROS by NAC decreased the H2O2 level and restored cell viability.
    CONCLUSION: Н2О2 generation begins in cells that have already lost mitochondrial membrane potential but have not yet externalized phosphatidylserine. Prevention of apoptosis by NAC confirmed the role of H2O2 in apoptosis induction.
    GENERAL SIGNIFICANCE: This is the first time that the sensor HyPer2 has been used in parallel with apoptotic markers and vital dye to demonstrate the role of H2O2 in different stages and types of tumor cell death under chemotherapeutic action.
    Keywords:  Apoptosis; Cancer cell; Cisplatin; Flow cytometry; Genetically encoded sensor HyPer2; Hydrogen peroxide
    DOI:  https://doi.org/10.1016/j.bbagen.2019.01.013
  4. Free Radic Res. 2018 Dec;52(11-12): 1371-1386
    Resveratrol provides neuroprotective effects through modulation of mitochondrial dynamics and ERK1/2 regulated autophagy.
    Kai-Lieh Lin, Kai-Jung Lin, Pei-Wen Wang, Jiin-Haur Chuang, Hung-Yu Lin, Shang-Der Chen, Yao-Chung Chuang, Sheng-Teng Huang, Mao-Meng Tiao, Jin-Bor Chen, Pei-Hsuan Huang, Chia-Wei Liou, Tsu-Kung Lin.
      Mitochondrial dysfunction and oxidative stress are underlying contributors to Parkinson's disease (PD). The reduction of aberrant proteins and dysfunctional mitochondria through constitutive autophagy is essential for neuronal survival. We investigated the neuroprotective effects of the natural red wine extract, resveratrol, on the Complex I inhibitor, rotenone-induced oxidative stress SH-SY5Y cellular model. With rotenone exposure, cellular reactive oxygen species (ROS), apoptosis and cell death increased at both 6 and 18 h; at the same time, mitochondrial membrane potential (ΔΨm) and the balance of mitochondrial dynamic proteins were disrupted, resulting with fragmented mitochondria. Rotenone was also noted to elevate autophagy initiation but downregulate the autophagy flux. Pretreatment with resveratrol to rotenone exposed cells lowered cellular ROS, apoptosis, and increased survival rates. Resveratrol administration also recovered rotenone induced ΔΨm, mitochondria dynamics alteration, and elongated fragmented mitochondria. Both autophagic induction and autophagic flux were enhanced with resveratrol pre-treatment which is compatible with cellular survival. The mitogen-activated protein kinase (MEK) inhibitor, U0126, abolished the rescuing effect of resveratrol on rotenone treated neurons through the inhibition of autophagy flux. Thus, our work implies that the neuroprotective effect of resveratrol works in part through modulation of mitochondria dynamics and upregulating autophagic flux via the MEK/extracellular signal-regulated kinase (ERK) signalling pathway.
    Keywords:  Autophagy; ERK1/2; Parkinson’s disease; mitochondrial dynamics; oxidative stress; resveratrol
    DOI:  https://doi.org/10.1080/10715762.2018.1489128
  5. Molecules. 2019 Jan 28. pii: E457. [Epub ahead of print]24(3):
    Synergistic Effects of The Enhancements to Mitochondrial ROS, p53 Activation and Apoptosis Generated by Aspartame and Potassium Sorbate in HepG2 Cells.
    Daofeng Qu, Mengxue Jiang, Dongping Huang, Hui Zhang, Lifang Feng, Yuewen Chen, Xuan Zhu, Suhua Wang, Jianzhong Han.
      The safety of food additives has been widely concerned. Using single additives in the provisions of scope is safe, but the combination of additives, may induce additive, synergy, antagonism and other joint effects. This study investigated the cytotoxicity of aspartame (AT) together with potassium sorbate (PS). Thiazolyl Blue Tetrazolium Bromide (MTT) assay indicated that AT and PS had IC50 values of 0.48 g/L and 1.25 g/L at 24 h, respectively. High content analysis (HCA) showed that both AT and PS had a negative effect on mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and DNA damage while the joint group behaved more obviously. The biochemical assays revealed typical cell morphological changes and the activation of cytochrome c and caspase-3 verified apoptosis induced by AT together with PS. With dissipation of MMP and increase of cell membrane permeability (CMP), it indicated AT together with PS-induced apoptosis was mediated by mitochondrial pathway. Meanwhile, p53 were involved in DNA damage, and the ratio of Bax/Bcl-2 was increased. Moreover, excessive ROS induced by AT together with PS is a key initiating factor for apoptosis. All these results proved that p53 was involved in apoptosis via mitochondria-mediated pathway and the process was regulated by ROS.
    Keywords:  HCA; ROS; food additives; joint toxicity; mitochondria pathway; p53
    DOI:  https://doi.org/10.3390/molecules24030457
  6. J Cell Physiol. 2019 Jan 30.
    Tanshinone IIA protects lens epithelial cells from H2 O 2 -induced injury by upregulation of lncRNA ANRIL.
    Defeng Qi, Mingming Wang, Duzhen Zhang, Haihui Li.
      Tanshinone IIA is a lipophilic diterpene extracted from the Salvia miltiorrhiza bunge, possessing antiapoptotic and antioxidant activities. The purpose of this study was to explore the effects of Tanshinone IIA on age-related nuclear cataract. Human lens epithelial cell line SRA01/04 was subjected to H 2 O 2 to mimic a cell model of cataract. Cell Counting Kit-8 assay, flow cytometer, and reactive oxygen species (ROS) detection were performed to evaluate the effect of Tanshinone IIA pretreatment on SRA01/04 cells injured by H 2 O 2 . Besides, the real-time quantitative polymerase chain reaction was used to assess the expression of long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL). Western blot analysis was performed to detect the expression of core proteins involved in cell survival and nuclear factor-κB (NF-κB) pathway. H 2 O 2 significantly decreased SRA01/04 cells viability, whereas increased apoptosis and ROS generation. This phenomenon was coupled with the upregulated p53, p21, Bax, cleaved caspase-3, and the downregulated cyclinD1, CDK4, and Bcl-2. Tanshinone IIA pretreatment protected SRA01/04 cells against H 2 O 2 -induced injury. In the meantime, the expression of lncRNA ANRIL was upregulated by Tanshinone IIA. And, the protective effects of Tanshinone IIA on H 2 O 2 -stimulated SRA01/04 cells were abolished when lncRNA ANRIL was silenced. Moreover, the elevated expression of lncRNA ANRIL induced by Tanshinone IIA was abolished by BAY 11-7082 (an inhibitor of NF-κB). To conclude, Tanshinone IIA protects SRA01/04 cells from apoptosis triggered by H 2 O 2 . Tanshinone IIA confers its protective effects possibly via modulation of NF-κB signaling and thereby elevating the expression of lncRNA ANRIL.
    Keywords:  NF-κB signaling; cataract; hydrogen peroxide; lncRNA ANRIL; tanshinone IIA
    DOI:  https://doi.org/10.1002/jcp.28189
  7. J Surg Res. 2019 Mar;pii: S0022-4804(18)30777-7. [Epub ahead of print]235 591-599
    The Dual Neuroprotective-Neurotoxic Effects of Sevoflurane After Hemorrhagic Shock Injury.
    Li-Min Zhang, Dong-Xue Zhang.
      BACKGROUND: The neuroprotection and neurotoxicity induced by sevoflurane have been gradually established. Choosing anesthetic agents after hemorrhage shock and resuscitation (HSR) induced by bleeding can be challenging. We determined the dual neuroprotective-neurotoxic effects of sevoflurane postconditioning after HSR injury using a model of blood loss and reinfusion in rats via the heme oxygenase-1 (HO-1)/reactive oxygen species (ROS) signal pathway.METHODS: The rats were exposed to 2%-4% sevoflurane postconditioning in vivo after HSR. Learning ability was assessed 30 d after HSR by Morris water maze tests. Hippocampal apoptosis was assessed 7 d after HSR by TdT-mediated dUTP nick-end labeling combined with cleaved caspase-3 (17 kDa). The ROS, mitochondrial membrane potential (MMP), HO-1 expression, and HO activity 1 d after HSR were assessed by fluorometric, JC-1, Western blot, and bilirubin assays, respectively.
    RESULTS: Compared with HSR alone, 2% sevoflurane postconditioning improved latency and increased MMP levels, HO-1 expression, and HO activity but decreased TdT-mediated dUTP nick-end labeling-positive cells, cleaved caspase-3 (17 kDa) expression, and ROS production. Pretreatment with hemin, an HO-1 agonist, reversed these effects. Compared with 2% sevoflurane postconditioning plus HSR, slower latency; decreased MMP levels; and increased TdT-mediated dUTP nick-end labeling-positive cells, cleaved caspase-3 (17 kDa), HO-1 expression, HO activity, and ROS production were shown in HSR plus 4% sevoflurane postconditioning, whereas Tin-mesoporphyrin, an HO-1 inhibitor, partially reversed the neurodegeneration of 4% sevoflurane postconditioning.
    CONCLUSION: The dual neuroprotective-neurotoxic effects of 2%-4% sevoflurane postconditioning after HSR injury might be associated with increased ROS via the "threshold effect" of HO-1.
    Keywords:  Heme oxygenase; Neuroprotection; Neurotoxicity; Reactive oxygen species; Sevoflurane
    DOI:  https://doi.org/10.1016/j.jss.2018.10.046
  8. Bratisl Lek Listy. 2019 ;120(1): 78-85
    The effect of melatonin on digoxin‑induced cardiac damage in cardiomyocytes.
    I S Ovey, C R Oncel.
      OBJECTIVES: Digoxin is a cardiac glycoside which is widely used in cardiovascular medicine. Oxidative stress, as well as intracellular Ca2+ overload, plays an important role in digoxin toxicity. Transient receptor potential vanilloid 1 (TRPV1) channels are found in cardiomyocyte cells and they are activated by reactive oxygen species. We investigated the effects of digoxin toxicity and alterations in Ca2+ influx, oxidative stress and apoptosis through TRPV1 channels and modulator role of melatonin in cardiomyocytes.METHODS: The cells were divided into seven main groups as control, digoxin, digoxin+capsazepine, digoxin+melatonin, digoxin+capsazepine+melatonin, melatonin and melatonin+capsazepine groups. Cells in the groups were stimulated with capsaicin and inhibited with capsazepine in related experiments for activation and inactivation of TRPV1 channels, respectively. We measured cytosolic calcium, intracellular reactive oxygen, mitochondrial depolarization, caspase 9 and caspase 3 levels.
    RESULTS: The apoptosis values were significantly lower in the melatonin and digoxin+melatonin groups than in the digoxin group of cardiomyocytes (p < 0.001). The cell viability values were higher in the digoxin+capsazepine (p < 0.001), digoxin+melatonin (p < 0.001) and digoxin+melatonin+capsazepine (p < 0.001) groups than in the digoxin group.
    CONCLUSION: TRPV1 channels are overactivated during digoxin toxicity and melatonin could show a cardioprotective effect through TRPV1 channel modulation (Fig. 5, Ref. 56).
    Keywords:  digoxin; oxidative stress cardiomyocyte.
    DOI:  https://doi.org/10.4149/BLL_2019_012
  9. Gene. 2019 Jan 24. pii: S0378-1119(19)30059-9. [Epub ahead of print]692 217-222
    Biological effects of whole Z.Officinale extract on chronic myeloid leukemia cell line K562.
    Pinar Mega Tiber, Sevgi Kocyigit Sevinc, Olca Kilinc, Oya Orun.
      The anticancer activity of Zingiber officinalis (ginger) is an area of active research. However, data is quite limited regarding its action and mechanism, especially in hematologic cancer types. Here, antiproliferative and apoptotic effects of whole extract of the rhizome of Zingiber officinalis (ZOWE), was investigated in K562 cell line derived from a chronic myeloid leukemia (CML) patient. Various concentrations of whole extract (0, 10, 25, 50 and 100 μM) were tested in K562 cultures. Cytotoxicity and apoptosis was assessed with appropriate methods, as well as cellular ROS levels. In this study, we showed that ZOWE inhibited proliferation of K562 cells substantially, when compared to peripheral blood mononuclear cells (PBMCs) isolated from healthy donor. Increased Bax/Bcl-2 ratio, reduced mitochondrial membrane potential and increased PARP cleavage demonstrated that ZOWE inhibited proliferation by induction of apoptosis. These changes were coupled with an increase of reactive oxygen species (ROS) production. Furthermore, ZOWE addition to the culture also reduced expression levels of survival proteins pAkt and survivin, in a concentration dependent manner. Our results clearly mark that ZOWE causes to a reduction in cell viability, an induction of apoptosis and elevation in ROS levels in chronic myeloid leukemia cells and effects are significantly different from healthy peripheral blood mononuclear cells, further supporting its potential therapeutic value.
    Keywords:  Apoptosis; K562; Peripheral blood mononuclear cells; Proliferation; ROS; Z.officinale
    DOI:  https://doi.org/10.1016/j.gene.2019.01.015
  10. J Agric Food Chem. 2019 Jan 28.
    Fucoxanthin induces apoptosis in human glioma cells by triggering ROS-mediated oxidative damage and regulating MAPKs and PI3K/AKT pathways.
    Hua-Lian Wu, Xiao-Yan Fu, Wen-Qiang Cao, Wen-Zhou Xiang, Ya-Jun Hou, Jin-Kui Ma, Ying Wang, Cundong Fan.
      Fucoxanthin a natural carotenoid derived from algae exhibits novel anticancer potential. However, fucoxanthin with high purity was hard to prepare and the anticancer mechanism remains elusive. In the present study, fucoxanthin with high purity was prepared and purified from marine micralgae Nitzschia sp. by silica gel column chromatography (SGCC), and the underlying mechanism against human giloma cells was evaluated. The results showed that fucoxanthin time- and dose-dependently inhibited U251 human glioma cells growth by induction of apoptosis (64.4±4.8, P<0.01), accompanied by PARP cleavage and caspases activation (244±14.2, P<0.01). Mechanically, fucoxanthin time-dependently triggered reactive oxygen species (ROS)-mediated DNA damage (100±7.38, P<0.01), as convinced by the phosphorylation activation of Ser1981-ATM, Ser428-ATR, Ser15-p53 and Ser139-histone. Moreover, fucoxanthin treatment also time-dependently caused dysfunction of MAPKs and PI3K/AKT pathways, as demonstrated by the phosphorylation activation of Thr183-JNK, Thr180-p38 and Thr202-ERK, and the phosphorylation inactivation of Ser473-AKT. Addition of kinase inhibitors further confirmed the importance of MAPKs and PI3K/AKT pathways in fucoxanthin-induced cells growth inhibition (32.5±3.6, P<0.01). However, ROS inhibition by antioxidant glutathione (GSH) effectively inhibited fucoxanthin-induced DNA damage, attenuated the dysfunction of MAPKs and PI3K/AKT pathways, and eventually blocked fucoxanthin-induced cytotoxicity (54.3±5.6, P<0.05) and cell apoptosis (32.7±2.5, P<0.05), indicating ROS as early apoptotic event involved in fucoxanthin-mediated anticancer mechanism. Taken together, these results suggested that fucoxanthin induced U251 human glioma cells apoptosis by triggering ROS-mediated oxidative damage and dysfunction of MAPKs and PI3K/AKT pathways, which validated that fucoxanthin may be candidates with potential application in cancer chemotherapy and chemoprevention.
    DOI:  https://doi.org/10.1021/acs.jafc.8b07126
  11. Redox Biol. 2019 Jan 14. pii: S2213-2317(18)30812-7. [Epub ahead of print] 101109
    HIF-1α protects against oxidative stress by directly targeting mitochondria.
    Hong-Sheng Li, Yan-Ni Zhou, Lu Li, Sheng-Fu Li, Dan Long, Xue-Lu Chen, Jia-Bi Zhang, Li Feng, You-Ping Li.
      The transcription factor hypoxia inducible factor-1α (HIF-1α) mediates adaptive responses to oxidative stress by nuclear translocation and regulation of gene expression. Mitochondrial changes are critical for the adaptive response to oxidative stress. However, the transcriptional and non-transcriptional mechanisms by which HIF-1α regulates mitochondria in response to oxidative stress are poorly understood. Here, we examined the subcellular localization of HIF-1α in human cells and identified a small fraction of HIF-1α that translocated to the mitochondria after exposure to hypoxia or H2O2 treatment. Moreover, the livers of mice with CCl4-induced fibrosis showed a progressive increase in HIF-1α association with the mitochondria, indicating the clinical relevance of this finding. To probe the function of this HIF-1α population, we ectopically expressed a mitochondrial-targeted form of HIF-1α (mito-HIF-1α). Expression of mito-HIF-1α was sufficient to attenuate apoptosis induced by exposure to hypoxia or H2O2-induced oxidative stress. Moreover, mito-HIF-1α expression reduced the production of reactive oxygen species, the collapse of mitochondrial membrane potential, and the expression of mitochondrial DNA-encoded mRNA in response to hypoxia or H2O2 treatment independently of nuclear pathways. These data suggested that mitochondrial HIF-1α protects against oxidative stress induced-apoptosis independently of its well-known role as a transcription factor.
    Keywords:  Apoptosis; HIF-1α; Mitochondria; Oxidative stress; ROS
    DOI:  https://doi.org/10.1016/j.redox.2019.101109
  12. Int J Mol Sci. 2019 Jan 30. pii: E600. [Epub ahead of print]20(3):
    Astragaloside IV Alleviates Ammonia-Induced Apoptosis and Oxidative Stress in Bovine Mammary Epithelial Cells.
    Fengge Wang, Yun Zhao, Shuxiong Chen, Lu Chen, Liting Sun, Maosheng Cao, Chunjin Li, Xu Zhou.
      Ammonia is one of the major toxic components of metabolites in blood and tissues of high-producing dairy cows and could affect the health of bovine mammary glands. Bovine mammary epithelial cells are sensitive to oxidative stress induced by intensive cell metabolism. In our previous study, we found that ammonia could induce oxidative stress, apoptosis and inflammatory responses in bovine mammary epithelial cells. In the present study, the cytoprotective effects of astragaloside IV against ammonia in vitro were explored. The results demonstrated that pretreatment of MAC-T cells with astragaloside IV could potently suppress the increase in the level of intracellular reactive oxygen species (ROS) and the rate of cell apoptosis, inhibit the ammonia-induced inflammatory responses, and rescue the decrease of cell viability. Astragaloside IV prevented ammonia-induced endoplasmic reticulum stress. Astragaloside IV also significantly suppressed the levels of BAX, caspase 3 and p53 phosphorylation in ammonia-induced MAC-T cells. Nuclear factor erythroid 2-related factor 2(Nrf2) was essential for cytoprotective effects of astragaloside IV in MAC-T cells, as knockdown of Nrf2 dramatically abolished the prosurvival effects of astragaloside IV on treated cells. Furthermore, the PI3K/AKT and ERK/MAPK pathways were responsible for the induction of Nrf2 by astragaloside IV. In conclusion, astragaloside IV played a beneficial role against ammonia-induced damage of MAC-T cells. This provides a cue for future study to use astragaloside IV as a protective and curative agent against ammonia exposure of mammary glands in dairy cows.
    Keywords:  ammonia; apoptosis; astragaloside IV; oxidative stress
    DOI:  https://doi.org/10.3390/ijms20030600
  13. J Pharmacol Sci. 2019 Jan 22. pii: S1347-8613(19)30006-4. [Epub ahead of print]
    Oxyresveratrol protects human lens epithelial cells against hydrogen peroxide-induced oxidative stress and apoptosis by activation of Akt/HO-1 pathway.
    Xin Hu, Yuanyuan Liang, Bo Zhao, Yongyi Wang.
      Oxidative stress induced by hydrogen peroxide (H2O2) triggers human lens epithelial cell (HLEC) apoptosis and initiates cataract formation. Oxyresveratrol (Oxy) was reported to possess antioxidant and free radical scavenging activities. Herein, we investigated the effects of Oxy on H2O2-induced oxidative stress and apoptosis in HLECs and the associated mechanisms. Cell viability was detected by MTT assay. The oxidative damage was assessed by measuring the activities of superoxide dismutases-1 (SOD-1), catalase (CAT), glutathione reductase (GSH), and malondialdehyde (MDA). Apoptosis was analyzed by flow cytometry analysis. The changed expressions of heme oxygenase-1 (HO-1) and protein kinase B (Akt) pathways were evaluated by qRT-PCR and western blot. We found that exposure to H2O2 dose-dependently reduced cell viability, and induced oxidative stress and apoptosis in HLECs, which were reversed by pretreatment with Oxy. Oxy increased p-Akt and HO-1 expressions in H2O2-stimulated HLECs. Akt and HO-1 expressions form a regulatory axis and Oxy activated the Akt/HO-1 pathway in H2O2-stimulated HLECs. Inhibition of the Akt/HO-1 pathway by LY294002 or ZnPP attenuated the effects of Oxy on oxidative stress and apoptosis in H2O2-stimulated HLECs. In conclusion, Oxy protected H2O2-induced oxidative stress and apoptosis through activating the Akt/HO-1 pathway, suggesting the protective effect of Oxy against H2O2-induced cataract.
    Keywords:  Cataract; Hydrogen peroxide; Oxidative stress; Oxyresveratrol; The Akt/HO-1 pathway
    DOI:  https://doi.org/10.1016/j.jphs.2019.01.003
  14. Drug Dev Res. 2019 Jan 30.
    Mechanisms underlying isoliquiritigenin-induced apoptosis and cell cycle arrest via ROS-mediated MAPK/STAT3/NF-κB pathways in human hepatocellular carcinoma cells.
    Jia-Ru Wang, Ying-Hua Luo, Xian-Ji Piao, Yi Zhang, Yu-Chao Feng, Jin-Qian Li, Wan-Ting Xu, Yu Zhang, Tong Zhang, Shi-Nong Wang, Hui Xue, Wen-Zhong Wang, Long-Kui Cao, Cheng-Hao Jin.
      Hit, Lead & Candidate Discovery Isoliquiritigenin (ISL), a natural flavonoid isolated from plant licorice, has various pharmacological properties, including anticancer, anti-inflammatory, and antiviral effects. However, the underlying mechanisms and signaling pathways of ISL in human hepatocellular carcinoma (HCC) cells remain unknown. In this study, we evaluated the effects of ISL on the apoptosis of human HCC cells with a focus on reactive oxygen species (ROS) production. Our results showed that ISL exhibited cytotoxic effects on two human liver cancer cells in a dose-dependent manner. ISL significantly induced mitochondrial-related apoptosis and cell cycle arrest at the G2/M phase, which was accompanied by ROS accumulation in HepG2 cells. However, pretreatment with an ROS scavenger, N-acetyl-l-cysteine (NAC), inhibited ISL-induced apoptosis. In addition, ISL increased the phosphorylation levels of c-Jun N-terminal kinase (JNK), p38 kinase and inhibitor of NF-κB (IκB), and decreased the phosphorylation levels of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappa B (NF-κB), these effects were blocked by NAC and mitogen-activated protein kinase (MAPK) inhibitors. Taken together, the findings of this study indicate that ISL induced HepG2 cell apoptosis via ROS-mediated MAPK, STAT3, and NF-κB signaling pathways. Therefore, ISL may be a potential treatment for human HCC, as well as other cancer types.
    Keywords:  apoptosis; cell cycle arrest; human hepatocellular carcinoma cells; isoliquiritigenin; reactive oxygen species
    DOI:  https://doi.org/10.1002/ddr.21518
  15. Arch Med Sci. 2019 Jan;15(1): 196-203
    Stilbene glycoside protects osteoblasts against oxidative damage via Nrf2/HO-1 and NF-κB signaling pathways.
    Jian Cheng, Haohao Wang, Zhida Zhang, Keyong Liang.
      Introduction: Oxidative stress is currently proposed as a risk factor associated with the development and progression of osteoporosis. Here, the effect of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glycoside (THSG) on oxidative damage was investigated in an osteoblast-like MC3T3-E1 cell model.Material and methods: In this study, MC3T3-E1 cells were treated with hydrogen peroxide (H2O2) (100 µM) and THSG (20, 50 and 100 μM), and alkaline phosphatase (ALP). ROS and MDA levels were measured using specific kits. Meanwhile, cell viability and apoptosis were also assessed using MTT methods and flow cytometry, respectively. Then, expression levels of Nrf2 and its downstream targets were determined using real-time PCR and western blotting, as well as the apoptosis related factors, including Bax, Bcl-2, caspase-3, and caspase-9.
    Results: Upon H2O2 treatment, cell viability was significantly decreased, while THSG clearly attenuated this decrease in a dose-dependent manner. Compared with the negative control, H2O2 significantly decreased ALP and increased the levels of MDA, ROS and apoptosis, while THSG markedly reversed these effects in a dose-dependent manner. Moreover, THSG was identified to reverse the elevation of caspase-3, caspase-9 and Bax and the reduction of Bcl-2 induced by H2O2. For the Nrf2 signaling pathway, THSG was also observed to attenuate the up-regulation of Nrf2, HO-1, and NQO1, and the down-regulation of NF-κB induced by H2O2.
    Conclusions: THSG could significantly attenuate oxidative damage induced by H2O2 via the Nrf2/NF-κB signaling pathway, providing new insights for treatments of osteoporosis induced by oxidative injury.
    Keywords:  NF-κB; Nrf2/HO-1; THSG; osteoblast; oxidative damage
    DOI:  https://doi.org/10.5114/aoms.2018.79937
  16. Lipids Health Dis. 2019 Feb 01. 18(1): 37
    Influence of total polar compounds on lipid metabolism, oxidative stress and cytotoxicity in HepG2 cells.
    Jingjie Ju, Zhaojun Zheng, Yong-Jiang Xu, Peirang Cao, Jingwei Li, Qiu Li, Yuanfa Liu.
      BACKGROUND: Recently, the harmful effects of frying oil on health have been gradually realized. However, as main components of frying oils, biochemical effects of total polar compounds (TPC) on a cellular level were underestimated.METHODS: The effects of total polar compounds (TPC) in the frying oil on the lipid metabolism, oxidative stress and cytotoxicity of HepG2 cells were investigated through a series of biochemical methods, such as oil red staining, real-time polymerase chain reaction (RT-PCR), cell apoptosis and cell arrest.
    RESULTS: Herein, we found that the survival rate of HepG2 cells treated with TPC decreased in a time and dose dependent manner, and thereby presented significant lipid deposition over the concentration of 0.5 mg/mL. TPC were also found to suppress the expression levels of PPARα, CPT1 and ACOX, elevate the expression level of MTP and cause the disorder of lipid metabolism. TPC ranged from 0 to 2 mg/mL could significantly elevate the amounts of reactive oxygen species (ROS) in HepG2 cells, and simultaneously increase the malondialdehyde (MDA) content from 21.21 ± 2.62 to 65.71 ± 4.20 μmol/mg of protein (p < 0.05) at 24 h. On the contrary, antioxidant enzymes superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) respectively decreased by 0.52-, 0.56- and 0.28-fold, when HepG2 cells were exposed to 2 mg/mL TPC for 24 h. In addition, TPC could at least partially induce the apoptosis of HepG2 cells, and the transition from G0/G1 to G2 phase in HepG2 cells was impeded.
    CONCLUSIONS: TPC could progressively cause lipid deposition, oxidative stress and cytotoxicity, providing the theoretical support for the detrimental health effects of TPC.
    Keywords:  HepG2 cell; Lipid metabolism; Oxidation stress; Total polar compounds (TPC)
    DOI:  https://doi.org/10.1186/s12944-019-0980-0
  17. Med Sci Monit. 2019 Jan 28. 25 811-818
    Sulforaphane Attenuates H₂O₂-induced Oxidant Stress in Human Trabecular Meshwork Cells (HTMCs) via the Phosphatidylinositol 3-Kinase (PI3K)/Serine/Threonine Kinase (Akt)-Mediated Factor-E2-Related Factor 2 (Nrf2) Signaling Activation.
    Yuzhen Liu, Pan Liu, Qiang Wang, Fengmei Sun, Fang Liu.
      BACKGROUND The aim of this study was to investigate whether and how sulforaphane (SFN), a novel promising nuclear factor-E2-related factor 2 (Nrf2) activator, exerted antioxidative stress through activating Nrf2 signaling. MATERIAL AND METHODS Cultured human trabecular meshwork cells (HTMCs) were treated with SFN for 6 hours after establishing the oxidative stress model by hydrogen peroxide (H₂O₂). The cell viability, the level of intercellular reactive oxygen species (ROS), and the apoptosis rate were observed using various kits. In addition, the gene and protein expression of Nrf2 and the phase II antioxidative enzymes were determined by performing qRT-PCR and western blotting. RESULTS In H₂O₂-treated HTMCs, SFN protected HTMCs from oxidative stress damage and decreased the intracellular ROS accumulation, thus inhibiting cell apoptosis. SFN also increased the gene and protein expression of phase II antioxidative enzymes such as NAD(P)H: quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM) by Nrf2-dependent pathway. Furthermore, investigations of the pathway showed that HTMCs pretreated with LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), downregulated the expression of phase II antioxidative enzymes, partly. CONCLUSIONS These results indicated a novel application for SFN in attenuating H₂O₂-induced oxidative stress in HTMCs through activating PI3K/Akt/Nrf2 signaling pathway.
    DOI:  https://doi.org/10.12659/MSM.913849
  18. Arch Med Sci. 2019 Jan;15(1): 152-164
    Renin-angiotensin system inhibitor attenuates oxidative stress induced human coronary artery endothelial cell dysfunction via the PI3K/AKT/mTOR pathway.
    Xuekun Shi, Yuhua Guan, Shaoyan Jiang, Tiandong Li, Bing Sun, Huan Cheng.
      Introduction: The renin-angiotensin system is associated with blood pressure regulation, inflammation, oxidative stress and insulin resistance. It can decrease intracellular oxidative stress. Stimulation with H2O2 leads to increased oxidative stress and activation of the AKT/mTOR pathway. However, the role of renin-angiotensin system inhibitors in oxidative stress-induced endothelial cell dysfunction and H2O2-induced AKT activation remains unclear.Material and methods: Human coronary artery endothelial cells (HCAECs) were used. The cells were treated with H2O2, captopril, the AKT inhibitor MK-2206, and the AKT activator SC79, either separately, or in combination. p53 and ICAM-1 expression, and p-eNOS, p-Akt and mTOR activation were measured by Western blot. Cell viability was assessed by MTT assay. Levels of reactive oxygen species (ROS) were assayed by flow cytometry. Proliferation was monitored by BrdU labeling, while cell migration and invasion were determined by wound healing and Transwell assays, respectively.
    Results: The renin-angiotensin system inhibitor captopril reversed H2O2-induced oxidative stress and apoptosis in HCAECs. Co-treatment with captopril and the AKT inhibitor MK-2206 reduced the H2O2-induced P53 and ICAM-1 protein expression (p < 0.05). The proliferation, migration and invasion of HCAECs were significantly enhanced by co-treatment with captopril and MK-2206 (p < 0.05).
    Conclusions: The study revealed the protective effect of captopril against H2O2-induced endothelial cell dysfunction through the AKT/mTOR pathway, and its enhancement of cell survival. These findings provide new insights into the protective effects of captopril and novel therapeutic approaches to treatment of cardiovascular disease.
    Keywords:  AKT/mTOR pathway; apoptosis; endothelial cell dysfunction; oxidative stress; renin-angiotensin system inhibitor
    DOI:  https://doi.org/10.5114/aoms.2018.74026
  19. Lasers Med Sci. 2019 Feb 02.
    The photocytotoxicity effect of cationic sulfonated corrole towards lung cancer cells: in vitro and in vivo study.
    Zhao Zhang, Hua-Jun Yu, Hui Huang, Bei Wan, Shang Wu, Hai-Yang Liu, Hai-Tao Zhang.
      Corrole is a kind of new and promising photosensitizer (PS) in cancer photodynamic therapy (PDT). However, the protein molecular mechanism of PDT activity for corrole under light irradiation is still not clear. In this paper, water-soluble cationic sulfonated corrole (1) and its metal complexes (1-Fe, 1-Mn, and 1-Cu) were prepared, and the photodynamic anti-cancer activity against various tumor cells was investigated by MTT assay. The potential molecular mechanism of PDT activity was elucidated by fluorescence microscope, flow cytometry, molecular docking, and western blotting analysis. Besides, the potential PDT anti-tumor effect of 1 in vivo was assessed in human tumor xenografts in mice. Quantitative analysis revealed that 1's phototoxicity triggered a significant generation of reactive oxygen species, causing disruption of mitochondrial membrane potential. The results of western blotting (WB) assay shown in 1's phototoxicity could induce cell apoptosis via ROS-mediated mitochondrial caspase apoptosis pathway, in which SIRT1 protein degradation played a key role. PTD activity in vivo shown in 1 could significantly reduce the growth of A549 xenografted tumor, without obvious loss of mice body weight. We clearly found that cationic sulfonated corrole is a potential candidate of PS in vitro and in vivo. The phototoxicity of 1 could induce A549 cell apoptosis by inducing ROS production increase, further to activate the mitochondrial apoptosis pathway. We concluded that SIRT1 protein is a more appropriate target in this progress.
    Keywords:  Corrole; Photocytotoxicity; ROS-mediated; SIRT1
    DOI:  https://doi.org/10.1007/s10103-019-02725-4
  20. Environ Toxicol. 2019 Jan 30.
    Prevention of ochratoxin A-induced oxidative stress-mediated apoptotic processes and impairment of embryonic development in mouse blastocysts by liquiritigenin.
    Chien-Hsun Huang, Fu-Ting Wang, Wen-Hsiung Chan.
      Ochratoxin A (OTA), a mycotoxin constituent of a range of food commodities, including coffee, wine, beer, grains, and spices, exerts toxicological and pathological effects in vivo, such as nephrotoxicity, hepatotoxicity, and immunotoxicity. In a previous report, we highlighted the potential of OTA to induce apoptosis via reactive oxygen species (ROS) generation in mouse blastocysts that led to impaired preimplantation and postimplantation embryo development in vitro and in vivo. Here, we have shown that liquiritigenin (LQ), a type of flavonoid isolated from Glycyrrhiza radix, effectively protects against OTA-mediated apoptosis and inhibition of cell proliferation in mouse blastocysts. Preincubation of blastocysts with LQ clearly prevented OTA-triggered impairment of preimplantation and postimplantation embryonic development and fetal weight loss, both in vitro and in vivo. Detailed investigation of regulatory mechanisms revealed that OTA mediated apoptosis and embryotoxicity through ROS generation, loss of mitochondrial membrane potential (MMP), and activation of caspase-9 and caspase-3, which were effectively prevented by LQ. The embryotoxic effects of OTA were further validated in an animal model in vivo. Intravenous injection of dams with OTA (3 mg/kg/day) led to apoptosis of blastocysts, impairment of embryonic development from zygote to blastocyst stage and decrease in day 18 fetal weight. Notably, preinjection of dams with LQ (5 mg/kg/day) effectively prevented OTA-induced apoptosis and toxic effects on embryo development. Our collective results clearly demonstrate that OTA exposure via injection has the potential to damage preimplantation and postimplantation embryonic development against which LQ has a protective effect.
    Keywords:  apoptosis; embryonic development; liquiritigenin; ochratoxin A; oxidative stress
    DOI:  https://doi.org/10.1002/tox.22724
  21. Neurochem Res. 2019 Jan 29.
    Dexmedetomidine Promotes SH-SY5Y Cell Resistance Against Impairment of Iron Overload by Inhibiting NF-κB Pathways.
    Xi-Bei Hu, Zhi-Yu Xi, Lin-Qing Liu, Kai Kang, Wan-Hong Li, Yu-Xian Shen, Fang Kang, Juan Li.
      Iron overload is a common pathophysiological state underlying many diseases that has a detrimental influence on cells. The protective effects of Dexmedetomidine (Dex), a high selective alpha-2-adrenoceptor agonist, have been revealed through many experimental models, whereas no study reports its effects on an iron overload model. To elucidate these effects, we used FeCl2 with or without Dex to treat SH-SY5Y cells for 24 h and then detected indicators of oxidative stress, inflammation and apoptosis and investigated possible mechanisms further. After treatment with FeCl2 for 24 h, cell viability decreased in a dose dependent manner, and Dex promoted cell survival in FeCl2 incubation, also in a dose-dependent manner. Compared with the FeCl2 group, 20 µM Dex significantly attenuated ROS accumulation, reduced pro-inflammatory cytokine expression, and inhibited apoptosis. Furthermore, 20 µM concentration of Dex remarkably downregulated the expression of pro-apoptotic protein and activation of caspase 3 while increasing anti-apoptotic protein expression. Additionally, Dex also effectively suppressed the expression of NF-κB and its activation. In conclusion, Dex exerted anti-oxidative stress, anti-inflammation, and anti-apoptosis effects on FeCl2-treated SH-SY5Y cells, possibly by inhibiting NF-κB signaling pathway.
    Keywords:  Apoptosis; Dexmedetomidine; Inflammation; Iron overload; NF-κB; Oxidative stress
    DOI:  https://doi.org/10.1007/s11064-019-02731-6
  22. ScientificWorldJournal. 2019 ;2019 4639165
    RASGRP2 Suppresses Apoptosis via Inhibition of ROS Production in Vascular Endothelial Cells.
    Takuma Sato, Jun-Ichi Takino, Kentaro Nagamine, Kazuto Nishio, Takamitsu Hori.
      We have identified ras guanyl releasing protein 2 (rasgrp2) as a blood vessel related gene from Xenopus embryo. In addition, we reported that RASGRP2 is also expressed in human umbilical vein endothelial cells (HUVEC). It is known that RASGRP2 activates Ras-related protein 1 (Rap1). However, the function of RASGRP2 in human vascular endothelium remains unknown. Therefore, we performed functional analysis of RASGRP2 using immortalized HUVEC (TERT HUVEC). We established a stable RASGRP2 overexpressing cell line (TERT HUVEC R) and mock cell line (mock). Furthermore, we compared the activity of Rap1 and the generation of intracellular reactive oxygen species (ROS), which is related to cell death, in both cell lines. Significant increase in Rap1 activity was observed in the TERT HUVEC R compared to the mock. Furthermore, apoptosis by tumor necrosis factor-α (TNF-α) stimulation was significantly more reduced in the TERT HUVEC R than in the mock. In the mock, apoptosis induced by TNF-α stimulation was decreased by pretreatment with diphenyleneiodonium (DPI), which is an inhibitor of NADPH oxidase (NOX). However, in the TERT HUVEC R, apoptosis induced by TNF-α stimulation was not reduced after pretreatment of DPI. Furthermore, there was no reduction in ROS production in the TERT HUVEC R after DPI pretreatment. In addition, the difference in the degree of apoptosis induced by TNF-α stimulation in both cell lines was consistent with the difference in ROS production in the cell lines. From these results, it was suggested that RASGRP2 activates Rap1 and the activated Rap1 suppresses apoptosis via NOX inhibition.
    DOI:  https://doi.org/10.1155/2019/4639165
  23. Eur J Med Chem. 2019 Jan 11. pii: S0223-5234(19)30004-2. [Epub ahead of print]165 293-308
    Identification of 3-(benzazol-2-yl)quinoxaline derivatives as potent anticancer compounds: Privileged structure-based design, synthesis, and bioactive evaluation in vitro and in vivo.
    Qing-Qing Liu, Ke Lu, Hai-Miao Zhu, Shi-Lin Kong, Jing-Mei Yuan, Guo-Hai Zhang, Nan-Ying Chen, Chen-Xi Gu, Cheng-Xue Pan, Dong-Liang Mo, Gui-Fa Su.
      Inspired by the common structural characteristics of numerous known antitumor compounds targeting DNA or topoisomerase I, 3-(benzazol-2-yl)-quinoxaline-based scaffold was designed via the combination of two important privileged structure units -quinoxaline and benzazole. Thirty novel 3-(benzazol-2-yl)-quinoxaline derivatives were synthesized and evaluated for their biological activities. The MTT assay indicated that most compounds possessed moderate to potent antiproliferation effects against MGC-803, HepG2, A549, HeLa, T-24 and WI-38 cell lines. 3-(Benzoxazol- -2-yl)-2-(N-3-dimethylaminopropyl)aminoquinoxaline (12a) exhibited the most potent cytotoxicity, with IC50 values ranging from 1.49 to 10.99 μM against the five tested cancer and one normal cell line. Agarose-gel electrophoresis assays suggested that 12a did not interact with intact DNA, but rather it strongly inhibited topoisomerase I (Topo I) via Topo I-mediated DNA unwinding to exert its anticancer activity. The molecular modeling study indicated that 12a adopt a unique mode to interact with DNA and Topo I. Detailed biological study of 12a in MGC-803 cells revealed that 12a could arrest the cell cycle in G2 phase, inducing the generation of reactive oxygen species (ROS), the fluctuation of intracellular Ca2+, and the loss of mitochondrial membrane potential (ΔΨm). Western Blot analysis indicated that 12a-treatment could significantly up-regulate the levels of pro-apoptosis proteins Bak, Bax, and Bim, down-regulate anti-apoptosis proteins Bcl-2 and Bcl-xl, and increase levels of cyclin B1 and CDKs inhibitor p21, cytochrome c, caspase-3, caspase-9 and their activated form in MGC-803 cells in a dose-dependent manner to induce cell apoptosis via a caspase-dependent intrinsic mitochondria-mediated pathway. Studies in MGC-803 xenograft tumors models demonstrated that 12a could significantly reduce tumor growth in vivo at doses as low as 6 mg/kg with low toxicity. Its convenient preparation and potent anticancer efficacy in vivo makes the 3-(benzazol-2-yl)quinoxaline scaffold a promising new chemistry entity for the development of novel chemotherapeutic agents.
    Keywords:  Anticancer; DNA unwinding; Privileged structure; Quinoxaline derivatives; Topoisomerase I inhibitor
    DOI:  https://doi.org/10.1016/j.ejmech.2019.01.004
  24. Mol Biol Rep. 2019 Jan 29.
    The anticancer activity of visnagin, isolated from Ammi visnaga L., against the human malignant melanoma cell lines, HT 144.
    Fatma Aydoğmuş-Öztürk, Humera Jahan, Neslihan Beyazit, Keriman Günaydın, Muhammad Iqbal Choudhary.
      Melanoma is a cancer of melanocyte cells and has the highest global incidence. There is a need to develop new drugs for the treatment of this deadly cancer, which is resistant to currently used treatment modalities. We investigated the anticancer activity of visnagin, a natural furanochromone derivative, isolated from Ammi visnaga L., against malignant melanoma (HT 144) cell lines. The singlet oxygen production capacity of visnagin was determined by the RNO bleaching method while cytotoxic activity by the MTT assay. Further, HT 144 cells treated with visnagin were also exposed to visible light (λ ≥ 400 nm) for 25 min to examine the illumination cytotoxic activity. The apoptosis was measured by flow cytometry with annexin V/PI dual staining technique. The effect of TNF-α secretion on apoptosis was also investigated. In standard MTT assay, visnagin (100 µg/mL) exhibited 80.93% inhibitory activity against HT 144 cancer cell lines, while in illuminated MTT assay at same concentration it showed lesser inhibitory activity (63.19%). Visnagin was induced apoptosis due to the intracellular generation of reactive oxygen species (ROS) and showed an apoptotic effect against HT 144 cell lines by 25.88%. However, it has no effect on TNF-α secretion. Our study indicates that visnagin can inhibit the proliferation of malignant melanoma, apparently by inducing the intracellular oxidative stress.
    Keywords:  Ammi visnaga L.; Apoptosis; Malignant melanoma; Visnagin
    DOI:  https://doi.org/10.1007/s11033-019-04620-1
  25. Neural Regen Res. 2019 May;14(5): 794-804
    Kai Xin San ameliorates scopolamine-induced cognitive dysfunction.
    Yu-Min Xu, Xin-Chen Wang, Ting-Ting Xu, Hong-Ying Li, Shang-Yan Hei, Na-Chuan Luo, Hong Wang, Wei Zhao, Shu-Huan Fang, Yun-Bo Chen, Li Guan, Yong-Qi Fang, Shi-Jie Zhang, Qi Wang, Wei-Xiong Liang.
      Kai Xin San (KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups (which received physiological saline), the doses of KXS (0.7, 1.4 and 2.8 g/kg per day) and donepezil (3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following. (1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze. (2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze. (3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies. (4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus. (5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.
    Keywords:  Kai Xin San; apoptosis; cholinergic system dysfunction; cognitive dysfunction; donepezil; neural regeneration; neuroprotection; oxidative stress; scopolamine hydrobromide; synaptic dysfunction
    DOI:  https://doi.org/10.4103/1673-5374.249227
  26. J Biomed Mater Res A. 2019 Jan 30.
    Effect of magnesium on reducing the UV-induced oxidative damage in marrow mesenchymal stem cells.
    Yangmei Chen, Shibing Xiong, Fenghua Zhao, Xugang Lu, Boyao Wu, Bangcheng Yang.
      Oxidative stress could cause damage to lipids, proteins and DNA, which is induced by the imbalance between the production of reactive oxygen species (ROS) and the biological system ability to counteract or detoxify their harmful effects. The oxidative stress damage significantly contributes to a number of diseases. Magnesium (Mg) is endowed with a novel function of removing excess ROS by releasing H2 during the degradation. In this study, in order to explore the property of anti-oxidative damage of Mg metal, rat bone marrow mesenchymal stem cells (MSCs) oxidative damaged by UV radiation was employed to co-culture with Mg metal. The effect of Mg metal on the response of antioxidant enzymes and mitochondria in MSCs was studied. We found that Mg metal could reduce the cellular oxidative stress damage and elevate the activities of antioxidant enzymes to maintain redox homeostasis. In addition, Mg metal could reduce the risk of UV-induced cell apoptosis by increasing the ratio of Bcl-2/Bax, elevating the mitochondrial membrane potential and blocking the release of cytochrome c. This finding showed Mg metal might have the potential for treating diseases caused by oxidative stress damage. This article is protected by copyright. All rights reserved.
    Keywords:  Magnesium; UV radiation; cell apoptosis; mitochondria; oxidative stress damage
    DOI:  https://doi.org/10.1002/jbm.a.36634
  27. Biomaterials. 2019 Jan 24. pii: S0142-9612(19)30057-2. [Epub ahead of print]197 393-404
    Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer's disease.
    Lei Zhang, Penghe Zhao, Caiping Yue, Zhaokui Jin, Qiong Liu, Xiubo Du, Qianjun He.
      Oxidative stress-induced mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease (AD). Hydrogen molecule, a special antioxidant, can selectively scavenge highly cytotoxic reactive oxygen species such as ·OH, exhibiting a potential to treat AD by reducing oxidative stress. However, there is no effective route to realize the continuous and efficient accumulation of administrated hydrogen in AD brain owing to its low solubility. Here, we develop the small-sized Pd hydride (PdH) nanoparticles for high payload of hydrogen and in situ sustained hydrogen release in AD brain. By virtue of the catalytic hydrogenation effect of Pd, the released hydrogen from PdH nanoparticles exhibits high bio-reductivity in favor of effectively scavenging cytotoxic ·OH in a self-catalysis way. Bio-reductive hydrogen is able to recover mitochondrial dysfunction, inhibit Aβ generation and aggregation, block synaptic and neuronal apoptosis and promote neuronal energy metabolism by eliminating oxidative stress and activating the anti-oxidative pathway, consequently ameliorating the cognitive impairment in AD mice. The proposed hydrogen-releasing nanomedicine strategy would open a new window for the treatment of AD.
    Keywords:  Alzheimer's disease; Controlled release; Drug delivery; Hydrogen therapy; Nanoparticles
    DOI:  https://doi.org/10.1016/j.biomaterials.2019.01.037
  28. J Reprod Dev. 2019 Jan 31.
    Lycium barbarum polysaccharide enhances development of previously-cryopreserved murine two-cell embryos via restoration of mitochondrial function and down-regulated generation of reactive oxygen species.
    Lei Yang, Zhen Gao, Lanjie Lei, Qizhuang Lv, Qihan Zhao, Lixin Li, Xiaoming Cao, Wenxue Fu.
      Lycium barbarum polysaccharide (LBP) exhibits multiple pharmacological and biological effects, including displaying antioxidant and cytoprotective properties. The current study investigated the effects of LBP-supplemented culture medium on mitochondrial distribution, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, mitochondrial deoxyribonucleic acid (mtDNA) copy number, reactive oxygen species (ROS) accumulation, and development of previously-cryopreserved murine two-cell embryos. Results indicate that LBP enhances development of such embryos, and that potential mechanisms include: (1) mitochondrial function enhancement via altering mitochondrial distribution and increasing MMP, ATP production, mtDNA copy number, and expression of genes involved in mitochondrial biogenesis and energy metabolism (NAD-dependent deacetyltransferase sirtuin-1 (SIRT1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK)); (2) down-regulation of ROS generation and enhanced expression of the antioxidant genes glutathione peroxidase 4 (GPX4) and superoxide dismutase 1 (SOD1), thereby increasing embryo oxidative stress tolerance; and (3) increased expression of B-cell lymphoma-2 (BCL2), a critical gene for cell survival and embryo development. These results demonstrate that LBP improves development of previously-cryopreserved murine two-cell embryos via restoration of mitochondrial function and down-regulated generation of ROS.
    Keywords:  Cryopreservation; Lycium barbarum polysaccharide; Mitochondria; Reactive oxygen species; Two-cell embryo
    DOI:  https://doi.org/10.1262/jrd.2018-104
  29. Planta Med. 2019 Jan 31.
    Icariin Attenuates High Glucose-Induced Apoptosis, Oxidative Stress, and Inflammation in Human Umbilical Venous Endothelial Cells.
    Si Sun, Le Liu, Xiaojun Tian, Yanghongyun Guo, Yingkang Cao, Yunqing Mei, Changhua Wang.
      Endothelial dysfunction is closely associated with diabetic complications. Icariin, a flavonoid glycoside isolated from the Epimedium plant species, exhibits antidiabetic properties. However, its impact on endothelial function remains poorly understood, particularly under hyperglycemia. In this study, we investigated the potential protective effect of icariin on high glucose-induced detrimental effects on vascular endothelial cells. Human umbilical venous endothelial cells were incubated in media containing 5.5 mM glucose (normal glucose) or 25 mM glucose (high glucose) in the presence or absence of 50 µM icariin for 72 h. We found that high glucose markedly induced cell apoptosis, enhanced reactive oxygen species generation, and elevated expression levels of inflammatory factors and cell adhesion molecules, which were greatly subdued by icariin supplementation. In conclusion, icariin exerted a beneficial effect on high glucose-induced endothelial dysfunction. This new finding provides a promising strategy for future treatment of diabetic vascular complications.
    DOI:  https://doi.org/10.1055/a-0837-0975
  30. Oncogene. 2019 Jan 28.
    RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer.
    Bo Ram Kim, Seong Hye Park, Yoon A Jeong, Yoo Jin Na, Jung Lim Kim, Min Jee Jo, Soyeon Jeong, Hye Kyeong Yun, Sang Cheul Oh, Dae-Hee Lee.
      RUNX3 is frequently inactivated by DNA hypermethylation in numerous cancers. Here, we show that RUNX3 has an important role in modulating apoptosis in immediate response to tumor necrosis factor-related apoptosis-including ligand (TRAIL). Importantly, no combined effect of TRAIL and RUNX3 was observed in non-cancerous cells. We investigated the expression of the death receptors (DRs) DR4 and DR5, which are related to TRAIL resistance. Overexpression of RUNX3 increased DR5 expression via induction of the reactive oxygen species (ROS)-endoplasmic reticulum (ER) stress-effector CHOP. Reduction of DR5 markedly decreased apoptosis enhanced by the combined therapy of TRAIL and RUNX3. Interestingly, RUNX3 induced reactive oxygen species production by inhibiting SOD3 transcription via binding to the Superoxide dismutase 3 (SOD3) promoter. Additionally, the combined effect of TRAIL and RUNX3 decreased tumor growth in xenograft models. Our results demonstrate a direct role for RUNX3 in TRAIL-induced apoptosis via activation of DR5 and provide further support for RUNX3 as an anti-tumor.
    DOI:  https://doi.org/10.1038/s41388-019-0693-x
  31. Fitoterapia. 2019 Jan 25. pii: S0367-326X(18)32239-1. [Epub ahead of print]
    The protective effects of vernicilignan A, a new flavonolignan isolated from Toxicodendron vernicifluum on SH-SY5Y cells against oxidative stress-induced injury.
    Meichen Li, Yanhua Fan, Ting Zhong, Ping Yi, Chengcheng Fan, Andong Wang, Jianyu Liu, Yongnan Xu.
      In this study, a new flavonolignan vernicilignan A was isolated from Toxicodendron vernicifluum. The neuroprotective effects of this compound against H2O2 induced cell injury in SH-SY5Y cells were evaluated by MTT assay and LDH release assay. Vernicilignan A dose-dependently attenuated the cell injury and LDH release induced by H2O2 in SH-SY5Y cells. Further study indicated that vernicilignan A reduced cell apoptosis caused by H2O2 treatment via regulation of some apoptotic related proteins including Bax, Bcl-2, caspase 3 and caspase 9. Also, vernicilignan A increase the cell viability of H2O2 treated cells via the activation of Akt and GSK3β. Base on the findings, vernicilignan A exhibited neuroprotective effects through the activation of PI3K/Akt signaling and inhibition of mitochondria apoptosis pathway. Vernicilignan A might be a promising therapeutic agent for oxidative stress induced neurodegenerative diseases.
    Keywords:  Flavonolignan; Protective effect; SH-SY5Y cell; Toxicodendron vernicifluum
    DOI:  https://doi.org/10.1016/j.fitote.2019.01.011
  32. Free Radic Biol Med. 2019 Jan 23. pii: S0891-5849(18)32244-5. [Epub ahead of print]
    Mitochondrial translocation of estrogen receptor β affords resistance to oxidative insult-induced apoptosis and contributes to the pathogenesis of endometriosis.
    Tien-Ling Liao, Yu-Ching Lee, Chii-Ruey Tzeng, Yi-Pei Wang, Heng-Yu Chang, Yung-Feng Lin, Shu-Huei Kao.
      Endometriosis is the major cause of female infertility and has been linked to the action of estrogen and estrogen receptor (ER). A new pool of ERβ locates within mitochondria, which regulates the endometriotic cell withstanding external insults, but its effect remains controversial. We hypothesize that mitochondrial estrogen receptor ERβ (mtERβ) is a pivotal regulator in estradiol-mediated cell protection leading to the endometriotic progression. We observed elevated levels of ERβ in the endometriotic tissues. A dramatic increase of ERβ in mitochondria (mtERβ) was found in the ectopic endometriotic tissues, or the estradiol-primed primary endometriotic cells. We analyzed the mtERβ-specific overexpressing clone (mtsERβ), which exhibited higher mitochondrial bioenergetics and lower reactive oxygen species (ROS) generation. The mtsERβ-overexpressed endometriotic cells displayed an enhanced migration phenotype, whereas significantly attenuated migration by mitochondrial respiratory inhibitor (oligomycin) or ERβ deficiency by shERβ. Further investigations revealed that ERβ directly modulated mitochondrial DNA (mtDNA) gene expression by interacting with mtDNA D-loop and polymerase γ. The mtsERβ afforded a resistance to oxidative insult-induced apoptosis through the induction of the ROS scavenger enzyme Mn-superoxide dismutase and anti-apoptotic protein Bcl-2. Collectively, the demonstration of mtERβ responses in restoration of mitochondrial bioenergetics and inhibition of mitochondria-dependent apoptotic events provides insight into the pathogenesis of endometriosis, suggesting ERβ-selective estrogen receptor modulator may serve as novel therapeutics of endometriosis in the future.
    Keywords:  Anti-apoptosis; Cell migration; Endometriosis; Mitochondrial bioenergetics; Mitochondrial estrogen receptor β; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.01.022
  33. Front Physiol. 2018 ;9 1907
    Selenium-Containing Protein From Selenium-Enriched Spirulina platensis Attenuates Cisplatin-Induced Apoptosis in MC3T3-E1 Mouse Preosteoblast by Inhibiting Mitochondrial Dysfunction and ROS-Mediated Oxidative Damage.
    Jing-Yi Sun, Ya-Jun Hou, Xiao-Yan Fu, Xiao-Ting Fu, Jin-Kui Ma, Ming-Feng Yang, Bao-Liang Sun, Cun-Dong Fan, Jinrok Oh.
      Accumulated evidences have verified that cancer chemotherapy may increase the risk of osteoporosis and severely affected the life quality. Osteoclasts hyperactivation was commonly accepted as the major pathogenesis of osteoporosis. However, the role of osteoblasts dysfunction in osteoporosis was little investigated. Our previous study has confirmed that selenium-containing protein from selenium-enriched Spirulina platensis (Se-SP) exhibited enhanced hepatoprotective potential through inhibiting oxidative damage. Herein, the protective effect of Se-SP against cisplatin-induced osteoblasts dysfunction in MC3T3-E1 mouse preosteoblast was investigated, and the underlying mechanism was evaluated. The results indicated that cisplatin dramatically decreased cell viability of preosteoblast by triggering mitochondria-mediated apoptosis pathway. Cisplatin treatment also caused mitochondrial dysfunction and reactive oxide species (ROS)-mediated oxidative damage. However, Se-SP pre-treatment effectively prevented MC3T3-E1 cells from cisplatin-induced mitochondrial dysfunction by balancing Bcl-2 family expression and regulating the opening of mitochondrial permeability transition pore (MPTP), attenuated cisplatin-induced oxidative damage through inhibiting the overproduction of ROS and superoxide anion, and eventually reversed cisplating-induced early and late apoptosis by inhibiting PARP cleavage and caspases activation. Our findings validated that Se-SP as a promising Se species could be a highly effective way in the chemoprevention and chemotherapy of oxidative damage-mediated bone diseases.
    Keywords:  apoptosis; cancer chemotherapy; mitochondrial dysfunction; osteoblasts dysfunction; osteoporosis; oxidative damage; selenium-containing protein
    DOI:  https://doi.org/10.3389/fphys.2018.01907
  34. J Exp Clin Cancer Res. 2019 Jan 31. 38(1): 44
    CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma.
    Zongyi Wang, Fei Yin, Jing Xu, Tao Zhang, Gangyang Wang, Ming Mao, Zhuoying Wang, Wei Sun, Jing Han, Mengkai Yang, Yafei Jiang, Yingqi Hua, Zhengdong Cai.
      BACKGROUND: Osteosarcoma (OS) is a common malignant cancer in children and adolescents and has a cure rate that has not improved in the last two decades. CYT997 (lexibulin) is a novel potent microtubule-targeting agent with various anticancer activities, such as proliferation inhibition, vascular disruption, and cell cycle arrest and apoptosis induction, in multiple cancers. However, the direct cytotoxic mechanisms of CYT997 have not yet been fully characterized.METHODS: We evaluated apoptosis and autophagy in human osteosarcomas after treatment with CYT997 and investigated the underlying mechanisms. To explore relationships, we used the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, ERO1 inhibitor EN460 and mitochondrial targeted protection peptide elamipretide. BALB/c-nu mice were inoculated with 143B tumor cells to investigate the in vivo effect of CYT997.
    RESULTS: We explored the efficacy and mechanism of CYT997 in osteosarcoma (OS) in vitro and in vivo and demonstrated that CYT997 potently suppresses cell viability and induces apoptosis and autophagy. CYT997 triggered production of ROS and exerted lethal effects via endoplasmic reticulum (ER) stress in OS cells. NAC attenuated these effects. The PERK inhibitor GSK2606414, which can block the ER stress pathway, reduced ROS production and enhanced cell viability. Moreover, activation of ERO1 in the ER stress pathway was responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravate ER stress. Protection of mitochondria can reduce apoptosis and autophagy. Finally, CYT997 prominently reduced tumor growth in vivo.
    CONCLUSIONS: This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS.
    Keywords:  CYT997; ER stress; ERO1A; Osteosarcoma; ROS
    DOI:  https://doi.org/10.1186/s13046-019-1047-9
  35. Med Sci Monit. 2019 Jan 28. 25 801-810
    The Effect of Overexpression of the Enhancer of Zeste Homolog 1 (EZH1) Gene on Aristolochic Acid-Induced Injury in HK-2 Human Kidney Proximal Tubule Cells In Vitro.
    Liping Wang, Ning Liu, Xiaoyan Xue, Shujun Zhou.
      BACKGROUND Acute kidney injury (AKI) involves the renal tubular epithelium. The enhancer of zeste homolog 1 (EZH1) gene has a role in cell development and differentiation. This study aimed to investigate the effect of overexpression of the EZH1 gene on aristolochic acid-induced injury in HK-2 human kidney proximal tubule epithelial cells in vitro. MATERIAL AND METHODS The HK-2 cells were cultured and treated with aristolochic acid and the effects of aristolochic acid-injury were evaluated using a cell counting kit-8 (CCK-8) assay. Overexpression of EZH1 used gene plasmid transfection into HK-2 cells. The cell apoptosis rate and levels of intracellular reactive oxygen species (ROS) were measured using flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to determine the expressions of inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), apoptosis-related genes, and the downstream target genes of NF-κB signaling pathway, including NFKBIA, CXCL8, and cyclin D1. RESULTS Aristolochic acid inhibited HK-2 cell viability, induced cell apoptosis, increased the levels of ROS and inflammatory cytokines, including IL-1β, IL-6, TNF-α, and activated the NF-κB pathway. Overexpression the EZH1 gene inhibited HK-2 cell apoptosis, reduced ROS levels, and down-regulated the expressions of IL-1β, IL-6, TNF-α, Bax and Cyt C mRNA and protein, and increased the expressions of Bcl-2 and NFKBIA, CXCL8 and cyclin D1, indicating that overexpression of EZH1 suppressed NF-κB signaling in aristolochic acid-injured HK-2 cells. CONCLUSIONS Overexpression of EZH1 reduced HK-2 cell injury induced by aristolochic acid in vitro by inhibition of NF-κB signaling.
    DOI:  https://doi.org/10.12659/MSM.911611
  36. Eur J Pharmacol. 2019 Jan 25. pii: S0014-2999(19)30063-9. [Epub ahead of print]
    Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt/mTOR signaling in methionine-choline deficiency-induced fatty liver disease.
    Milena Veskovic, Dusan Mladenovic, Marina Milenkovic, Jelena Tosic, Suncica Borozan, Kristina Gopcevic, Milica Labudovic-Borovic, Vesna Dragutinovic, Danijela Vucevic, Bojan Jorgacevic, Aleksandra Isakovic, Vladimir Trajkovic, Tatjana Radosavljevic.
      We examined the effects of betaine, an endogenous and dietary methyl donor essential for the methionine-homocysteine cycle, on oxidative stress, inflammation, apoptosis, and autophagy in methionine-choline deficient diet (MCD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6 mice received: standard chow (control), standard chow and betaine (1.5% w/v in drinking water), MCD, or MCD and betaine. After six weeks, serum and liver samples were collected for analysis. Betaine reduced MCD-induced increase in liver transaminases and inflammatory infiltration, as well as hepatosteatosis and serum levels of low-density lipoprotein, while it increased that of high-density lipoprotein. MCD-induced hepatic production of reactive oxygen and nitrogen species was significantly reduced by betaine, which also improved liver antioxidative defense by increasing glutathione content and superoxide-dismutase, catalase, glutathione peroxidase, and paraoxonase activity. Betaine reduced the liver expression of proinflammatory cytokines tumor necrosis factor and interleukin-6, as well as that of proapoptotic mediator Bax, while increasing the levels of anti-inflammatory cytokine interleukin-10 and antiapoptotic Bcl-2 in MCD-fed mice. In addition, betaine increased the expression of autophagy activators beclin 1, autophagy-related (Atg)4 and Atg5, as well as the presence of autophagic vesicles and degradation of autophagic target sequestosome 1/p62 in the liver of NAFLD mice. The observed effects of betaine coincided with the increase in the hepatic phosphorylation of mammalian target of rapamycin (mTOR) and its activator Akt. In conclusion, the beneficial effect of betaine in MCD-induced NAFLD is associated with the reduction of liver oxidative stress, inflammation, and apoptosis, and the increase in cytoprotective Akt/mTOR signaling and autophagy.
    Keywords:  apoptosis; autophagy; betaine; inflammation; non-alcoholic fatty liver disease; oxidative stress
    DOI:  https://doi.org/10.1016/j.ejphar.2019.01.043
  37. Brain Res Bull. 2019 Jan 25. pii: S0361-9230(18)30605-1. [Epub ahead of print]
    Neuroprotection by urate on the Mutant hSOD1-related Cellular and Drosophila Models of Amyotrophic Lateral Sclerosis: Implication for GSH synthesis via Activating Akt/GSK3β/Nrf2/GCLC Pathways.
    Chunting Zhang, Yueqing Yang, Weiwei Liang, Tianhang Wang, Shuyu Wang, Xudong Wang, Ying Wang, Hongquan Jiang, Honglin Feng.
      Oxidative stress has been considered as a principal mechanism of motor neuron death in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease which could be caused by dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1). The aim of the present study was to investigate the potential neuroprotective effects and mechanisms of urate, an important endogenous antioxidant and a biomarker of favorable ALS progression rates, in the mutant human SOD1-related cellular and Drosophila models of ALS. Our results showed that urate treatment provided neuroprotective effects as confirmed by enhanced survival, attenuated motor impairments, reduced oxidative damage and increased antioxidant defense in hSOD1-G85R-expressing Drosophila models of ALS. In vitro studies, we demonstrated that urate protected motor neurons (NSC-34 cells) against hSOD1-G93 A-induced cell damage and apoptosis by decreasing reactive oxygen specials (ROS) production and oxidative damage. Moreover, urate markedly increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2-targeted antioxidant gene glutathione cysteine ligase catalytic subunit (GCLC) expression and glutathione (GSH) synthesis by upregulating Akt/GSK3β pathway. Furthermore, the inhibition of Akt pathway with LY294002 abolished urate-mediated elevation of GSH synthesis and neuroprotective effects both in vivo and in vitro. Overall, these results suggested that, in addition to its direct scavenging of ROS, urate markedly enhanced GSH expression by activating Akt/GSK3β/Nrf2/GCLC pathway, and thus offering neuroprotective effects on motor neurons against oxidative stress.
    Keywords:  Akt; Amyotrophic lateral sclerosis; Glutathione; Neuroprotection; Oxidative stress; Urate
    DOI:  https://doi.org/10.1016/j.brainresbull.2019.01.019
  38. Br J Pharmacol. 2019 Feb 01.
    Aspirin eugenol ester attenuates oxidative injury of vascular endothelial cells by regulating NOS and Nrf2 signaling pathways.
    Mei-Zhou Huang, Ya-Jun Yang, Xi-Wang Liu, Zhe Qin, Jian-Yong Li.
      BACKGROUND AND PURPOSE: Aspirin eugenol ester (AEE) is a new drug compound synthesized by combining aspirin with eugenol. It was reported to possess anti-thrombotic, anti-atherosclerotic and anti-oxidative effects. However, its molecular mechanism against oxidative injury is unclear. This study investigated how AEE affected the oxidative injury of vascular endothelial cells in vivo and in vitro.EXPERIMENTAL APPROACH: The high diet fat (HFD) induced atherosclerotic hamsters model and the model of H2 O2 -indcuced human umbilical vein endothelial cells (HUVECs) apoptosis were to investigate the anti-oxidative effects of AEE.
    KEY RESULTS: AEE significantly reduced the stimulatory effect of HFD on MDA, the inhibitory effect of HFD on SOD activity and GSH/GSSG ratio and the overexpression of inducible nitric oxide synthase (iNOS) in the aorta induced by HFD. In vitro experiment, incubation of HUVECs with H2 O2 led to cells apoptosis, dysfunctions of NO systems (including increased iNOS activity, decreased endothelial nitric oxide synthase (eNOS) activity and increased production of NO), the imbalance of calcium homeostasis and energy metabolism featured with the increased intracellular free calcium and decreased ATP and downregulated Nrf2, while in the HUVECs pre-treated with 1 μM AEE for 24 h, the above disorders induced by H2 O2 were significantly ameliorated. Moreover, the effect of AEE on reducing NO productions and the activity of iNOS was significantly attenuated in the Nrf2-inhibted HUVECs.
    CONCLUSION AND IMPLICATION: AEE could protect vascular endothelial cells from oxidative stress by regulating NOS and Nrf2 signaling pathways. This suggests that AEE is a novel potential agent for the prevention of atherosclerosis.
    Keywords:  Aspirin eugenol ester (AEE); apoptosis; nitric oxide synthase; oxidative stress
    DOI:  https://doi.org/10.1111/bph.14592
  39. Cancers (Basel). 2019 Jan 28. pii: E150. [Epub ahead of print]11(2):
    MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells.
    Hyun Ji Lim, Moon Nyeo Park, Changmin Kim, Beomku Kang, Hyo-Sook Song, Hyemin Lee, Sung-Hoon Kim, Bum-Sang Shim, Bonglee Kim.
      Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer.
    Keywords:  C/EBP homologous protein; N-Acetyl-L-cysteine; Spatholobus suberectus Dunn; activating transcription factor 2; apoptosis; endoplasmic reticulum stress; miR-657; multiple myeloma; myeloid leukemia; reactive oxygen species
    DOI:  https://doi.org/10.3390/cancers11020150
  40. J Ethnopharmacol. 2019 Jan 28. pii: S0378-8741(18)34252-1. [Epub ahead of print]
    Cytotoxicity of the crude extract and constituents of the bark of Fagara tessmannii towards multi-factorial drug resistant cancer cells.
    Armelle T Mbaveng, Francois Damen, İlhami Çelik, Pierre Tane, Victor Kuete, Thomas Efferth.
      ETHNOPHARMACOLOGICAL RELEVANCE: Fagara tessmannii Engl. is an African medicinal plant used in Cameroonian traditional medicine to treat various types of cancers.AIM OF THE STUDY: This work was designed to determine the cytotoxicity of the crude extract (FTB), fractions (FTBa-d) and compounds isolated from the bark of Fagara tessmannii, namely lupeol (1), fagaramide (2), zanthoxyline (3), hesperidin (4), nitidine chloride (5), fagaridine chloride (6), and β-sitosterol-3-O-β-D-glucopyranoside (7). The study was extended to the mode of induction of apoptosis by FTB, compounds 5 and 6.
    MATERIALS AND METHODS: The resazurin reduction assay was used to evaluate the cytotoxicity of samples. The cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were measured by flow cytometry. Column chromatography was used for the purification of FTB. Meanwhile, nuclear magnetic resonance (NMR) spectroscopic analysis was applied for structural elucidation.
    RESULTS: The crude extract, fractions FTBa, FTBc, FTBd as well as compounds 5 and 6 revealed cytotoxicity towards the 9 tested cancer cell lines. The IC50 values ranged from 17.34µg/mL (towards U87MG.ΔEGFR glioblastoma cells) to 40.68µg/mL (against CCRF-CEM leukemia cells) for FTB, from 16.78µg/mL (towards U87.MGΔEGFR cells) to 37.42µg/mL (against CEM/ADR5000 leukemia cells) for FTBa, from 19.47µg/mL (towards U87.MG glioblastoma cells) to 41.62µg/mL (against CCRF-CEM cells) for FTBc, from 14.17µg/mL (against HCT116p53-/- colon adenocarcinoma cells) to 22.28µg/mL (towards CEM-ADR5000 cells) for FTBd, from 1.75µM (against CCRF-CEM cells) to 23.52µM (against U87.MGΔEGFR cells) for compound 5, from 1.69µM (against CCRF-CEM cells) to 22.06µM (against HepG2 hepatocarcinoma cells) for compound 6 and from 0.02µM (against CCRF-CEM cells) to 122.96µM (against CEM/ADR5000 cells) for doxorubicin. FTB induced apoptosis in CCRF-CEM cells mediated by enhanced ROS production. Compound 5 induced apoptosis through caspases activation and increase ROS production. Meanwhile, 6 induced apoptosis mediated by caspases activation, MMP alteration and enhanced ROS production.
    CONCLUSION: Fagara tessmannii as well as its constituents 5 and 6 revealed considerable cytotoxicity and may be suitable candidates deserving to be further explored to develop new anticancer drugs to combat sensitive and resistant phenotypes.
    Keywords:  2´,7´-dichlorodihydrofluorescein diacetate; 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide; Alkaloids; Apoptosis; Cytotoxicity; Fagara tessmanniii; Multi-drug resistance; Traditional medicine; dimethyl sulfoxide; doxorubicin; fagaramide; fagaridine chloride; hesperidin; hydrogen peroxide; lupeol; nitidine chloride; valinomycin; zanthoxyline; β-sitosterol-3-O-β-(D)-glucopyranoside
    DOI:  https://doi.org/10.1016/j.jep.2019.01.031
  41. Front Mol Neurosci. 2018 ;11 486
    Ferroptosis Contributes to Isoflurane Neurotoxicity.
    Yimeng Xia, Xiaoyun Sun, Yan Luo, Creed M Stary.
      The underlying mechanisms of isoflurane neurotoxicity in the developing brain remain unclear. Ferroptosis is a recently characterized form of programmed cell death distinct from apoptosis or autophagy, characterized by iron-dependent reactive oxygen species (ROS) generation secondary to failure of glutathione-dependent antioxidant defenses. The results of the present study are the first to demonstrate in vitro that ferroptosis is a central mechanism contributing to isoflurane neurotoxicity. We observed in embryonic mouse primary cortical neuronal cultures (day-in-vitro 7) that 6 h of 2% isoflurane exposure was associated with decreased transcription and protein expression of the lipid repair enzyme glutathione peroxidase 4. In parallel, isoflurane exposure resulted in increased ROS generation, disruption in mitochondrial membrane potential, and cell death. These effects were significantly attenuated by pre-treatment with the selective ferroptosis inhibitor ferrostatin-1 (Fer-1). Collectively, these observations provide a novel mechanism for isoflurane-induced injury in the developing brain and suggest that pre-treatment with Fer-1 may be a potential clinical intervention for neuroprotection.
    Keywords:  ferrostatin-1; glutathione peroxidase; iron; mitochondria; reactive oxygen species; volatile anesthetic
    DOI:  https://doi.org/10.3389/fnmol.2018.00486
  42. Front Aging Neurosci. 2018 ;10 429
    The Effect of Fucoidan on Cellular Oxidative Stress and the CatD-Bax Signaling Axis in MN9D Cells Damaged by 1-Methyl-4-Phenypyridinium.
    Zhigang Liang, Zhuli Liu, Xuwen Sun, Manli Tao, Xiao Xiao, Guoping Yu, Xiaomin Wang.
      Background: The purpose of this study was to investigate the impact of fucoidan (FUC) on the oxidative stress response and lysosomal apoptotic pathways in the Parkinson disease (PD) cell model. Methods: The Dopaminergic nerve precursor cell line(MN9D) cells that served as a PD model in this study underwent damage induced by 100 μM 1-methyl-4-phenyl pyridine (MPP+). Cell viability was assessed after FUC treatment and intracellular SOD GSH was measured via immunofluorescence assay. Cellular changes in cathepsin D, Autophagy marker Light Chain 3-II (LC3-II), and apoptotic protein Bax were assessed by Western blot. The expression of Cat D, LC3-II, and B cell lymphoma-2-associated x protein (Bax) was also measured after addition of the cathepsin inhibitor, pepstatin A. Results: The results indicated that MN9D cell viability decreased by 50% within 24 h after 100 μM MPP+ induced toxicity. Pretreatment with 100 μM Fucoidan reduced cellular expression of LC3-II and CatD in 3 h and suppressed the induction of Bax protein. After pepstatin A treatment, Bax expression was significantly downregulated.FUC reversed the reduction of superoxide dismutase (SOD) L-Glutathione(GSH), decreased cell viability, and apoptosis induced by MPP+ in 6 h, suggesting that Fucoidan can attenuate damage to MN9D cells induced by MPP+. Conclusions: Fucoidan protected lysosomes, reduced the expression of LC3-II, inhibited the expression of CatD-Bax and the oxidative stress response, suppressed apoptosis, and thus conferred protective effects for dopaminergic neural cells. FUC may have neuroprotective effects on PD and further research is needed.
    Keywords:  1-methyl-4-phenyl pyridine; MN9D cells; apoptosis; fucoidan; lysosome; oxidative stress
    DOI:  https://doi.org/10.3389/fnagi.2018.00429
  43. Exp Mol Pathol. 2019 Jan 26. pii: S0014-4800(18)30422-2. [Epub ahead of print]
    Silence of lncRNA CHRF protects H9c2 cells against lipopolysaccharide-induced injury via up-regulating microRNA-221.
    Lijuan Zhang, Li Wang, Enyu Guo, Yuefeng Qi.
      BACKGROUND: Cardiac hypertrophy related factor (CHRF), a newly recognized long non-coding RNA (lncRNA), is a central regulator in cardiac hypertrophy responses. This study attempted to show the potential role of lncRNA CHRF in bacterial infection caused myocarditis.METHODS: H9c2 cells were transfected with small interfering RNAs (siRNAs) specific for lncRNA CHRF alone or in combination with miR-221 inhibitor, and then subjected to lipopolysaccharide (LPS). The following parameters were measured: cell viability, apoptosis, reactive oxygen species (ROS) generation, pro-inflammatory cytokines release, microRNA (miR)-221 expression and the activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways.
    RESULTS: Silence of lncRNA CHRF impeded the LPS injury to H9c2 cells, as cell viability was increased (p < .05), apoptosis was inhibited (p < .05), ROS generation was decreased (p < .01), and the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α was suppressed (p < .05). However, silence of lncRNA CHRF had no impacts on normal H9c2 cells growth (p > .05). miR-221 was negatively regulated by lncRNA CHRF (p < .01). LncRNA CHRF silence did not protect H9c2 cells against LPS when miR-221 was suppressed (p < .05 or p < .01). Also, the inhibitory effects of lncRNA CHRF silence on the activation of NF-κB and JNK pathways were flattened by miR-221 suppression (p < .05 or p < .01).
    CONCLUSION: These in vitro data collectively demonstrated that lncRNA CHRF silence protected H9c2 cells against LPS-induced injury via up-regulating miR-221 and modulating NF-κB and JNK pathways.
    Keywords:  H9c2 cell; Lipopolysaccharide (LPS); LncRNA CHRF; Myocarditis; miR-221
    DOI:  https://doi.org/10.1016/j.yexmp.2019.01.010
  44. Neuroscience. 2019 Jan 29. pii: S0306-4522(19)30067-3. [Epub ahead of print]
    Astragaloside IV Protects Primary Cerebral Cortical Neurons from Oxygen and Glucose Deprivation/Reoxygenation by Activating the PKA/CREB Pathway.
    Bingjie Xue, Jisheng Huang, Bo Ma, Bin Yang, Dennis Chang, Jianxun Liu.
      Stroke is one of the major leading causes of death and disability worldwide, and post-stroke cognitive impairment is a major contributor to this disability. Astragaloside IV (AST-IV) is a primary bioactive compound of Radix Astragali, which is widely used in traditional Chinese medicine to treat stroke. AST-IV was found to possess cognition-enhancing properties against ischemic stroke; however, the mechanisms underlying this effect remain largely elusive. Mitochondrial health is critical to cell viability after ischemic injury. Cyclic AMP response element-binding protein (CREB) is a transcription factor that can be activated by protein kinase A (PKA) to preserve mitochondria, regulate memory and cognitive functions. We used an in vitro model of ischemic injury via oxygen and glucose deprivation (OGD) of cultured neurons, which led to PKA inactivation and decreased CREB phosphorylation, reduced cell viability, and increased neuronal apoptosis. We hypothesized that AST-IV could protect OGD-exposed cerebral cortical neurons by modulating the PKA/CREB signaling pathway and preserving mitochondrial function. We found that the mitochondrial and cellular injuries induced by OGD were reversed following treatment with AST-IV. The activity of neuronal mitochondria was evaluated by measuring the mitochondrial potential and the levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP). AST-IV significantly enhanced PKA and CREB phosphorylation and prevented OGD-induced mitochondrial dysfunction, thereby protecting neurons exposed to OGD from injury and death. Furthermore, the effects of AST-IV were partially blocked by a PKA inhibitor. Collectively, these data elucidated the molecular mechanisms underlying the protective effects of AST-IV against ischemic injury in cortical neurons.
    Keywords:  Apoptosis; Astragalus; Cyclic AMP response element-binding protein; Ischemic stroke; Mitochondria; Protein kinase a; ROS
    DOI:  https://doi.org/10.1016/j.neuroscience.2019.01.040
  45. Diabetes Metab J. 2019 Jan 16.
    Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5.
    Udayakumar Karunakaran, Suma Elumalai, Jun Sung Moon, Jae Han Jeon, Nam Doo Kim, Keun Gyu Park, Kyu Chang Won, Jaechan Leem, In Kyu Lee.
      BACKGROUND: Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced β-cell apoptosis and explored the relationship between myricetin and CDK5.METHODS: To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis.
    RESULTS: Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to β-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Δψm) loss.
    CONCLUSION: Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.
    Keywords:  Apoptosis; Cyclin-dependent kinase 5; Endoplasmic reticulum stress; Insulin-secreting cells; Myricetin
    DOI:  https://doi.org/10.4093/dmj.2018.0052
  46. J Nutr Biochem. 2018 Dec 21. pii: S0955-2863(18)30517-5. [Epub ahead of print]66 17-28
    Dietary pomegranate supplement alleviates murine pancreatitis by modulating Nrf2-p21 interaction and controlling apoptosis to survival switch.
    Payal Gupta, Sreetama Choudhury, Sayan Ghosh, Sudeshna Mukherjee, Olivia Chowdhury, Arindam Sain, Sreya Chattopadhyay.
      Dietary supplementation of polyphenol-rich pomegranate extract (POMx) has been shown to have anti-oxidant and anti-inflammatory activities. Here, we evaluate the efficacy of POMx in mitigating pancreatitis in mice and provide a mechanistic outline of the process. Age-matched male Swiss albino mice were injected with Lipopolysaccharide (LPS) and given POMx supplement alone or in combination with LPS. After 4 weeks of treatment histological scoring for pancreatic edema and vacuolization was performed. Serum insulin levels were estimated and the glucose tolerance test (IPGTT) data revealed that POMx reduced inflammation induced hyperglycemia in mice. Analysis of TLR4, IκB expression, and NF-κB nuclear translocation, and concentrations of IL-6 and TNFα showed that POMx is able to modulate the molecular instigators of inflammatory responses. Annexin V assay indicated that POMx protects against inflammation-mediated apoptosis in the pancreas. Expression profile of SAPK/JNK pathway, p53, Bax, Bcl-2 and Caspase-3 validate an apoptotic to survival shift in POMx treatment group. Co-immunoprecipitation studies show that POMx stabilizes p21 and Nrf2 interaction and increases its nuclear translocation. The study also proves that the nuclear fraction of Nrf2 is able to bind to the Bcl-2 promoter and activate an anti-apoptotic program. The findings of our study underline an anti-inflammatory, anti-oxidative and anti-apoptotic role of POMx and provide a mechanistic idea of how POMx confers protection during pancreatitis.
    Keywords:  Apoptosis; Bcl-2; Nrf2; Oxidative stress; Pancreatitis; Pomegranate
    DOI:  https://doi.org/10.1016/j.jnutbio.2018.12.009
  47. Toxicol Appl Pharmacol. 2019 Jan 25. pii: S0041-008X(19)30038-9. [Epub ahead of print]
    M1 macrophage mediated increased reactive oxygen species (ROS) influence wound healing via the MAPK signaling in vitro and in vivo.
    Zheng Deng, Fei Shi, Zheng Zhou, Feng Sun, Meng-Hao Sun, Qian Sun, Lei Chen, Deng Li, Chen-Yi Jiang, Rui-Zhe Zhao, Di Cui, Xing-Jie Wang, Yi-Feng Jing, Shu-Jie Xia, Bang-Min Han.
      Thulium laser resection of the prostate (TmLRP), a major treatment for benign prostatic hyperplasia (BPH), has several postoperative complications that affect the patients' quality of life. The aim of this study was to investigate the effect of the M1 macrophage-secreted reactive oxygen species (ROS) on prostatic wound healing, and the role of MAPK signaling in this process. A co-culture model in vitro was established using macrophages and prostate epithelial or stromal cells. Cell proliferation, migration, apoptosis, MAPK pathway-related gene expression levels were evaluated by standard assays. In addition, an in vivo model of prostatectomy was established in beagles by subjecting them to TmLRP, and were either treated with N-acetyl-L-cysteine (NAC) and or placebo. Wound healing and re-epithelialization were analyzed histopathologically in both groups, in addition to macrophage polarization, oxidative stress levels and MAPK pathway-related proteins expressions. Intracellular ROS levels were significantly increased in the prostate epithelial and stromal cells following co-culture with M1-like macrophages and H2O2 exposure via MAPK activation, which affected their proliferation, migration and apoptosis, and delayed the wound healing process. The cellular functions and wound healing capacity of the prostate cells were restored by blocking or clearing the macrophage-secreted ROS. In the beagle model, increased ROS levels impaired cellular functions, and appropriate removing ROS accelerated the wound healing process.
    Keywords:  Benign prostatic hyperplasia; M1 macrophage; MAPK; ROS; Wound healing
    DOI:  https://doi.org/10.1016/j.taap.2019.01.022
  48. Front Oncol. 2018 ;8 679
    Aspirin Inhibits Natural Killer/T-Cell Lymphoma by Modulation of VEGF Expression and Mitochondrial Function.
    Hongyu Zhang, Jianping Lu, Yun Jiao, Qi Chen, Min Li, Zichen Wang, Zhendong Yu, Xiaodong Huang, Athena Yao, Qiong Gao, Weiguo Xie, Ling Li, Paul Yao.
      Extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated lymphoma with a strong tendency relapse or be refractory in response to chemotherapy. Development of a new strategy for NKTCL treatment is still quite necessary. In this study, we found that aspirin treatment suppresses VEGF expression in NKTCL SNK-6 cells. Further investigation showed that aspirin treatment increases histone methylation in the range of -100~0 that is proximal to the transcription start site on the VEGF promoter, subsequently decreasing the binding ability of Sp1 to the VEGF promoter with VEGF suppression. Furthermore, aspirin treatment modulates mitochondrial function with increased ROS formation and apoptosis in NKTCL cells. Aspirin treatment alone slightly inhibits NKTCL SNK-6 tumor growth and EBV replication; while in the presence of histone deacetylase inhibitor (HDACi) chidamide (CDM), aspirin significantly suppresses the VEGF signaling pathway with increased ROS overgeneration and EBV inhibition. We also showed that with the addition of chidamide, aspirin significantly suppresses NKTCL tumor growth in both in vitro cell culture and in vivo mouse model with prolonged mouse survival. This is the first time that the potential mechanism for aspirin-mediated VEGF suppression and anti-tumor effect has been discovered, and this study provides a new strategy for anti-tumor drug development for NKTCL treatment based on aspirin-mediated targeting of the VEGF signaling pathway and ROS formation.
    Keywords:  NKTCL; aspirin; epstein-barr virus; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3389/fonc.2018.00679
  49. Invest Ophthalmol Vis Sci. 2019 Feb 01. 60(2): 500-516
    Characterization and Regulation of Carrier Proteins of Mitochondrial Glutathione Uptake in Human Retinal Pigment Epithelium Cells.
    Mo Wang, Lin-Ing Lau, Parameswaran G Sreekumar, Christine Spee, David R Hinton, Srinivas R Sadda, Ram Kannan.
      Purpose: To characterize two mitochondrial membrane transporters 2-oxoglutarate (OGC) and dicarboxylate (DIC) in human RPE (hRPE) and to elucidate their role in the regulation of mitochondrial glutathione (mGSH) uptake and cell death in oxidative stress.Methods: The localization of OGC and DIC proteins in confluent hRPE, polarized hRPE monolayers and mouse retina was assessed by immunoblotting and confocal microscopy. Time- and dose-dependent expression of the two carriers were determined after treatment of hRPE with H2O2, phenyl succinate (PS), and butyl malonate (BM), respectively, for 24 hours. The effect of inhibition of OGC and DIC on apoptosis (TUNEL), mGSH, and mtDNA was determined. Silencing of OGC by siRNA knockdown on RPE cell death was studied. Kinetics of caspase 3/7 activation with OGC and DIC inhibitors and effect of cotreatment with glutathione monoethyl ester (GSH-MEE) was determined using the IncuCyte live cell imaging.
    Results: OGC and DIC are expressed in hRPE mitochondria and exhibited a time- and dose-dependent decrease with stress. Pharmacologic inhibition caused a decrease in OGC and DIC in mitochondria without changes in mtDNA and resulted in increased apoptosis and mGSH depletion. GSH-MEE prevented apoptosis through restoration of mGSH. OGC siRNA exacerbated apoptotic cell death in stressed RPE which was inhibited by increased mGSH from GSH-MEE cotreatment.
    Conclusions: Characterization and mechanism of action of two carrier proteins of mGSH uptake in RPE are reported. Regulation of OGC and DIC will be of value in devising therapeutic strategies for retinal disorders such as AMD.
    DOI:  https://doi.org/10.1167/iovs.18-25686
  50. Anticancer Drugs. 2019 Jan 29.
    Sinensetin induces apoptosis and autophagy in the treatment of human T-cell lymphoma.
    Kok-Tong Tan, Meng-Xian Lin, Shih-Chao Lin, Yu-Tang Tung, Sheng-Hao Lin, Chi-Chien Lin.
      The present study was carried out to explore the effect of sinensetin in human T-cell lymphoma Jurkat cells and to reveal the underlying molecular mechanisms. We found that sinensetin significantly impeded Jurkat cell proliferation in a dose-dependent and time-dependent manner. Additionally, sinensetin treatment triggered apoptosis and autophagy in Jurkat cells. The apoptosis induction was related to a loss of mitochondrial membrane potential and to increased caspase-3/-8/-9 and poly(ADP-ribose) polymerase (PARP) cleavage. Sinensetin also induced autophagy, as evidenced by the formation of acidic vacuoles, the upregulation of LC3-II and beclin-1, and the downregulation of p62. In addition, the inhibition of autophagy by 3-methyladenine significantly enhanced the apoptosis rate and improved the sensitivity of the Jurkat cells to sinensetin. Moreover, sinensetin induced cell death, apoptosis, and autophagy through the activation of the reactive oxygen species/ c-Jun N-terminal kinase signaling pathway and the inhibition of the Akt/mTOR signaling pathways. In summary, our results revealed that sinensetin induced apoptosis and autophagy in human T-cell lymphoma Jurkat cells by activating reactive oxygen species/ c-Jun N-terminal kinase and blocking the Akt/mTOR signaling pathways. Thus, sinensetin might be a potential candidate in the development of antitumor drugs targeting T-cell leukemia.
    DOI:  https://doi.org/10.1097/CAD.0000000000000756
  51. Front Plant Sci. 2018 ;9 1928
    Programmed Cell Death and Aerenchyma Formation in Water-Logged Sunflower Stems and Its Promotion by Ethylene and ROS.
    Xi-Lu Ni, Meng-Yuan Gui, Ling-Ling Tan, Qiang Zhu, Wen-Zhe Liu, Chang-Xiao Li.
      Previous studies have shown that waterlogging/ hypoxic conditions induce aerenchyma formation to facilitate gas exchange. Ethylene (ET) and reactive oxygen species (ROS), as regulatory signals, might also be involved in these adaptive responses. However, the interrelationships between these signals have seldom been reported. Herein, we showed that programmed cell death (PCD) was involved in aerenchyma formation in the stem of Helianthus annuus. Lysigenous aerenchyma formation in the stem was induced through waterlogging (WA), ethylene and ROS. Pre-treatment with the NADPH oxidase inhibitor diphenyleneiodonium (DPI) partially suppressed aerenchyma formation in the seedlings after treatment with WA, ET and 3-amino-1, 2, 4-triazole (AT, catalase inhibitor). In addition, pre-treatment with the ethylene perception inhibitor 1-methylcyclopropene (1-MCP) partially suppressed aerenchyma formation induced through WA and ET in the seedlings, but barely inhibited aerenchyma formation induced through ROS. These results revealed that ethylene-mediated ROS signaling plays a role in aerenchyma formation, and there is a causal and interdependent relationship during WA, ET and ROS in PCD, which regulates signal networks in the stem of H. annuus.
    Keywords:  Ethylene; Helianthus annuus; aerenchyma; programmed cell death; reactive oxygen species; waterlogging
    DOI:  https://doi.org/10.3389/fpls.2018.01928
  52. Neurotoxicology. 2019 Jan 28. pii: S0161-813X(18)30482-0. [Epub ahead of print]
    Modulation Of Caspase-3 Gene Expression And Protective Effects Of Garlic And Spirulina Against CNS Neurotoxicity Induced By Lead Exposure In Male Rats.
    Mona K Galal, Ebtihal M M Elleithy, Mohamed I Abdrabou, Noha A E Yasin, Youssef M Shaheen.
      Lead (Pb) is a ubiquitous environmental and industrial pollutant with worldwide health problems. The present study was designed to investigate the neurotoxic effects of Pb in albino rats and to evaluate the ameliorative role of garlic as well as Spirulina maxima against such toxic effects. Forty adult male rats were used in this investigation (10 rats/group). Group I: served as control, Group II: rats received lead acetate (100 mg/kg), Group III: rats received both lead acetate (100 mg/kg) and garlic (600 mg/kg) and Group IV: rats received both lead acetate (100 mg/kg) and spirulina (500 mg/kg) daily by oral gavage for one month. Exposure to Pb acetate adversely affected the measured acetyl cholinesterase enzyme activity, oxidative stress and lipid peroxidation parameters as well as caspase-3 gene expression in brain tissue (cerebrum and cerebellum). Light and electron microscopical examination of the cerebrum and cerebellum showed various lesions after exposure to Pb which were confirmed by immunohistochemistry. On the other hand, administration of garlic and spirulina concomitantly with lead acetate ameliorated most of the undesirable effects. It could be concluded that, the adverse effects induced by lead acetate, were markedly ameliorated by co-treatment with S. maxima more than garlic.
    Keywords:  Apoptosis; Garlic; Histopathology; Lead acetate; Oxidative stress; Spirulina
    DOI:  https://doi.org/10.1016/j.neuro.2019.01.006
  53. J Cell Mol Med. 2019 Jan 31.
    FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway.
    Leilei Yin, Yingying Fang, Tao Song, Dan Lv, Zheng Wang, Li Zhu, Zihui Zhao, Xinhua Yin.
      Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)-induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)-induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC β2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte-specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC β2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.
    Keywords:  Apoptosis; Diabetic cardiomyopathy; FBXL10; Inflammation; PKC β2; oxidative stress
    DOI:  https://doi.org/10.1111/jcmm.14146
  54. J Cell Physiol. 2019 Jan 30.
    MicroRNA-128 confers protection against cardiac microvascular endothelial cell injury in coronary heart disease via negative regulation of IRS1.
    Ping Yan, Chen Sun, Jiale Ma, Zhigang Jin, Rui Guo, Bin Yang.
      OBJECTIVE: Cardiac microvascular endothelial cells (CMECs) play a critical role in the physiological regulation of coronary blood flow and its dysfunction is associated with myocardium ischemic injury. This study was performed to clarify the effect of microRNA-128 (miR-128) on the CMEC injury in coronary heart disease (CHD) by binding to insulin receptor substrate 1 (IRS1).METHODS: The rat CMECs were cultured by explant culture method and identified by CD31 immunofluorescence assay. CMECs were treated with homocysteine (Hcy), which underwent stress of CHD, followed by treatment of miR-128 mimics/inhibitors or IRS1 siRNA. Expression of miR-128, IRS1, and vascular endothelial growth factor (VEGF) was determined. The viability, apoptosis, migration ability, and tube formation ability of CMECs were evaluated. The superoxide dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS) of CMECs were evaluated, respectively.
    RESULTS: In rat CMECs, miR-128 was poorly expressed and IRS1 was highly expressed. Notably, miR-128 targeted and negatively regulated IRS1. Additionally, the treatment with Hcy in CMECs led to reduced viability, migration ability, tube formation, VEGF expression, SOD activity as well as increased cell apoptosis, MDA and ROS levels. The experimental results demonstrated that miR-128 mimics and IRS1 siRNA in rat CMECs promoted viability, migration ability, tube formation, VEGF expression, SOD activity, while repressing cell apoptosis, MDA and ROS levels. MiR-128 inhibitors could reverse the tendencies.
    CONCLUSION: Collectively, our study provides evidence that miR-128 targeted and negatively regulated IRS1 expression, whereby the functional injury of CMECs induced by Hcy was ameliorated. Furthermore, protection of miR-128 was stimulated by reducing oxidative stress.
    Keywords:  cardiac microvascular endothelial cell; coronary heart disease; homocysteine; injury; insulin receptor substrate 1; microRNA-128; oxidative stress; viability
    DOI:  https://doi.org/10.1002/jcp.28025
  55. Angew Chem Int Ed Engl. 2019 Jan 28.
    Restraining Cancer Cells by Dual-Metabolic Inhibitions with a Mitochondrion-Targeted Platinum(II) Complex.
    Kun Wang, Chengcheng Zhu, Yafeng He, Zhenqin Zhang, Wen Zhou, Nafees Muhammad, Yan Guo, Xiaoyong Wang, Zijian Guo.
      Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibits enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent way, and shows preferential inhibition on mitochondrial TrxR. The morphology and function of mitochondria are severely damaged, and the levels of mitochondrial and cellular reactive oxygen species are decreased. As a result, TTP exerts strong inhibition to both mitochondrial and glycolytic bioenergetics, inducing cancer cells to enter into a hypometabolic state.
    Keywords:  anticancer drug; metabolism; mitochondrion; platinum(II) complex; thioredoxin reductase
    DOI:  https://doi.org/10.1002/anie.201900387
  56. Eur J Pharmacol. 2019 Jan 25. pii: S0014-2999(19)30047-0. [Epub ahead of print]
    Dietary protocatechuic acid abrogates male reproductive dysfunction in streptozotocin-induced diabetic rats via suppression of oxidative damage, inflammation and caspase-3 activity.
    Isaac A Adedara, Edozie S Okpara, Esther O Busari, Olubunmi Omole, Solomon E Owumi, Ebenezer O Farombi.
      Clinical and experimental studies demonstrated that reproductive dysfunction is a non-lethal complication of diabetes. Protocatechuic acid (PCA) reportedly elicited several pharmacological effects in diabetic animals. However, there is paucity of information on the role of PCA in reproductive dysfunction associated with diabetes. The present study investigated the influence of PCA on the functional changes along the hypothalamic-pituitary-testicular axis in male diabetic rats. Streptozotocin (STZ)-induced diabetic rats were orally treated with PCA at 25 and 50mg/kg body weight for 45 consecutive days. Results showed that PCA treatment significantly dwindled blood glucose level as well as prevented diabetes mediated decrease in body weight gain and organo-somatic indices of the testes and epididymis in the treated rats.Moreover, PCA increased the reproductive hormone levels, marker enzymes of testicular function and sperm functional characteristics in the treated rats. Further, PCA augmented the antioxidant status, inhibited lipid peroxidation and suppressed pro-inflammatory biomarkers including myeloperoxidase (MPO) activity, nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) levels as well as caspase-3 activity inhypothalamus, testes and epididymis of diabetic rats. Collectively, PCA effectively abrogated reproductive deficits in diabetic rats via mechanisms involving suppression of oxidative stress, inflammation and caspase-3 activity along with enhancement of sperm functional parameters. Thus, PCA may preserve reproductive health in humans suffering from diabetes.
    Keywords:  Diabetes; antioxidant; inflammation; protocatechuic acid; reproductive dysfunction
    DOI:  https://doi.org/10.1016/j.ejphar.2019.01.033
  57. BMC Complement Altern Med. 2019 Jan 28. 19(1): 30
    Protective effects of Camellia japonica flower extract against urban air pollutants.
    Minkyung Kim, Dahee Son, Seoungwoo Shin, Deokhoon Park, Sangyo Byun, Eunsun Jung.
      BACKGROUND: Exposure of skin to urban air pollutants is closely related to skin aging and inflammatory responses such as wrinkles formation, pigmentation spot, atopic dermatitis, and acne. Thus, a great deal of interest has been focused on the development of natural resources that can provide a protective effect to skin from pollutants.METHODS: The antioxidative activity of Camellia japonica flower extract (CJFE) was evaluated by 1,2-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) assay, and the inhibitory effect of CJFE by urban air pollutants-induced reactive oxygen species (ROS) production was determined in cultured normal human dermal fibroblasts (NHDFs). We additionally investigated the protective effects of CJFE against urban air pollutant using in vitro and ex vivo model.
    RESULTS: CJFE with high phenolic concentration showed antioxidative activity on scavenging capacity of 1,2-diphenyl-2-picrylhydrazyl (DPPH) radicals and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical cation in a concentration dependent manner. CJFE inhibited urban air pollutants-induced ROS generation, matrixmetalloproteinase-1 (MMP-1) production and a xenobiotic response element (XRE)-luciferase activity indicating the aryl hydrocarbon receptor (AhR) transactivation. In addition, CJFE showed an excellent protective activity against pollutants-induced deteriorating effect in ex vivo model. CJFE reduced the level of pollutants-induced malondialdehyde (MDA), lipid peroxidation marker, inhibited MMP-1 expression and increased collagen synthesis. It also reduced the cell numbers with pyknotic nuclei (mainly occurring in apoptosis) and detachment of dermo-epidermal junction (DEJ) induced by pollutants.
    CONCLUSIONS: Apparently, it is proposed that CJFE can be used as a protective material against pollutant-induced skin damages.
    Keywords:  Anti-aging; Anti-pollution; Antioxidant; Camellia japonica; Urban dust
    DOI:  https://doi.org/10.1186/s12906-018-2405-4
  58. Front Aging Neurosci. 2018 ;10 428
    Royal Jelly Alleviates Cognitive Deficits and β-Amyloid Accumulation in APP/PS1 Mouse Model Via Activation of the cAMP/PKA/CREB/BDNF Pathway and Inhibition of Neuronal Apoptosis.
    Mengmeng You, Yongming Pan, Yichen Liu, Yifan Chen, Yuqi Wu, Juanjuan Si, Kai Wang, Fuliang Hu.
      Alzheimer's disease (AD) is characterized clinically by progressive cognitive decline and pathologically by the accumulation of amyloid-β (Aβ) in the brain. Royal jelly (RJ), a secretion of honeybee hypopharyngeal and mandibular glands, has previously been shown to have anti-aging and neuromodulatory activities. In this study, we discovered that 3 months of RJ treatment substantially ameliorated behavioral deficits of APP/PS1 mice in the Morris Water Maze (MWM) test and step-down passive avoidance test. Our data also showed that RJ significantly diminished amyloid plaque pathology in APP/PS1 mice. Furthermore, RJ alleviated c-Jun N-terminal kinase (JNK) phosphorylation-induced neuronal apoptosis by suppressing oxidative stress. Importantly, hippocampal cyclic adenosine monophosphate (cAMP), p-PKA, p-CREB and BDNF levels were significantly increased in the APP/PS1 mice after RJ treatment, indicating that the cAMP/PKA/CREB/BDNF pathway might be related to the ameliorative effect of RJ on cognitive decline. Collectively, these results provide a scientific basis for using RJ as a functional food for targeting AD pathology.
    Keywords:  Alzheimer’s disease; amyloid-β; apoptosis; cAMP-response element binding protein; cognitive deficits; royal jelly
    DOI:  https://doi.org/10.3389/fnagi.2018.00428
  59. Int J Mol Sci. 2019 Jan 31. pii: E613. [Epub ahead of print]20(3):
    TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model.
    Jun Hee Lee, Yeo Min Yoon, Sang Hun Lee.
      Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.
    Keywords:  anti-oxidant; chronic kidney disease; endoplasmic reticulum stress; mesenchymal stem cells; tauroursodeoxycholic acid
    DOI:  https://doi.org/10.3390/ijms20030613
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:17:55.