bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019–05–05
fifty-four papers selected by
Gavin McStay, Staffordshire University
  1. Involvement of NADPH-oxidase enzyme in the nephroprotective effect of (-)-α-bisabolol on HK2 cells exposed to ischemia - Reoxygenation.
  2. Costunolide Inhibits the Growth of OAW42-A Multidrug-Resistant Human Ovarian Cancer Cells by Activating Apoptotic and Autophagic Pathways, Production of Reactive Oxygen Species (ROS), Cleaved Caspase-3 and Cleaved Caspase-9.
  3. SCM-198 protects endometrial stromal cells from oxidative damage through Bax/Bcl-2 and ERK signaling pathways.
  4. NADPH Oxidase Isoforms Are Involved in Glucocorticoid-Induced Preosteoblast Apoptosis.
  5. Antitumor Effects of Chrysophanol in Malignant Optic Nerve Meningioma Cell Lines are Mediated via Caspase Activation, Induction of Mitochondrial Mediated Apoptosis, Mitochondrial Membrane Depolarization and Targeting the Mitogen-Activated Protein Kinase Signaling Pathway.
  6. Repurposing the Electron Transfer Reactant Phenazine Methosulfate (PMS) for the Apoptotic Elimination of Malignant Melanoma Cells through Induction of Lethal Oxidative and Mitochondriotoxic Stress.
  7. MiR-455-5p ameliorates HG-induced apoptosis, oxidative stress and inflammatory via targeting SOCS3 in retinal pigment epithelial cells.
  8. β3-Adrenoreceptor Activity Limits Apigenin Efficacy in Ewing Sarcoma Cells: A Dual Approach to Prevent Cell Survival.
  9. Biotin attenuation of oxidative stress, mitochondrial dysfunction, lipid metabolism alteration and 7β-hydroxycholesterol-induced cell death in 158N murine oligodendrocytes.
  10. Discovery of the theobromine derivative MQS-14 that induces death of MGC-803 cells mainly through ROS-mediated mechanisms.
  11. [The oxLDL/β2GPI/anti-β2GPI antibody complex induces apoptosis of human umbilical vein endothelial cells by promoting the production of reactive oxygen species].
  12. Melatonin protects rabbit spermatozoa from cryo-damage via decreasing oxidative stress.
  13. Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells.
  14. Reactive oxygen species mediate the chemopreventive effects of syringin in breast cancer cells.
  15. Flavonoid morin inhibits proliferation and induces apoptosis of melanoma cells by regulating reactive oxygen species, Sp1 and Mcl-1.
  16. Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways.
  17. Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-κB/NLRP3 inflammasome activation and up-regulating Nrf2/ARE/HO-1 signaling.
  18. Cytotoxicity of ungeremine towards multi-factorial drug resistant cancer cells and induction of apoptosis, ferroptosis, necroptosis and autophagy.
  19. Conformational and functional effects of MPA-CdTe quantum dots on SOD: Evaluating the mechanism of oxidative stress induced by quantum dots in the mouse nephrocytes.
  20. Norepinephrine protects against apoptosis of mesenchymal stem cells induced by high glucose.
  21. Sophoraflavanone G from Sophora flavescens induces apoptosis in triple-negative breast cancer cells.
  22. Protective Effects of Kaempferol on D-Ribose-Induced Mesangial Cell Injury.
  23. Selenepezil, a selenium-containing compound, exerts neuroprotective effect via modulation of Keap1-Nrf2-ARE pathway and attenuates Aβ-induced cognitive impairment in vivo.
  24. Melatonin protects circulatory death heart from ischemia/reperfusion injury via the JAK2/STAT3 signalling pathway.
  25. Protective effects of pyrroloquinoline quinine against oxidative stress-induced cellular senescence and inflammation in human renal tubular epithelial cells via Keap1/Nrf2 signaling pathway.
  26. MiR-153 regulates cardiomyocyte apoptosis by targeting Nrf2/HO-1 signaling.
  27. Silver Nanoparticles Induced Cell Apoptosis, Membrane Damage of Azotobacter vinelandii and Nitrosomonas europaea via Generation of Reactive Oxygen Species.
  28. The characteristics of the ancient cell death suppressor, TMBIM6, and its related signaling pathways after endoplasmic reticulum stress.
  29. Effect of ginsenoside Rh2 on renal apoptosis in cisplatin-induced nephrotoxicity in vivo.
  30. Epigallocatechin gallate prevents mitochondrial impairment and cell apoptosis by regulating miR-30a/p53 axis.
  31. Triclosan-induced liver injury in zebrafish (Danio rerio) via regulating MAPK/p53 signaling pathway.
  32. Effective and new potent drug combination: Histone deacetylase and Wnt/β-catenin pathway inhibitors in lung carcinoma cells.
  33. Fas/FasL-mediated cell death in rat's diabetic hearts involves activation of calcineurin/NFAT4 and is potentiated by a high-fat diet rich in corn oil.
  34. Ginkgolides B alleviates hypoxia-induced PC-12 cell injury by up-regulation of PLK1.
  35. Heme Oxygenase-1 is a Key Molecule Underlying Differential Response of TW-37-Induced Apoptosis in Human Mucoepidermoid Carcinoma Cells.
  36. Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy.
  37. Dioscin Alleviates Crystalline Silica-Induced Pulmonary Inflammation and Fibrosis through Promoting Alveolar Macrophage Autophagy.
  38. Mechanisms of Cisplatin-Induced Ototoxicity and Prevention.
  39. ROS Generated by Upconversion Nanoparticle-Mediated Photodynamic Therapy Induces Autophagy via PI3K/AKT/ mTOR Signaling Pathway in M1 Peritoneal Macrophage.
  40. Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo.
  41. Time-restricted feeding reduces high-fat diet associated placental inflammation and limits adverse effects on fetal organ development.
  42. Brosimone I, an isoprenoid-substituted flavonoid, induces cell cycle G1 phase arrest and apoptosis through ROS-dependent endoplasmic reticulum stress in HCT116 human colon cancer cells.
  43. Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial-lysosomal crosstalk.
  44. Silymarin protects against radiocontrast-induced nephropathy in mice.
  45. GATA-1 isoforms differently contribute to the production and compartmentation of reactive oxygen species in the myeloid leukemia cell line K562.
  46. The synthetic tubulysin derivative, tubugi-1, improves the innate immune response by macrophage polarization in addition to its direct cytotoxic effects in a murine melanoma model.
  47. Berberine Protects Glomerular Podocytes via Inhibiting Drp1-Mediated Mitochondrial Fission and Dysfunction.
  48. Modulating the Chemical and Biological Properties of Cancer Stem Cell-Potent Copper(II)-Nonsteroidal Anti-Inflammatory Drug Complexes.
  49. Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics.
  50. Supercritical CO2 fluid extraction of croton crassifolius Geisel root: Chemical composition and anti-proliferative, autophagic, apoptosis-inducing, and related molecular effects on A549 tumour cells.
  51. Protective effect of the glucagon-like peptide-1 analogue liraglutide on carbon tetrachloride-induced acute liver injury in mice.
  52. CircPRKCI-miR-545/589-E2F7 axis dysregulation mediates hydrogen peroxide-induced neuronal cell injury.
  53. Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors.
  54. H2Se Induces Reductive Stress in HepG2 Cells and Activates Cell Autophagy by Regulating the Redox of HMGB1 Protein under Hypoxia.
  1. Eur J Pharmacol. 2019 Apr 29. pii: S0014-2999(19)30286-9. [Epub ahead of print]
    Involvement of NADPH-oxidase enzyme in the nephroprotective effect of (-)-α-bisabolol on HK2 cells exposed to ischemia - Reoxygenation.
    Tiago Lima Sampaio, Ramon Róseo Paula Pessoa Bezerra de Menezes, Dânya Bandeira Lima, Rose Anny Costa Silva, Isabella Evelyn Prado de Azevedo, Emanuel Paula Magalhães, Márcia Machado Marinho, Ricardo Pires Dos Santos, Alice Maria Costa Martins.
      Acute Kidney Injury (AKI) is associated with high morbidity and mortality. Ischemia and reperfusion (I/R) are events that lead to AKI through hypoxia, reactive oxygen species (ROS) production, oxidative stress and apoptosis. We aimed to evaluate the mechanism of nephroprotection mediated by Bisabolol in human tubular kidney cells after injury by I/R in vitro. HK2 cells were exposed to I/R and treated with Bisabolol. Cell viability was accessed by MTT assay. Cells were submitted to flow cytometry to evaluate necrotic/apoptotic cells, reactive oxygen species production and mitochondrial transmembrane depolarization. TBARS and GSH were used as parameters of redox balance. Also, KIM-1 supernatant levels were measured. In order to identify an interaction between bisabolol and NOX4, molecular docking and enzymatic assays were performed. Expression of isoform NOX4 on treated cells was examined by western-blot. Finally, cells were visualized by scanning electron microscopy. Bisabolol improved cell viability and prevented cell death by apoptosis, indicated also by the decreased levels of KIM-1. It was observed a decrease on reactive oxygen species production and mitochondrial depolarization, with antioxidant regulation by increased GSH and decreased lipid peroxidation. It was also demonstrated that bisabolol treatment can inhibit NOX4. Finally, SEM images showed that bisabolol reduced I/R-induced cell damage. Bisabolol treatment protects HK2 cells against oxidative damage occasioned by I/R. This effect is related to inhibition of apoptosis, decrease on KIM-1 release, reactive oxygen species accumulation and mitochondrial dysfunction. Bisabolol inhibited NOX4 activity in the tubular cells, impairing reactive oxygen species synthesis.
    Keywords:  Bisabolol; Kidney ischemia/reoxygenation; NADPH oxidase
    DOI:  https://doi.org/10.1016/j.ejphar.2019.04.044
  2. Med Sci Monit. 2019 May 02. 25 3231-3237
    Costunolide Inhibits the Growth of OAW42-A Multidrug-Resistant Human Ovarian Cancer Cells by Activating Apoptotic and Autophagic Pathways, Production of Reactive Oxygen Species (ROS), Cleaved Caspase-3 and Cleaved Caspase-9.
    Yichen Fang, Jie Li, Yinan Wu, Jing Gui, Yang Shen.
      BACKGROUND Worldwide, ovarian cancer has a high mortality rate due to the difficulty in diagnosing early-stage disease and resistance to chemotherapy agents. Costunolide is a plant-derived sesquiterpene lactone with anti-oxidant properties. This study aimed to investigate the effects of costunolide on cell growth, apoptosis, autophagy, the production of reactive oxygen species (ROS), cleaved caspase-3, and cleaved caspase-9 on the multidrug-resistant ovarian cancer cell line, OAW42-A. MATERIAL AND METHODS The MTT assay determined the proliferation rate of OAW42-A multidrug-resistant ovarian cancer cells and the apoptosis rate was determined using propidium iodide (PI) staining. Autophagy was detected by measuring the expression of LC3 II. Fluorescence flow cytometry was used to measure the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. Protein expression of LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9 were measured by Western blot. RESULTS Costunolide treatment inhibited the growth of OAW42-A cells with an IC₅₀ of 25 µM, resulted in apoptotic cell death, increased the expression of Bax, and decreased the expression of Bcl-2. Confocal electron microscopy showed that costunolide induced autophagy in the OAW42-A cells. Western blot showed that costunolide treatment of OAW42-A cells increased the expression of the LC3 II, beclin 1, cleaved caspase-3, and cleaved caspase-9. Costunolide treatment significantly increased the levels of ROS and reduced the OAW42-A cell mitochondrial membrane potential. CONCLUSIONS Costunolide inhibited growth, apoptosis, ROS generation, and was associated with loss of mitochondrial membrane potential of OAW42-A multidrug-resistant ovarian cancer cells.
    DOI:  https://doi.org/10.12659/MSM.914029
  3. Acta Biochim Biophys Sin (Shanghai). 2019 Apr 29. pii: gmz035. [Epub ahead of print]
    SCM-198 protects endometrial stromal cells from oxidative damage through Bax/Bcl-2 and ERK signaling pathways.
    Yunyun Li, Yikong Lin, Xixi Huang, Chunfang Xu, Xinhua Liu, Li Wang, Min Yu, Dajin Li, Yizhun Zhu, Meirong Du.
      Increasing amounts of evidence demonstrated that accumulative reactive oxygen species (ROS) and apoptosis of human endometrial stromal cells (ESCs) are closely associated with endometrial dysfunction induced by oxidative stress, which plays an important role in the pathological process of multiple gynecological and reproduction-related diseases. SCM-198, an alkaloid active component of Leonurus japonicas Houtt, has been reported to have anti-oxidative activity. However, the specific mechanisms of SCM-198 in the prevention of endometrial damage remain unknown. In the present study, we assessed the effect of SCM-198 on hydrogen peroxide (H2O2)-induced oxidative injury in ESCs. ESCs were pretreated with SCM-198 for 4 h and then challenged with H2O2. Morphology changes, apoptosis rate, and intracellular ROS production were measured to assess the level of oxidative injury. Flow cytometry and western blot analysis were performed to detect the expression levels of Bax, Bcl-2, active-caspase-3, and mitogen-activated protein kinases pathways. Classic inflammation cytokines were measured by real-time polymerase chain reactions. Our results showed that SCM-198 attenuated apoptosis and ROS generation of ESCs induced by H2O2. H2O2 induced the apparent apoptotic characteristics, including fragmentation of DNA, upregulation of Bax/Bcl2, activation of caspase-3, and secretion of inflammation cytokines, which were all ameliorated by SCM-198. Furthermore, H2O2-induced apoptosis-related ERK1/2 pathway activation was restrained by SCM-198 pretreatment. These findings suggested that SCM-198 could protect ESCs from oxidative injury, mainly by inhibiting oxidative stress and reducing apoptosis.
    Keywords:  SCM-198; endometrial stromal cell; hydrogen peroxide; oxidative stress
    DOI:  https://doi.org/10.1093/abbs/gmz035
  4. Oxid Med Cell Longev. 2019 ;2019 9192413
    NADPH Oxidase Isoforms Are Involved in Glucocorticoid-Induced Preosteoblast Apoptosis.
    Shu-Cai Bai, Qian Xu, Hui Li, Ya-Fei Qin, Li-Cheng Song, Chen-Guang Wang, Wen-Hao Cui, Zhi Zheng, De-Wen Yan, Zhi-Jun Li, Dong Li, Xin Wan, Hua-Feng Zhang.
      Oxidative stress induced by long-term glucocorticoid (GC) use weakens the repair capacity of bone tissue. Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase (NOX) is a superoxide-generating enzyme that plays an important role in regulating bone metabolism. To clarify the role of nonphagocytic NOX isoforms in osteoblast reactive oxygen species (ROS) generation and apoptosis, dexamethasone was used to establish a high-dose GC environment in vitro. A dose-dependent increase in intracellular ROS generation was demonstrated, which was accompanied by increased osteoblastic MC3T3-E1 cell apoptosis. Addition of the ROS inhibitor NAC (N-acetyl-L-cysteine) or NOX inhibitor DPI (diphenyleneiodonium) reversed this effect, indicating that NOX-derived ROS can induce osteoblast apoptosis under high-dose dexamethasone stimulation. NOX1, NOX2, and NOX4 are NOX homologs recently identified in bone tissue. To clarify the NOX isoforms that play a role in osteoblast ROS generation, Nox1, Nox2, and Nox4 mRNA expression and NOX2 and NOX4 protein expression were analyzed. Nox1 and Nox4 mRNA expression was elevated in a dose-dependent manner after culture in 100 nM, 250 nM, 500 nM, or 1000 nM dexamethasone, and the increased expression of NOX1 mRNA was more significant compared with NOX4 mRNA. Small interfering RNAs (siRNAs) were used to confirm the role of NOX1 and NOX4 in ROS generation. To clarify the signaling pathway in ROS-induced osteoblast apoptosis, mitogen-activated protein kinase (MAPK) signaling molecules were analyzed. Phosphorylated ASK1 and p38 levels were significantly higher in the 1000 nM dexamethasone group, which NAC or DPI markedly attenuated. However, the total mRNA and protein levels of ASK1 and p38 between the dexamethasone group and control were not significantly different. This is related to ROS regulating the posttranslational modification of ASK1 and p38 in MC3T3-E1 cell apoptosis. Altogether, NOX1- and NOX4-derived ROS plays a pivotal role in high-dose dexamethasone-induced preosteoblast apoptosis by increasing phosphorylated ASK1 and p38 and may be an important mechanism in steroid-induced avascular necrosis of the femoral head (SANFH).
    DOI:  https://doi.org/10.1155/2019/9192413
  5. Pharmacology. 2019 Apr 30. 104(1-2): 28-35
    Antitumor Effects of Chrysophanol in Malignant Optic Nerve Meningioma Cell Lines are Mediated via Caspase Activation, Induction of Mitochondrial Mediated Apoptosis, Mitochondrial Membrane Depolarization and Targeting the Mitogen-Activated Protein Kinase Signaling Pathway.
    Changhong Zeng, Bo Guo, Jun Chen, Weimin He.
       BACKGROUND: Anthroquinones are considered remarkable anticancer agents. Chrysophanol is an important anthroquinone and it has shown to have the potential to inhibit the growth of the range of cancers. However, there are no studies regarding the anticancer effects of chrysophanol against the malignant meningioma of optic nerve. In this review, the potential of chrysophanol in the treatment of malignant -meningioma of optic nerve was explored by evaluating its anticancer activity against the malignant meningioma CH157-MN cells.
    MATERIALS AND METHODS: The 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay was used for cell viability determination. The 4',6-diamidino-2-phenylindole (DAPI), acridine orange and ethidium bromide (AO/EB) and annexin V/PI assays were used to determine the induction of apoptosis. The potential of reactive oxygen species and the mitochondrial membrane was estimated by flow cytometry. Western blot analysis was performed to determine the protein expression.
    RESULTS: The results showed that chrysophanol caused significant decline in the viability of the CH157-MN cells and exhibited an IC50 of 30 µmol/L. Anticancer effects were found to be due to the induction of apoptosis as evident form the DAPI and AO/EB staining. The annexin V/PI staining revealed that the apoptotic cells increased from 1.77% in control to 37.21% at 60 µmol/L concentration of chrysophanol. The Bcl-2/Bax expression ratio was decreased and the caspases-3 and 9 were activated upon chrysophanol treatment of the CH157-MN cells. Chrysophanol also triggered the formation of reactive oxygen species and reduction of the mitochondrial membrane potential in the CH157-MN cells and also blocked the Mitogen-activated protein kinase signaling pathway.
    CONCLUSION: The findings of the present study suggest that chrysophanol may prove beneficial in the treatment of malignant meningioma of optic nerve. Key Message: The study revealed the anticancer potential of chrysophanol against the malignant optic nerve meningioma.
    Keywords:  Anthroquinone; Apoptosis; Chrysophanol; Meningioma
    DOI:  https://doi.org/10.1159/000499336
  6. Cancers (Basel). 2019 Apr 27. pii: E590. [Epub ahead of print]11(5):
    Repurposing the Electron Transfer Reactant Phenazine Methosulfate (PMS) for the Apoptotic Elimination of Malignant Melanoma Cells through Induction of Lethal Oxidative and Mitochondriotoxic Stress.
    Anh B Hua, Rebecca Justiniano, Jessica Perer, Sophia L Park, Hui Li, Christopher M Cabello, Georg T Wondrak.
      Redox-directed pharmacophores have shown potential for the apoptotic elimination of cancer cells through chemotherapeutic induction of oxidative stress. Phenazine methosulfate (PMS), a N-alkylphenazinium cation-based redox cycler, is used widely as an electron transfer reactant coupling NAD(P)H generation to the reduction of tetrazolium salts in biochemical cell viability assays. Here, we have explored feasibility of repurposing the redox cycler PMS as a superoxide generating chemotherapeutic for the pro-oxidant induction of cancer cell apoptosis. In a panel of malignant human melanoma cells (A375, G361, LOX), low micromolar concentrations of PMS (1-10 μM, 24 h) displayed pronounced apoptogenicity as detected by annexin V-ITC/propidium iodide flow cytometry, and PMS-induced cell death was suppressed by antioxidant (NAC) or pan-caspase inhibitor (zVAD-fmk) cotreatment. Gene expression array analysis in A375 melanoma cells (PMS, 10 µM; 6 h) revealed transcriptional upregulation of heat shock (HSPA6, HSPA1A), oxidative (HMOX1) and genotoxic (EGR1, GADD45A) stress responses, confirmed by immunoblot detection demonstrating upregulation of redox regulators (NRF2, HO-1, HSP70) and modulation of pro- (BAX, PUMA) and anti-apoptotic factors (Bcl-2, Mcl-1). PMS-induced oxidative stress and glutathione depletion preceded induction of apoptotic cell death. Furthermore, the mitochondrial origin of PMS-induced superoxide production was substantiated by MitoSOX-Red live cell fluorescence imaging, and PMS-induced mitochondriotoxicity (as evidenced by diminished transmembrane potential and oxygen consumption rate) was observable at early time points. After demonstrating NADPH-driven (SOD-suppressible) superoxide radical anion generation by PMS employing a chemical NBT reduction assay, PMS-induction of oxidative genotoxic stress was substantiated by quantitative Comet analysis that confirmed the introduction of formamido-pyrimidine DNA glycosylase (Fpg)-sensitive oxidative DNA lesions in A375 melanoma cells. Taken together, these data suggest feasibility of repurposing the biochemical reactant PMS as an experimental pro-oxidant targeting mitochondrial integrity and redox homeostasis for the apoptotic elimination of malignant melanoma cells.
    Keywords:  cancer; experimental therapeutic; melanoma; oxidative stress; phenazine methosulfate; reactive oxygen species; redox cycler
    DOI:  https://doi.org/10.3390/cancers11050590
  7. J Cell Physiol. 2019 Apr 30.
    MiR-455-5p ameliorates HG-induced apoptosis, oxidative stress and inflammatory via targeting SOCS3 in retinal pigment epithelial cells.
    Pan Chen, Ying Miao, PuJun Yan, Xiao Jie Wang, ChunXia Jiang, Yi Lei.
      Diabetic retinopathy (DR) remains the leading cause of blindness in adults with diabetes mellitus. Numerous microRNAs (miRNAs) have been identified to modulate the pathogenesis of DR. The main purpose of this study was to evaluate the potential roles of miR-455-5p in high glucose (HG)-treated retinal pigment epithelial (RPE) cells and underlying mechanisms. Our present investigation discovered that the expression of miR-455-5p was apparently downregulated in ARPE-19 cells stimulated with HG. In addition, forced expression of miR-455-5p markedly enhanced cell viability and restrained HG-induced apoptosis accompanied by decreased BCL2-associated X protein (Bax)/B-cell leukemia/lymphoma 2 (Bcl-2) ratio and expression of apoptotic marker cleaved caspase-3 during HG challenged. Subsequently, augmentation of miR-455-5p remarkably alleviated HG-triggered oxidative stress injury as reflected by decreased the production of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content as well as NADPH oxidase 4 expression, concomitant with enhanced the activities of superoxide dismutase, catalase, and GPX stimulated with HG. Furthermore, enforced expression of miR-455-5p effectively ameliorated HG-stimulated inflammatory response as exemplified by repressing the secretion of inflammatory cytokines interleukin 1β (IL-1β), IL-6, and tumour necrosis factor-α in ARPE-19 cells challenged by HG. Most importantly, we successfully identified suppressor of cytokine signaling 3 (SOCS3) as a direct target gene of miR-455-5p, and miR-455-5p negatively regulated the expression of SOCS3. Mechanistically, restoration of SOCS3 abrogated the beneficial effects of miR-455-5p on apoptosis, accumulation of ROS, and inflammatory factors production in response to HG. Taken together, these findings demonstrated that miR-455-5p relieved HG-induced damage through repressing apoptosis, oxidant stress, and inflammatory response by targeting SOCS3. The study gives evidence that miR-455-5p may serve as a new potential therapeutic agent for DR treatment.
    Keywords:  MiR-455-5p; SOCS3; apoptosis; diabetic retinopathy; inflammatory response; oxidative stress
    DOI:  https://doi.org/10.1002/jcp.28755
  8. Int J Mol Sci. 2019 Apr 30. pii: E2149. [Epub ahead of print]20(9):
    β3-Adrenoreceptor Activity Limits Apigenin Efficacy in Ewing Sarcoma Cells: A Dual Approach to Prevent Cell Survival.
    Amada Pasha, Marina Vignoli, Angela Subbiani, Alessio Nocentini, Silvia Selleri, Paola Gratteri, Annalisa Dabraio, Tommaso Casini, Luca Filippi, Ilaria Fotzi, Claudio Favre, Maura Calvani.
      Ewing Sarcoma (ES) is an aggressive paediatric tumour where oxidative stress and antioxidants play a central role in cancer therapy response. Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression. Flavonoid intake can affect free radical and nutritional status in children receiving cancer treatment, but it is not clear if it can arrest cancer progression. In particular, apigenin may enhance the effect of cytotoxic chemotherapy by inducing cell growth arrest, apoptosis, and by altering the redox state of the cells. Little is known about the use of apigenin in paediatric cancer. Recently, β3-adrenergic receptor (β3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS. In this study we show that apigenin induces cell death in ES cells by modulating apoptosis, but not increasing ROS content. Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of β3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying β3-AR as a potential discriminating factor that could address the use of apigenin in ES.
    Keywords:  Ewing Sarcoma; apigenin; β3-adrenoreceptor
    DOI:  https://doi.org/10.3390/ijms20092149
  9. Free Radic Res. 2019 May 01. 1-11
    Biotin attenuation of oxidative stress, mitochondrial dysfunction, lipid metabolism alteration and 7β-hydroxycholesterol-induced cell death in 158N murine oligodendrocytes.
    Randa Sghaier, Amira Zarrouk, Thomas Nury, Badreddine Ilham, Nora O'Brien, John J Mackrill, Anne Vejux, Mohammad Samadi, Boubker Nasser, Claudio Caccia, Valerio Leoni, Thibault Moreau, Mustapha Cherkaoui-Malki, Ahmed Salhedine Masmoudi, Gérard Lizard.
      Mitochondrial dysfunction and oxidative stress are involved in neurodegenerative diseases associated with an enhancement of lipid peroxidation products such as 7β- hydroxycholesterol (7β-OHC). It is therefore important to study the ability of 7β-OHC to trigger mitochondrial defects, oxidative stress, metabolic dysfunctions and cell death, which are hallmarks of neurodegeneration, and to identify cytoprotective molecules. The effects of biotin were evaluated on 158N murine oligodendrocytes, which are myelin synthesizing cells, exposed to 7β-OHC (50 µM) with or without biotin (10 and 100 nM) or α-tocopherol (positive control of cytoprotection). The effects of biotin on 7β-OHC activities were determined using different criteria: cell adhesion; plasma membrane integrity; redox status. The impact on mitochondria was characterized by the measurement of transmembrane mitochondrial potential (ΔΨm), reactive oxygen species (ROS) overproduction, mitochondrial mass, quantification of cardiolipins and organic acids. Sterols and fatty acids were also quantified. Cell death (apoptosis, autophagy) was characterized by the numeration of apoptotic cells, caspase-3 activation, identification of autophagic vesicles, and activation of LC3-I into LC3-II. Biotin attenuates 7β-OHC-induced cytotoxicity: loss of cell adhesion was reduced; antioxidant activities were normalized. ROS overproduction, protein and lipid oxidation products were decreased. Biotin partially restores mitochondrial functions: attenuation of the loss of ΔΨm; reduced levels of mitochondrial O2•- overproduction; normalization of cardiolipins and organic acid levels. Biotin also normalizes cholesterol and fatty acid synthesis, and prevents apoptosis and autophagy (oxiapoptophagy). Our data support that biotin, which prevents oligodendrocytes damages, could be useful in the treatment of neurodegeneration and demyelination.
    Keywords:  158N oligodendrocytes; 7β-hydroxycholesterol; apoptosis; autophagy; biotin; lipid metabolism; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1080/10715762.2019.1612891
  10. Eur J Med Chem. 2019 Apr 17. pii: S0223-5234(19)30362-9. [Epub ahead of print]174 76-86
    Discovery of the theobromine derivative MQS-14 that induces death of MGC-803 cells mainly through ROS-mediated mechanisms.
    Ting Ma, Qi-Sheng Ma, Bin Yu, Hong-Min Liu.
      Reactive oxygen species (ROS) play crucial roles in maintaining redox balance and regulating physiological processes, ROS levels in cancer cells are relatively higher than those in normal cells. Therefore, elevating cellular ROS levels may be a viable strategy for selective killing of cancer cells. In this work, we synthesized a series of new theobromine derivatives and evaluated their cytotoxicity against gastric cancer cells MGC-803, SGC-7901 and HGC-27. Particularly, MQS-14 potently inhibited cell growth of MGC-803, SGC-7901 and HGC-27 cells at low micromolar levels. Mechanistic studies showed that compound MQS-14 decreased cell viability of MGC-803 cells and inhibited cell division revealed by the CFDA and EdU staining assays. MQS-14 increased cellular ROS levels and activated the MAPK pathway accompanied by the decreased p-ERK and increased p-JNK expression. MQS-14 also induced DNA damage and apoptosis in MGC-803 cells. To conclude, MQS-14 induced cell death of MGC-803 cells partly through elevating cellular ROS levels.
    Keywords:  Apoptosis; DNA damage; Gastric cancer; MAPK pathway; Reactive oxygen species (ROS); Theobromine
    DOI:  https://doi.org/10.1016/j.ejmech.2019.04.044
  11. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2019 Mar;35(3): 223-229
    [The oxLDL/β2GPI/anti-β2GPI antibody complex induces apoptosis of human umbilical vein endothelial cells by promoting the production of reactive oxygen species].
    Yudan Chen, Hong Zhou, Chao He, Ting Wang, Guiting Zhang, Peng Zhang, Ren Wang, Qianqian Wu, Yuye Yao.
      Objective To investigate the effect of oxidative low-density lipoprotein/β2 glycoprotein I/anti-β2 glycoprotein I antibody (oxLDL/β2GPI/αβ2GPIAb) complex on the apoptosis of human umbilical vein endothelial cells (HUVECs) and the role of reactive oxygen species (ROS) in the process. Methods HUVECs were stimulated by β2GPI, aβ2GPIAb, β2GPI/aβ2GPIAb complex, oxLDL, oxLDL/β2GPI complex, oxLDL/β2GPI/rabbit (R)-IgG complex, and oxLDL/β2GPI/aβ2GPIAb complex. The protein levels of apoptosis-related proteins including BAX, Bcl2 and cleaved caspase-3 (c-caspase-3) were detected by Western blot analysis. Annexin V-FITC/PI double labeling combined with flow cytometry was performed to detect apoptosis rate; dichlorofluorescein diacetate (DCFH-DA) labeling combined with flow cytometry was used to detect ROS level. And the effect of each treatment on cell viability was analyzed by CCK-8 assay. The changes of mean fluorescence intensity of ROS and the apoptosis of HUVECs induced by oxLDL/β2GPI/aβ2GPIAb complex were observed by the pretreatment with antioxidant apocynin or diphenylphosphonium iodide (DPI). Results The oxLDL/β2GPI/aβ2GPIAb complex significantly reduced the viability of HUVECs, increased the expression of BAX and cleaved caspase-3 protein, decreased the level of Bcl2 protein, and promoted the apoptosis of HUVECs. In addition, oxLDL/β2GPI/aβ2GPIAb complex induced an increase of ROS level during apoptosis, which could be attenuated by antioxidants. The effect of complex-induced apoptosis could also be reversed to some extent by antioxidants. Conclusion The oxLDL/β2GPI/aβ2GPIAb complex can induce the apoptosis in HUVECs by increasing ROS.
  12. Cryobiology. 2019 Apr 26. pii: S0011-2240(17)30349-8. [Epub ahead of print]
    Melatonin protects rabbit spermatozoa from cryo-damage via decreasing oxidative stress.
    Zhendong Zhu, Rongnan Li, Yinghua Lv, Wenxian Zeng.
      Mammalian spermatozoa are highly susceptible to reactive oxygen species (ROS) stress. The aim of the present study was to investigate whether and how melatonin protects rabbit spermatozoa against ROS stress during cryopreservation. Semen was diluted with Tris-citrate-glucose extender in present of different concentrations of melatonin. It was observed that addition of 0.1 mM melatonin significantly improved spermatozoa motility, membrane integrity, acrosome integrity, mitochondrial membrane potential as well as AMP-activated protein kinase (AMPK) phosphorylation. Meanwhile, the lipid peroxidation (LPO), ROS levels and apoptosis of post-thawed spermatozoa were reduced in present of melatonin. Interestingly, when fresh spermatozoa were incubated with 100 μM H2O2, addition of 0.1 mM melatonin significantly decreased the oxidative damage compared to the H2O2 treatment, whereas addition of luzindole, a MT1 receptor inhibitor, decrease the effect of melatonin in sperm. It was observed that the glutathione (GSH) content and activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were significantly increased with addition of melatonin during cryopreservation. In conclusion, addition of melatonin to the freezing extender protects rabbit spermatozoa against ROS attack by enhancing AMPK phosphorylation for increasing the antioxidative defense.
    Keywords:  AMPK; Apoptosis; Cryopreservation; Melatonin; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cryobiol.2019.04.009
  13. J Exp Clin Cancer Res. 2019 May 03. 38(1): 184
    Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells.
    Xihong Liu, Peiyuan Zhao, Xiujuan Wang, Lei Wang, Yingjun Zhu, Yadi Song, Wei Gao.
       BACKGROUND: Celastrol, a triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies. However, the effect of celastrol on glioma cells and the underlying molecular mechanisms remain elusive.
    METHODS: Glioma cells, including the U251, U87-MG and C6 cell lines and an animal model were used. The effects of celastrol on cells were evaluated by flow cytometry, confocal microscopy, reactive oxygen species production assay and immunoblotting after treatment of celastrol. Fisher's exact test, a one-way ANOVA and the Mann-Whitney U-test were used to compare differences between groups. All data were analyzed using SPSS version 21.0 software.
    RESULTS: Here, we found that exposure to celastrol induced G2/M phase arrest and apoptosis. Celastrol increased the formation of autophagosomes, accumulation of LC3B and the expression of p62 protein. Celastrol-treated glioma cells exhibited decreased cell viability after the use of autophagy inhibitors. Additionally, autophagy and apoptosis caused by celastrol in glioma cells inhibited each other. Furthermore, celastrol induced JNK activation and ROS production and inhibited the activities of Akt and mTOR kinases. JNK and ROS inhibitors significantly attenuated celastrol-trigged apoptosis and autophagy, while Akt and mTOR inhibitors had opposite effects.
    CONCLUSIONS: In conclusion, our study revealed that celastrol caused G2/M phase arrest and trigged apoptosis and autophagy by activating ROS/JNK signaling and blocking the Akt/mTOR signaling pathway.
    Keywords:  Apoptosis; Autophagosome; Celastrol; Cell cycle; Glioma
    DOI:  https://doi.org/10.1186/s13046-019-1173-4
  14. Phytomedicine. 2019 Jan 28. pii: S0944-7113(19)30016-9. [Epub ahead of print]61 152844
    Reactive oxygen species mediate the chemopreventive effects of syringin in breast cancer cells.
    Chien-Hsing Lee, Chiung-Wei Huang, Po-Chih Chang, Jun-Ping Shiau, In-Pin Lin, Mei-Ying Lin, Chih-Cheng Lai, Chung-Yi Chen.
       BACKGROUND: Syringin (Syr), a phenylpropanoid glycoside extracted from Eleutherococcus senticosus, possesses various biological properties, including anticancer activities. However, the cytotoxicity effects of Syr on breast cancer have not yet been elucidated.
    PURPOSE: In this study, we evaluated the anticancer potential of Syr on breast carcinoma and the mechanism involved.
    STUDY DESIGN/METHODS: Non-tumorigenic (M10), tumorigenic (MCF7) and metastatic (MDA-MB-231) breast cancer cell lines as well as xenograft model were treated with Syr. Proliferation and cell cycle distribution were evaluated using the MTT, the colony formation assay and flow cytometry. The expression levels of cytotoxicity-related proteins were detected by Western blot.
    RESULTS: Here, we found that colony formation inhibition, cell cycle arrest in the G2/M phase, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3/9 activation were observed in MCF7 and MDA-MB-231 cells treated with Syr. Moreover, pretreatment with a pan-caspase inhibitor (Z-DEVD-FMK) inhibited Syr-induced apoptosis. In addition, treatment with Syr also increased the production of reactive oxygen species (ROS). However, the antioxidant N-acetyl-cysteine (NAC) reversed the ROS levels and rescued the apoptotic changes. Meanwhile, Syr inhibited the growth of breast cancer xenograft models and dramatically decreased tumor volume without any obvious body weight loss in vivo.
    CONCLUSION: Our findings suggest that Syr induces oxidative stress to suppress the proliferation of breast cancer and thus might be an effective therapeutic agent to treat breast cancer.
    Keywords:  Apoptosis; Breast cancer; Reactive oxygen species; Syringin; X-linked inhibitor of apoptosis protein
    DOI:  https://doi.org/10.1016/j.phymed.2019.152844
  15. Arch Pharm Res. 2019 May 02.
    Flavonoid morin inhibits proliferation and induces apoptosis of melanoma cells by regulating reactive oxygen species, Sp1 and Mcl-1.
    Yoon Jin Lee, Woo Il Kim, Soo Young Kim, Sung Woo Cho, Hae Seon Nam, Sang Han Lee, Moon Kyun Cho.
      Reactive oxygen species (ROS) is associated with cancer progression in different cancers, including melanoma. It also affects specificity protein (Sp1), a transcription factor. Flavonoid morin is known to inhibit growth of cancer cells, including lung cancer and breast cancer. Herein, we hypothesized that morin can inhibit cancer activities in melanoma by altering ROS generation. The aim of this study is to determine the effects of morin and its underlying mechanisms in melanoma cells. Effects of morin on cell proliferation and apoptosis were determined using standardized assays. Changes in pro-apoptotic and anti-apoptotic proteins were analyzed by western blot analysis. Cellular ROS levels and mitochondrial function were evaluated by measuring DCF-DA fluorescence and rhodamine-123 fluorescence intensities, respectively. Morin induced ROS production and apoptosis, as presented by increased proportion of cells with Annexin V-PE(+) staining and sub-G0/G1 peak in cell cycle analysis. It also downregulated Sp1, Mcl-1, Bcl-2, and caspase-3 but upregulated cleaved caspase-3, Bax, and PUMA. In immunohistochemical staining, Sp1 was overexpressed in melanoma tissues compared to normal skin tissues. Collectively, our data suggest that morin can induce apoptosis of melanoma cells by regulating pro-apoptotic and anti-apoptotic proteins through ROS, and may be a potential substance for treatment of melanoma.
    Keywords:  Mcl-1; Melanoma; Morin; Proliferation; ROS; Sp1
    DOI:  https://doi.org/10.1007/s12272-019-01158-5
  16. Vet Microbiol. 2019 May;pii: S0378-1135(19)30165-8. [Epub ahead of print]232 1-12
    Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways.
    Xingang Xu, Ying Xu, Qi Zhang, Feng Yang, Zheng Yin, Lixiang Wang, Qinfan Li.
      Porcine epidemic diarrhea virus (PEDV) is a member of Coronavirus, which causes severe watery diarrhea in piglets with high morbidity and mortality. ROS and p53 play key roles in regulating many kinds of cell process during viral infection, however, the exact function in PEDV-induced apoptosis remains unclear. In this study, the pro-apoptotic effect of PEDV was examined in Vero cells and we observed that PEDV infection increased MDM2 and CBP, promoted p53 phosphorylation at serine 20 and, promoted p53 nuclear translocation, leading to p53 activation in Vero cells. Treatment with the p53 inhibitor PFT-α could significantly inhibit PEDV-induced apoptosis. We also observed PEDV infection induced time-dependent ROS accumulation. Treatment with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited PEDV-induced apoptosis. Moreover, further inhibition tests were established to prove that p53 was regulated by ROS in PEDV-induced apoptosis. In addition, we also found that p38 MAPK and SAPK/JNK were activated in PEDV-infected Vero cells. However, treatment with the p38 MAPK inhibitor SB203580, and the SAPK/JNK inhibitor SP600125 reversed PEDV-induced apoptosis. Taken together, the results of this study demonstrate that activated p53 and accumulated ROS participated in PEDV-induced apoptosis and p53 could be regulated by ROS during PEDV infection. Activated p38 MAPK and SAPK/JNK exerted no influence on PEDV-induced apoptosis. These findings provide new insights into the function of p53 and ROS in the interaction of PEDV with Vero cells.
    Keywords:  Apoptosis; PEDV; Reactive oxygen species; p53 pathway
    DOI:  https://doi.org/10.1016/j.vetmic.2019.03.028
  17. Inflamm Res. 2019 Apr 29.
    Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-κB/NLRP3 inflammasome activation and up-regulating Nrf2/ARE/HO-1 signaling.
    Sanaa M Abd El-Twab, Omnia E Hussein, Walaa G Hozayen, May Bin-Jumah, Ayman M Mahmoud.
       OBJECTIVE: Chicoric acid (CA) is a natural product with promising antioxidant and anti-inflammatory properties; however, its protective effect on methotrexate (MTX)-induced acute kidney injury (AKI) hasn't been reported. We investigated the effect of CA on MTX-induced AKI in rats, pointing to the role of NF-κB/NLRP3 inflammasome and Nrf2/ARE/HO-1 signaling.
    MATERIALS AND METHODS: Wistar rats received 25 mg/kg and 50 mg/kg CA for 15 days and a single injection of MTX at day 16. At day 19, the rats were killed, and samples were collected for analyses.
    RESULTS: MTX induced a significant increase in serum creatinine and urea, and kidney Kim-1, reactive oxygen species (ROS), malondialdehyde and nitric oxide levels. In addition, MTX-induced rats exhibited multiple histopathological alterations, diminished antioxidant defenses, and decreased expression of Nrf2, NQO-1 and HO-1. CA prevented histological alterations, ameliorated kidney function markers, attenuated ROS production and lipid peroxidation, and boosted antioxidant defenses. CA suppressed the expression of NF-κB p65, NLRP3, caspase-1 and IL-1β in the kidney of MTX-induced rats. Furthermore, CA inhibited MTX-induced apoptosis as evidenced by the decreased expression of BAX and caspase-3, and increased Bcl-2 gene expression.
    CONCLUSIONS: CA prevented MTX-induced AKI through activation of Nrf2/ARE/HO-1 signaling, and attenuation of ROS-induced activation of NF-κB/NLRP3 inflammasome signaling.
    Keywords:  Chicoric acid; Methotrexate; NLRP3 inflammasome; Nrf2; ROS
    DOI:  https://doi.org/10.1007/s00011-019-01241-z
  18. Phytomedicine. 2019 Jan 15. pii: S0944-7113(19)30010-8. [Epub ahead of print] 152832
    Cytotoxicity of ungeremine towards multi-factorial drug resistant cancer cells and induction of apoptosis, ferroptosis, necroptosis and autophagy.
    Armelle T Mbaveng, Gabin T M Bitchagno, Victor Kuete, Pierre Tane, Thomas Efferth.
       BACKGROUND: Successful cancer chemotherapy is hampered by resistance of cancer cells to established anticancer drugs. Numerous natural products reveal cytotoxicity towards tumor cells.
    PURPOSE: The present study was aimed to determine the cytotoxicity of a betaine-type alkaloid, ungeremine, towards 9 cancer cell lines including various sensitive and drug-resistant phenotypes. The mode of action of this compound was further investigated.
    METHODS: The cytotoxicity, ferroptotic and necroptotic cell death were determined by the resazurin reduction assay. Caspase activation was evaluated using the caspase-Glo assay. Flow cytometry was applied for the analysis of cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). Apoptotic, necroptotic and autophagic markers were determined by Western blotting. CCRF-CEM leukemia cells were used for all mechanistic studies.
    RESULTS: Ungeremine displayed cytotoxic activity towards the 9 cancer cell lines tested, including drug-sensitive and MDR phenotypes. The IC50values obtained varied from 3.67 µM (in MDA-MB-231-BCRP breast carcinoma cells) to 75.24 µM (against in CEM/ADR5000 leukemia cells) for ungeremine and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against CEM/ADR5000 cells) for doxorubicin (control drug). Ungeremine induced ferroptosis, necroptosis, autophagy as well as apoptosis mediated by caspase activation, MMP alteration and increase ROS production.
    CONCLUSION: The present investigation showed that ungeremine is a promising cytotoxic compoundthat could be further explored in the future to develop new anticancer drugs to fight sensitive and resistant phenotypes.
    Keywords:  Alkaloid; Cell death; Multi-drug resistance; Natural product
    DOI:  https://doi.org/10.1016/j.phymed.2019.152832
  19. J Mol Recognit. 2019 May 02. e2783
    Conformational and functional effects of MPA-CdTe quantum dots on SOD: Evaluating the mechanism of oxidative stress induced by quantum dots in the mouse nephrocytes.
    Minglu Hao, Rutao Liu.
      The application of quantum dots (QDs) is restricted by the biosafety issue. QDs contribute to the adverse effects of organisms probably because of the ability to induce oxidative stress via changing the activity of antioxidant enzyme, for example, superoxide dismutase (SOD). But the underlying molecular mechanisms still remain unclear. This study investigated the harmful effects of oxidative stress induced by mercaptopropionic acid capped CdTe QDs (MPA-CdTe QDs) on the mouse primary nephrocytes as well as the structure and function of SOD molecule and explored the underlying molecular mechanism. After 24-hour MPA-CdTe QD exposure, the activation level of extracellular regulated protein kinase (ERK) signaling pathway and cysteinyl-directed aspartate-specific proteases (Caspases) significantly increased, which led to the increasing level of reactive oxygen species (ROS) and cell apoptosis; the group pretreated with ROS scavenger N-acetyl-L-cysteine (NAC) significantly reduced the apoptotic cell percentage, indicating that ROS played a critical role in QD-induced cytotoxicity. Further molecular experiments showed that the interacting processes between the MPA-CdTe QDs and SOD were spontaneous which changed the conformation, secondary structure of SOD. The interaction significantly resulted in the tightening of polypeptide chains and the shrinkage of SOD, leading to the inhibition of molecular SOD activity. This study demonstrates the adverse effects of QDs, revealing their potential risk in biomedical applications.
    Keywords:  molecular level; nephrocytes; oxidative stress; quantum dot; toxicity
    DOI:  https://doi.org/10.1002/jmr.2783
  20. J Cell Physiol. 2019 Apr 29.
    Norepinephrine protects against apoptosis of mesenchymal stem cells induced by high glucose.
    Yanan Kong, Liuhanghang Cheng, Li Ma, Haihong Li, Biao Cheng, Yu Zhao.
      In diabetes, the number of bone mesenchymal stem cells (MSCs) decreases and their differentiation is impaired. However, the exact mechanism is unclear. Patients with diabetes often experience sympathetic nerve injury. Norepinephrine (NE), a major mediator of the sympathetic nervous system, influences rat MSC migration in culture and in vivo. The present study aimed to investigate the effect of NE on MSCs under high glucose conditions; therefore MSCs were treated with high glucose and NE. High glucose-induced MSCs apoptosis, which was reversed by NE. To verify the effect of NE, mice underwent sympathectomy and were used to establish a diabetic model. Diabetic mice with sympathectomy had a higher apoptosis rate and higher levels of reactive oxygen species in their bone marrow-derived cells than diabetic mice without sympathectomy. High glucose inhibited p-AKT production and B-Cell CLL/Lymphoma 2 expression, and promoted BAX and caspase-3 expression. NE reversed these effects of high glucose. An AKT inhibitor enhanced the effects of high glucose. Thus, NE had a protective effect on MSC apoptosis induced by high glucose, possibly via the AKT/BCL-2 pathway.
    Keywords:  apoptosis; diabetes mellitus; mesenchymal stem cells; norepinephrine
    DOI:  https://doi.org/10.1002/jcp.28686
  21. Phytomedicine. 2019 Jan 29. pii: S0944-7113(19)30023-6. [Epub ahead of print]61 152852
    Sophoraflavanone G from Sophora flavescens induces apoptosis in triple-negative breast cancer cells.
    Wen-Chung Huang, Pei-Yu Gu, Li-Wen Fang, Yu-Ling Huang, Chwan-Fwu Lin, Chian-Jiun Liou.
       BACKGROUND: A compound isolated from Sophora flavescens-sophoraflavanone G (SG)-showed anti-tumor and anti-inflammatory properties. We previously demonstrated that SG promoted apoptosis in human leukemia HL-60 cells. In the present study, we investigated the effects of SG on apoptosis in human breast cancer MDA-MB-231 cells, and explored the underlying molecular mechanisms.
    METHODS: MDA-MB-231 cells were treated with various SG concentrations, and cell viability was evaluated by MTT assay. Apoptotic signal proteins were detected by western blotting, and cell apoptosis was assessed using flow cytometry.
    RESULTS: Our results demonstrated that SG induced nuclear condensation, DNA fragmentation, reactive oxygen species production, and increased cell apoptosis in MDA-MB-231 cells. SG also suppressed migration and invasion, likely via blockage of the MAPK pathway. In the apoptotic signaling pathway, SG increased cleaved caspase-8, caspase-3, and caspase-9. SG treatment also decreased Bcl-2 and Bcl-xL expression, increased Bax expression, and prompted release of more cytochrome c from mitochondria to the cytoplasm in MDA-MB-231 cells.
    CONCLUSION: Overall, our findings suggest that SG might increase apoptosis, and decrease migration and invasion, in MDA-MB-231 cells through suppression of a MAPK-related pathway.
    Keywords:  Apoptosis; Caspase-3; MDA-MB-231 cells; Sophoraflavanone G
    DOI:  https://doi.org/10.1016/j.phymed.2019.152852
  22. Oxid Med Cell Longev. 2019 ;2019 7564207
    Protective Effects of Kaempferol on D-Ribose-Induced Mesangial Cell Injury.
    Ning Zhang, Shaoyang Zhao, Jinni Hong, Weiwei Li, Xuemei Wang.
      Recently, it has been found that the level of urinary D-ribose in type 2 diabetes is notably higher than that in age-matched normal control, and D-ribose is more reactive in the glycation than D-glucose and induces oxidative stress. Kaempferol is one of the main bioactive components in Astragalus membranaceus, with numerous physiological actives, such as antioxidant. The present study investigated the protective effects of kaempferol on D-ribose-treated mesangial cells. CCK-8 and LDH assay were used to test cell viability and cell toxicity. Immunofluorescence and flow cytometry were used to detect the AGE formation and ROS accumulation. GSH level was measured to reflect oxidation resistance. Cell apoptosis was evaluated by Hoechst 33258 staining, AO/EB staining, and western blot. Mitochondrial membrane integrity was detected by JC-1 staining, western blot, and RT-PCR. The change of autophagy level was tested by western blot. The results indicated that D-ribose induced not only cell damage and increased AGE formation and ROS accumulation but also GSH depletion. Further studies demonstrated that D-ribose induced mitochondrial depolarization and the activation of caspase-9/3. But kaempferol could partly block these damages. Subsequently, it was confirmed that kaempferol repaired the autophagy disturbance induced by D-ribose, and 3-MA could reverse the protective effect of kaempferol under D-ribose condition. Our study demonstrated that D-ribose induced AGE accumulation and ROS production in mesangial cell and caused mitochondrial apoptosis, but kaempferol could attenuate these changes and its protective effect might be related to the repair of autophagy.
    DOI:  https://doi.org/10.1155/2019/7564207
  23. ACS Chem Neurosci. 2019 Apr 29.
    Selenepezil, a selenium-containing compound, exerts neuroprotective effect via modulation of Keap1-Nrf2-ARE pathway and attenuates Aβ-induced cognitive impairment in vivo.
    Jun Yan, Yanqing Pang, Jialing Zhuang, Haibiao Lin, Qiaoxuan Zhang, Liqiao Han, Peifeng Ke, Junhua Zhuang, Xianzhang Huang.
      Oxidative stress is a major risk factor for neurodegenerative disease. The Keap1- Nrf2 - ARE pathway is one of the most potent defensive systems against oxidative stress. Selenepezil, a selenium-based compound, was previously found to exhibit excellent acetylcholinesterase (AChE) inhibition, mimicked endogenous glutathione peroxidase (GPx) activity and exhibited scavenging activity for hydrogen peroxide in vitro. However, none of these activities are evaluated in cellular model, and detailed molecular mechanisms are not elucidated. Moreover, whether Selenepezil ameliorates memory deficits in vivo remains unknown. This study validated the cytoprotective effect of Selenepezil against 6-hydroxydopamine (6-OHDA)- or H2O2-induced SH-SY5Y cell damage via alleviation or neutralization of intracellular microtubules disorder, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction and cell apoptosis. Our study clearly demonstrated that Selenepezil pre-treatment exhibited a remarkable cytoprotective effect in Nrf2-dependent manner via activating the Keap1-Nrf2-ARE pathway and stimulating the transcription of Nrf2-ARE-regulated cytoprotective genes. Moreover, Selenepezil·HCl exerts neuroprotective effect via attenuating Aβ-induced cognitive impairment in Alzheimer's disease (AD) rat, which was more active than the reference drug Donepezil. In summary, Selenepezil deserves further consideration for AD therapy.
    DOI:  https://doi.org/10.1021/acschemneuro.9b00106
  24. Life Sci. 2019 Apr 24. pii: S0024-3205(19)30319-4. [Epub ahead of print]
    Melatonin protects circulatory death heart from ischemia/reperfusion injury via the JAK2/STAT3 signalling pathway.
    Hongwen Lan, Yunshu Su, Yakun Liu, Cheng Deng, Jing Wang, Taiqiang Chen, Kouevidjin Ekue Dodzi Jules, Jackson Ferdinand Masau, Huiling Li, Xiang Wei.
       AIMS: The shortage of donor hearts could be alleviated with the use of the allografts from donation after circulatory death (DCD). Here, we evaluated the protective effect of melatonin on myocardial ischemia/reperfusion (MI/R) injury in a DCD heart model after ex vivo perfusion.
    MAIN METHODS: Donor hearts were harvested from DCD model rats pre-treated with or without melatonin and subjected to 30 min of ex vivo perfusion, followed by transplantation. Tissue samples were obtained at 3, 12, and 24 h after heart transplantation. Myocardial oedema was evaluated based on the water content and wet/dry ratio, while inflammation was examined with hematoxylin & eosin staining. The expression levels of matrix metalloproteinase-9, interleukin-6, and tumour necrosis factor-α were evaluated. Oxidative stress level was determined from the content of malondialdehyde, activities of superoxide dismutase and glutathione peroxidase, and expression of Nrf2, NQO1 and cytochrome-C. Myocardial apoptosis was detected with TUNEL assay and measurement of the expression levels of Bax, Bcl-2, caspase-3, and cleaved caspase-3. The activation of the JAK2/STAT3 signalling pathway was evaluated by determining the levels of p-JAK2 and p-STAT3.
    KEY FINDINGS: Melatonin pre-treatment protected the heart from MI/R by reducing myocardial oedema and inflammation, attenuating oxidative stress, and decreasing myocardial apoptosis. Furthermore, the JAK2/STAT3 signalling pathway was activated after melatonin treatment during MI/R. The protective effects of melatonin were abolished by AG490.
    SIGNIFICANCE: Melatonin pre-treatment protected the heart from MI/R in a DCD heart model after ex vivo perfusion. Melatonin exerted cardioprotective effects through the activation of the JAK2/STAT3 signalling pathway.
    Keywords:  Donation after circulatory death; JAK2/STAT3 signalling pathway; Melatonin; Myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.1016/j.lfs.2019.04.057
  25. Int Immunopharmacol. 2019 Apr 26. pii: S1567-5769(19)30184-5. [Epub ahead of print]72 445-453
    Protective effects of pyrroloquinoline quinine against oxidative stress-induced cellular senescence and inflammation in human renal tubular epithelial cells via Keap1/Nrf2 signaling pathway.
    Ziqiang Wang, Ning Han, Kunxiao Zhao, Ying Li, Yanqing Chi, Baoxing Wang.
      Oxidative stress-induced cellular senescence and inflammation are important biological events in diabetic nephropathy (DN). Our recent studies have found that pyrroloquinoline quinine (PQQ) has protective effects against HG-induced oxidative stress damage and apoptosis in HK-2 cells. Nevertheless, whether PPQ has the effect of anti-inflammation and anti-senescence in HK-2 cells remains unclear. Here, we showed that low-dose PPQ treatment (100 nM) downregulates the expression of P16, P21, IL-1β, TNF-α and NF-κB in HG cultured HK-2 cells. A low dose of PPQ also upregulated the protein expression of SOD2, CAT and inhibited the generation of ROS. We also indicated that PPQ affected the activity of Keap1/Nrf2 pathway, increased the nuclear accumulation of Nrf2 and the downstream pathway protein expression of Keap1/Nrf2 signaling pathway (HO-1, NQO-1, GST and GPx-3). When ML385 was added to inhibit the activity of Keap1/Nrf2 signaling pathway, the effects of PPQ on anti-oxidative stress, anti-inflammation and anti-senescence in HK-2 cells under HG condition were weakened. In conclusion, our results suggest that PPQ could modulate HG-induced inflammation and senescence in HK-2 cells via the inhibition of ROS generation and achieves the protective effects through Keap1/Nrf2 pathway and upregulating the expression of its target protein.
    Keywords:  Cellular senescence; High glucose; Inflammation; Keap1/Nrf2 signaling pathway; Pyrroloquinoline quinine; Renal tubular epithelial cells
    DOI:  https://doi.org/10.1016/j.intimp.2019.04.040
  26. Chromosome Res. 2019 Apr 29.
    MiR-153 regulates cardiomyocyte apoptosis by targeting Nrf2/HO-1 signaling.
    Xianting Zhu, Yuling Zhao, Wei Hou, Ling Guo.
      MicroRNAs (miRNAs) play various roles in the regulation of human disease, including cardiovascular diseases. MiR-153 has been previously shown to be involved in regulating neuron survival during cerebral ischemia/reperfusion (I/R) injury. However, whether miR-153 is involved in I/R-induced cardiomyocyte apoptosis remains to be elucidated. In this study, we aimed to explore the role of miR-153 in the regulation of I/R-induced cardiomyocyte apoptosis and to investigate the miR-153-mediated molecular signaling pathway responsible for its effect on cardiomyocytes using an oxygen-glucose deprivation and reoxygenation (OGD/R) cellular model. We found that OGD/R treatment induced significant upregulation of miR-153 in cardiomyocytes causing reactive oxygen species (ROS) production and cell apoptosis signaling activation and subsequently leading to cardiomyocyte apoptosis. Suppression of miR-153 protected cardiomyocytes against OGD/R treatment. We further identified that nuclear factor-like 2 (Nrf2) is a functional target of miR-153. Nrf2/ heme oxygenase-1 (HO-1) signaling plays a critical role in miR-153 regulated OGD/R-induced cardiomyocyte apoptosis. Our study indicates that the inhibition of miR-153 or restoration of Nrf2 may serve as a potential therapeutic strategy for ischemia/reperfusion injury prevention.
    Keywords:  Apoptosis; Cardiomyocytes; Ischemia/reperfusion; Nrf2; miR-153
    DOI:  https://doi.org/10.1007/s10577-019-09608-y
  27. Bull Environ Contam Toxicol. 2019 May 02.
    Silver Nanoparticles Induced Cell Apoptosis, Membrane Damage of Azotobacter vinelandii and Nitrosomonas europaea via Generation of Reactive Oxygen Species.
    Li Zhang, Lingli Wu, Yazhu Mi, Youbin Si.
      Silver nanoparticles (AgNPs) is widely used as an antibacterial agent, but the specific antibacterial mechanism is still conflicting. This study aimed to investigate the size dependent inhibition of AgNPs and the relationship between inhibition and reactive oxygen species (ROS). Azotobactervinelandii and Nitrosomonaseuropaea were exposed to AgNPs with different particles size (10 nm and 50 nm). The ROS production was measured and the results showed that the generation of ROS related to the particle size and concentrations of AgNPs. At 10 mg/L of 10 nm Ag particles, the apoptosis rate of A. vinelandii and N. europaea were 20.23% and 1.87% respectively. Additionally, the necrosis rate of A. vinelandii and N. europaea reached to 15.20% and 42.20% respectively. Furthermore, transmission electron microscopy images also indicated that AgNPs caused severely bacterial cell membrane damage. Together these data suggested that the toxicity of AgNPs depends on its particle size and overproduction of ROS.
    Keywords:  Apoptosis; Azotobacter vinelandii; Nitrosomonas europaea; Reactive oxygen species; Silver nanoparticles
    DOI:  https://doi.org/10.1007/s00128-019-02622-0
  28. J Neurosci Res. 2019 May 01.
    The characteristics of the ancient cell death suppressor, TMBIM6, and its related signaling pathways after endoplasmic reticulum stress.
    Desislava Doycheva, Harpreet Kaur, Jiping Tang, John H Zhang.
      Activation of the unfolded protein response in combination with generation of reactive oxygen species, from cytochrome P450 members and NADPH-P450 reductases, are two major consequences of Endoplasmic Reticulum (ER) stress that cause oxidative damage and cell death. Herein, we reviewed the role of Bax Inhibitor-1 (BI-1), an evolutionarily conserved protein encoded by the Transmembrane Bax inhibitor Motif Containing 6 gene, in protection from ER stress. As BI-1 has multimodal properties that can target a wide array of pathophysiological consequences after injury, our main objective was to explore BI-1's protective role in ER stress and its potential signaling pathways.
    Keywords:  BI-1; ER stress; apoptosis; oxidative stress
    DOI:  https://doi.org/10.1002/jnr.24434
  29. Phytomedicine. 2019 Feb 06. pii: S0944-7113(19)30033-9. [Epub ahead of print]61 152862
    Effect of ginsenoside Rh2 on renal apoptosis in cisplatin-induced nephrotoxicity in vivo.
    Zeng Qi, Wei Li, Jing Tan, Cuizhu Wang, Hongqiang Lin, Baisong Zhou, Jinping Liu, Pingya Li.
       BACKGROUND: Ginsenoside Rh2 (Rh2), an important ingredient from Panax ginseng, has received much attention due to a range of pharmacological actions.
    PURPOSE: The aim of the study was to investigate the therapeutic potential Rh2 on cisplatin (CDDP)-induced nephrotoxicity and to elucidate involved mechanisms.
    STUDY DESIGN: An in vivo mice model of CDDP-induced nephrotoxicity was established by a single intraperitoneal injection of CDDP (20 mg/kg) to assess the effects of Rh2 on renal biochemical parameter, oxidative stress, inflammation tubular cell apoptosis and serum metabolic profiles.
    RESULTS: Rh2 protected against CDDP-induced renal dysfunction and ameliorated CDDP-induced oxidative stress, histopathological damage, inflammation and tubular cell apoptosis in kidney. Rh2 treatment had significantly increased expression of Bcl-2 and decreased expression of p53, Bax, cytochrome c, caspase-8, caspase-9, and caspase-3 in kidney tissues. Metabolomic analysis identified 29 altered serum metabolites in Rh2 treatment mice.
    CONCLUSION: These results suggest that Rh2 protects against CDDP-induced nephrotoxicity via action on caspase-mediated pathway.
    Keywords:  Anti-apoptosis; CDDP-induced acute kidney injury; Caspase; Ginsenoside Rh(2); Serum metabolomics
    DOI:  https://doi.org/10.1016/j.phymed.2019.152862
  30. Phytomedicine. 2019 Jan 30. pii: S0944-7113(19)30017-0. [Epub ahead of print]61 152845
    Epigallocatechin gallate prevents mitochondrial impairment and cell apoptosis by regulating miR-30a/p53 axis.
    Chan Zhang, Ping Liao, Ronggan Liang, Xiaojia Zheng, Jie Jian.
       PURPOSE: This study was designed to investigate whether EGCG prevents cardiac I/R mitochondrial impairment and cell apoptosis by regulating miR-30a/p53 axis.
    METHODS: The H9c2 cardiomyocytes hypoxia/reoxygenation (H/R) model in vitro and myocardial ischemia /reperfusion (I/R) model in vivo were made, with or without EGCG treatment. The levels of I/R-induced creatine kinase-MB (CK-MB) and the release of lactate dehydrogenase (LDH), as well as the adenosine triphosphate (ATP) and cardiac functional impairment were examined. Stablely transfecting miR-30a mimic or inhibitor in H9c2 cardiomyocytes was built. The expression of miR-30a, p53 and related proteins in cells was measured by western blotting and qRT-PCR. Cell viability and apoptosis were examined using CCK-8 assay and flow cytometry. The content of reactive oxygen species (ROS), mitochondrial permeability transition pores (MPTP) opening and mitochondrial transmembrane potential (ΔΨm) in cells was measured by fluorescent probes. The levels of miR-30a and p53, some related proteins expression and apoptosis in the cardiac muscle tissues were determined by quantitative real-time PCR (qRT-PCR), H&E staining, western blotting and TUNEL assays.
    RESULTS: We found that EGCG preconditioning significantly decreased the levels of CK-MB and LDH, increased the activity of ATP, reduced the apoptotic rate and partially preserved heart function. Furthermore, EGCG decreased ROS levels, MPTP opening and depolarization of ΔΨm, and improved the activity of post-I/R cardiomyocyte. The beneficial effect of EGCG was associated with restored levels of miR-30a expression in the I/R injury that correspond to p53 mRNA downregulation. The regulatory effect of EGCG was greatly enhanced by miR-30a mimic and suppressed by miR-30a inhibitor. More importantly, EGCG pretreatment inhibited the expression of mitochondrial apoptotic related proteins downstream of the miR-30a/p53 pathway.
    CONCLUSION: This study demonstrated that EGCG pretreatment may attenuate mitochondrial impairment and myocardial apoptosis by regulation of miR-30a/p53 axis.
    Keywords:  Apoptosis; Epigallocatechin Gallate(EGCG); Ischemia-reperfusion (I/R); Mitochondrial pathway; miR-30a/p53
    DOI:  https://doi.org/10.1016/j.phymed.2019.152845
  31. Comp Biochem Physiol C Toxicol Pharmacol. 2019 Apr 29. pii: S1532-0456(19)30152-8. [Epub ahead of print]
    Triclosan-induced liver injury in zebrafish (Danio rerio) via regulating MAPK/p53 signaling pathway.
    Mi Liu, Weiming Ai, Limei Sun, Fang Fang, Xuedong Wang, Shaobo Chen, Huili Wang.
      Long-term exposure of triclosan (TCS), an important antimicrobial agent, can lead to deleterious effects on liver growth and development. However, the related mechanisms on TCS-induced hepatocyte injury remain unclear. Herein, we found that after long-time TCS exposure to adult zebrafish (Danio rerio) from 6 hpf (hours post-fertilization) to 90 dpf (days post-fertilization), the body weight and hepatic weight were significantly increased in concomitant with a large amount of lipid droplet accumulation in liver. Also, TCS exposure resulted in occurrence of oxidative stress by increasing the concentrations of malondialdehyde and reducing the activity of superoxide dismutase both in zebrafish larvae (120 hpf) and adult liver. By H&E staining, we observed a series of abnormal phenomena such as severely hepatocellular atrophy and necrosis, as well as prominently increased hepatic plate gap in TCS-exposure treatment groups. Through AO staining, TCS induced obvious apoptosis in larval heart and liver; through TUNEL assay, a concentration-dependent apoptosis was found to mainly occur in adult liver and its surrounding tissues. The mRNA and protein expression of anti-apoptotic protein Bcl-2 decreased, while that of pro-apoptosis protein Bax significantly increased, identifying that liver injury was closely related to hepatocyte apoptosis. The significant up-regulation of MAPK and p53 at both mRNA and protein levels proved that TCS-induced hepatocyte apoptosis was closely related to activating the MAPK/p53 signaling pathway. These results strongly suggest that long-term TCS-exposure may pose a great injury to zebrafish liver development by means of activating MAPK/p53 apoptotic signaling pathway, also lay theoretical foundation for further assessing TCS-induced ecological healthy risk.
    Keywords:  Bax; Bcl-2; Hepatocyte apoptosis; Liver injury; MAPK/p53 signaling pathway; Triclosan exposure
    DOI:  https://doi.org/10.1016/j.cbpc.2019.04.016
  32. J Cell Biochem. 2019 Apr 29.
    Effective and new potent drug combination: Histone deacetylase and Wnt/β-catenin pathway inhibitors in lung carcinoma cells.
    Oguzhan Akgun, Merve Erkisa, Ferda Ari.
      Lung cancer is the most commonly diagnosed cancer worldwide with a high mortality rate. In this study, the therapeutic effect of combination valproic acid and niclosamide was investigated on human lung cancer cell line. The effects of the compounds alone and combination therapy on cell viability were determined by sulforhodamine B and adenosine 5'-triphosphate viability assays. Flow cytometry was used to determine the cell death mechanism and DNA damage levels responsible for the cytotoxic effects of combination therapy. The presence of apoptosis in cells was supported by fluorescence microscopy and also by using inhibitors of the apoptotic signaling pathway. The increase in cellular reactive oxygen species (ROS) level in combination therapy was determined by H2DCFDA staining. The effect of N-acetyl-l-cysteine combination on ROS increase was investigated on cell viability. In addition, the expression levels of the proteins associated with epigenetic regulation and cell death were analyzed by Western blotting and gene expression levels were determined using real-time quantitative polymerase chain reaction.It was observed that the combination therapy showed a cytotoxic effect on the A549 lung cancer cells compared to the individual use of the inhibitors. The absence of this effect on normal lung cells revealed the presence of a selective toxic effect. When the mechanism of cytotoxicity is examined, it has been observed that combination therapy initiates the activation of tumor necrosis receptors and causes apoptosis by activated caspase. It was also observed that this extrinsic apoptotic pathway was activated on the mitochondrial pathway. In addition, ER stress and mitochondrial membrane potential loss associated with increased ROS levels induce cell death. When the data in this study were evaluated, combination therapy caused a dramatic decrease in cell viability by inducing the extrinsic apoptotic pathway in lung cancer cell line. Therefore, it was concluded that it can be used as an effective and new treatment option for lung cancer.
    Keywords:  apoptosis; lung cancer; niclosamide; valproic acid
    DOI:  https://doi.org/10.1002/jcb.28813
  33. J Nutr Biochem. 2019 Mar 28. pii: S0955-2863(18)31246-4. [Epub ahead of print]68 79-90
    Fas/FasL-mediated cell death in rat's diabetic hearts involves activation of calcineurin/NFAT4 and is potentiated by a high-fat diet rich in corn oil.
    Refaat A Eid, Mahmoud A Alkhateeb, Samy M Eleawa, Mohamed Samir Ahmed Zaki, Attalla Farag El-Kott, Fahmy El-Sayed, Hassan Otifi, Sultan Alqahtani, Ziad A Asiri, Hussain Aldera.
      This study investigated if calcineurin/nuclear factor of activated T cells (NFAT) axis mediates the cardiac apoptosis in rats with type 1 diabetes mellitus (T1DM)-induced rats or administered chronically high-fat diet rich in corn oil (CO-HFD). Also, it investigated the impact of chronic administration of CO-HFD on Fas/Fas ligand (Fas/FasL)-induced apoptosis in the hearts of T1DM-induced rats. Adult male Wistar rats (140-160 g) were classified as control: (10% fat) CO-HFD: (40% fat), T1DM, and T1DM + CO-HFD (n=20/each). In vitro, cardiomyocytes were cultured in either low glucose (LG) or high glucose (HG) media in the presence or absence of linoleic acid (LA) and other inhibitors. Compared to the control, increased reactive oxygen species (ROS), protein levels of cytochrome C, cleaved caspase-8 and caspase-3, myocardial damage and impeded left ventricular (LV) function were observed in the hearts of all treated groups and maximally in T1DM + CO-HFD-treated rats. mRNA of all NFAT members (NFAT1-4) were not affected by any treatment. CO-HFD or LA significantly up-regulated Fas levels in both LVs and cultured cardiomyocytes in a ROS dependent mechanism and independent of modulating intracellular Ca2+ levels or calcineurin activity. T1DM or hyperglycemia significant up-regulated mRNA and protein levels of Fas and FasL by activating Ca2+/calcineurin/NFAT-4 axis. Furthermore, Fas/FasL cell death induced by recombinant FasL (rFasL) or HG media was enhanced by pre-incubating the cells with LA. In conclusion, activation of the Ca2+/calcineurin/NFAT4 axis is indispensable for hyperglycemia-induced Fas/FasL cell death in the cardiomyocytes and CO-HFD sensitizes this by up-regulation of Fas.
    Keywords:  Apoptosis; Corn oil; Diabetes mellitus; Fas/FasL; Heart; Linoleic acid
    DOI:  https://doi.org/10.1016/j.jnutbio.2019.03.007
  34. Biomed Pharmacother. 2019 Apr 25. pii: S0753-3322(19)30406-8. [Epub ahead of print]115 108885
    Ginkgolides B alleviates hypoxia-induced PC-12 cell injury by up-regulation of PLK1.
    Jian Gao, Mingyang Kang, Yingying Han, Tuo Zhang, Hui Jin, Chunyang Kang.
       BACKGROUND: Finding novel agent for cerebral ischemia therapy is urgently required. In our present study, we aimed to investigate the regulatory mechanism of Ginkgolides B (GB) in hypoxia-injured PC-12 cells.
    METHODS: PC-12 cells were exposed to hypoxia and administrated with GB. Cell viability was detected by MTT assay. Flow cytometry assay was conducted for the detection of cell apoptosis, ROS generation and cell cycle assay. The changes of protein levels of Bax, Pro/Cleaved-Caspase-3, CyclinD1, CDK4, CDK6, PI3K/AKT and MEK/ERK pathways were detected by Western blot. Transfection was conducted for Polo-like kinase 1 (PLK1) knockdown.
    RESULTS: Hypoxia-induced decrease of cell viability and increase of ROS generation, apoptosis and cell cycle arrest were ameliorated by GB. Hypoxia disposition hindered PI3 K/AKT and MEK/ERK signaling pathways while GB had the opposite effects. Then we observed that hypoxia exposure suppressed PLK1 expression while GB increased PLK1 expression dose-dependently. Knockdown of PLK1 attenuated the neuroprotective effects of GB on hypoxia-injured PC-12 cells and also inhibited PI3 K/AKT and MEK/ERK pathways.
    CONCLUSION: The above observations corroborated that GB alleviated hypoxia-induced PC-12 cell injury by up-regulation of PLK1 via activating PI3K/AKT and MEK/ERK pathways. These findings implied the neuro-protective impacts in hypoxia-injured PC-12 cells.
    Keywords:  Cerebral ischemia; Ginkgolides B; MEK/ERK pathway; PC-12 cells; PI3K/AKT pathway; Polo-like kinase 1
    DOI:  https://doi.org/10.1016/j.biopha.2019.108885
  35. Molecules. 2019 May 01. pii: E1700. [Epub ahead of print]24(9):
    Heme Oxygenase-1 is a Key Molecule Underlying Differential Response of TW-37-Induced Apoptosis in Human Mucoepidermoid Carcinoma Cells.
    In-Hyoung Yang, Chi-Hyun Ahn, Nam-Pyo Cho, Bohwan Jin, WonWoo Lee, Yun Chan Jung, Seong Doo Hong, Ji-Ae Shin, Sung-Dae Cho.
      TW-37 is a small-molecule inhibitor of Bcl-2 family proteins, which can induce anti-cancer activities in various types of cancer. In the current study, we investigated the potential molecular mechanism underlying the differential response to TW-37-induced apoptosis in two human mucoepidermoid carcinoma (MEC) cell lines. The differential response and underlying molecular mechanism of human MEC cells to TW-37 was evaluated by trypan blue exclusion assay, western blotting, 4', 6-diamidino-2-phenylindole staining, annexin V/propidium iodide double staining, analysis of the sub-G1 population, human apoptosis array, and measurements of intracellular reactive oxygen species (ROS). TW-37 decreased cell viability and induced apoptosis in YD-15 cells, but not in MC3 cells. Proteome profiling using a human apoptosis array revealed four candidate proteins and of these, heme oxygenase-1 (HO-1) was mainly related to the differential response to TW-37 of YD-15 and MC3 cells. TW-37 also led to a significant increase in intracellular levels of ROS in YD-15 cells, which is associated with apoptosis induction. The ectopic expression of HO-1 recovered YD-15 cells from TW-37-induced apoptosis by reducing intracellular levels of ROS. The expression of HO-1 was reduced through both transcriptional and post-translational modification during TW-37-mediated apoptosis. We conclude that HO-1 is a potential indicator to estimate response to TW37-induced apoptosis in human MEC.
    Keywords:  TW-37; apoptosis; heme oxygenase-1; mucoepidermoid carcinoma; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules24091700
  36. Int J Nanomedicine. 2019 ;14 2415-2431
    Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy.
    Feifei Li, Zihou Li, Xiaodong Jin, Yan Liu, Pengcheng Zhang, Ping Li, Zheyu Shen, Aiguo Wu, Weiqiang Chen, Qiang Li.
       Background: Gadolinium-based nanoparticles (GdNPs) have been used as theranostic sensitizers in clinical radiotherapy studies; however, the biomechanisms underlying the radio-sensitizing effects of GdNPs have yet to be determined. In this study, ultra-small gadolinium oxide nanocrystals (GONs) were employed to investigate their radiosensitizing effects and biological mechanisms in non-small-cell lung cancer (NSCLC) cells under X-ray irradiation.
    Method and materials: GONs were synthesized using polyol method. Hydroxyl radical production, oxidative stress, and clonogenic survival after X-ray irradiation were used to evaluate the radiosensitizing effects of GONs. DNA double-strand breakage, cell cycle phase, and apoptosis and autophagy incidences were investigated in vitro to determine the radiosensitizing biomechanism of GONs under X-ray irradiation.
    Results: GONs induced hydroxyl radical production and oxidative stress in a dose- and concentration-dependent manner in NSCLC cells after X-ray irradiation. The sensitizer enhancement ratios of GONs ranged between 19.3% and 26.3% for the NSCLC cells under investigation with a 10% survival rate compared with that of the cells treated with irradiation alone. Addition of 3-methyladenine to the cell medium decreased the incidence rate of autophagy and increased cell survival, supporting the idea that the GONs promoted cytostatic autophagy in NSCLC cells under X-ray irradiation.
    Conclusion: This study examined the biological mechanisms underlying the radiosensitizing effects of GONs on NSCLC cells and presented the first evidence for the radiosensitizing effects of GONs via activation of cytostatic autophagy pathway following X-ray irradiation.
    Keywords:  apoptosis; cytostatic autophagy; gadolinium oxide nanocrystal; oxidative stress; radiosensitization
    DOI:  https://doi.org/10.2147/IJN.S193676
  37. Theranostics. 2019 ;9(7): 1878-1892
    Dioscin Alleviates Crystalline Silica-Induced Pulmonary Inflammation and Fibrosis through Promoting Alveolar Macrophage Autophagy.
    Sitong Du, Chao Li, Yiping Lu, Xue Lei, Yiting Zhang, Siyi Li, Fangwei Liu, Ying Chen, Dong Weng, Jie Chen.
      Occupational exposure to crystalline silica (CS) particles leads to silicosis, which is characterized by chronic inflammation and abnormal tissue repair. Alveolar macrophages (AMs) play a crucial role in the process of silicosis. Previously, we demonstrated positive effect of dioscin on silicosis through modulating macrophage-elicited innate immune response. However, the concrete molecular mechanism remains to be discovered. Methods: We established experimental model of silicosis with wildtype and Atg5flox/floxDppa3Cre/+ mice and oral administrated dioscin daily to explore the effects of dioscin on macrophages and pulmonary fibrosis. AM cell line MH-S with Atg5 silence was used to explore specific function of dioscin on macrophage-derived inflammation and the underlying molecular mechanism. Results: Dioscin could promote autophagy in macrophages. Dioscin-triggered AMs autophagy limited mitochondrial reactive oxygen species (mtROS) mass stimulated by CS, reduced mitochondria-dependent apoptosis pathway activation and facilitated cell survival. Relieved oxidative stress resulted in decreased secretion of inflammatory factors and chemokines. Dioscin treatment alleviated macrophage-derived inflammation and subsequent abnormal collagen repair. All the dioscin's protective effects were diminished in Atg5flox/floxDppa3Cre/+ mice. Conclusion: Dioscin promoting autophagy leads to reduced CS-induced mitochondria-dependent apoptosis and cytokine production in AMs, which may provide concrete molecular mechanism for the therapy of silicosis.
    Keywords:  autophagy; crystalline silica; dioscin; macrophage; mitochondrial dysfunction
    DOI:  https://doi.org/10.7150/thno.29682
  38. Semin Hear. 2019 May;40(2): 197-204
    Mechanisms of Cisplatin-Induced Ototoxicity and Prevention.
    Leonard P Rybak, Debashree Mukherjea, Vickram Ramkumar.
      Cisplatin is a highly effective antineoplastic agent used to treat solid tumors. Unfortunately, the administration of this drug leads to significant side effects, including ototoxicity, nephrotoxicity, and neurotoxicity. This review addresses the mechanisms of cisplatin-induced ototoxicity and various strategies tested to prevent this distressing adverse effect. The molecular pathways underlying cisplatin ototoxicity are still being investigated. Cisplatin enters targeted cells in the cochlea through the action of several transporters. Once it enters the cochlea, cisplatin is retained for months to years. It can cause DNA damage, inhibit protein synthesis, and generate reactive oxygen species that can lead to inflammation and apoptosis of outer hair cells, resulting in permanent hearing loss. Strategies to prevent cisplatin ototoxicity have utilized antioxidants, transport inhibitors, G-protein receptor agonists, and anti-inflammatory agents. There are no FDA-approved drugs to prevent cisplatin ototoxicity. It is critical that potential protective agents do not interfere with the antitumor efficacy of cisplatin.
    Keywords:  antioxidants; apoptosis; cisplatin; cochlea; otoprotection
    DOI:  https://doi.org/10.1055/s-0039-1684048
  39. Cell Physiol Biochem. 2019 ;52(6): 1325-1338
    ROS Generated by Upconversion Nanoparticle-Mediated Photodynamic Therapy Induces Autophagy via PI3K/AKT/ mTOR Signaling Pathway in M1 Peritoneal Macrophage.
    Xiaobo Han, Jiayuan Kou, Yinghong Zheng, Zhongni Liu, Yueqing Jiang, Ziyu Gao, Lin Cong, Liming Yang.
       BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory cardiovascular disease. Macrophages are major components of atherosclerotic plaques and play a key role in the development of atherosclerosis by secreting a variety of pro-inflammatory factors. Our previous studies have confirmed that upconversion nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) mediated photodynamic therapy (PDT) can promote cholesterol efflux and induce apoptosis in THP-1 macrophages. In this study, we investigated whether reactive oxygen species (ROS) generated by UCNPs-Ce6-mediated PDT can induce autophagy to inhibit the expression of pro-inflammatory factor in M1 peritoneal macrophages.
    METHODS: Peritoneal macrophages were collected from C57/BL6 mice injected with 3% thioglycollate broth medium and induced by lipopolysaccharides and interferon-γ. Intracellular ROS production was assessed by 2'-7'-dichloroflorescein diacetate and flow cytometry. Autophagy was assayed by western blot, transmission electron microscopy and immunofluorescence. Pro-inflammatory cytokines were detected by enzyme-linked immunosorbent assay and western blot.
    RESULTS: Model M1 peritoneal macrophages were established after 24 h induction. Protein expression levels of LC3 II and Beclin1, and degradation of p62 increased and peaked at 2 h in the PDT group. Meanwhile, levels of inflammatory cytokines iNOS, IL-12, and TNF-α markedly decreased after PDT. The increase in autophagy levels and decrease in pro-inflammatory cytokines were significantly inhibited by 3-methyladenine. Furthermore, ROS generated by UCNPs- Ce6 mediated PDT activated autophagy. The expression of autophagy related-protein and inflammatory cytokines iNOS, IL-12, and TNF-α were inhibited by the ROS inhibitor N-acetyl cysteine.
    CONCLUSION: ROS generated by UCNPs-Ce6-mediated PDT activated autophagy and inhibited the expression of pro-inflammatory factors of M1 peritoneal macrophage via the PI3K/AKT/mTOR signaling pathway.
    Keywords:  Autophagy; M1 Peritoneal macrophage; Photodynamic therapy; Reactive oxygen species; Upconversion nanoparticle
    DOI:  https://doi.org/10.33594/000000093
  40. Nutrients. 2019 Apr 27. pii: E963. [Epub ahead of print]11(5):
    Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo.
    Chenxuan Wu, Jun Liu, Yanbin Tang, Yanxiao Li, Qiaojuan Yan, Zhengqiang Jiang.
      Natural polysaccharides, particularly galactomannans, are potential candidates for treatment of alcoholic liver diseases (ALD). However, applications are restricted due to the physicochemical properties associated with the high molecular weight. In this work, guar gum galactomannans were partially hydrolyzed by β-mannanase, and the molecular mechanisms of hepatoprotective effects were elucidated both in vitro and in vivo. Release of lactate dehydrogenase and cytochrome C were attenuated by partially hydrolyzed guar gum (PHGG) in HepG2 cells, due to protected cell and mitochondrial membrane integrity. PHGG co-administration decreased serum amino transaminases and cholinesterase levels of acute alcohol intoxicated mice, while hepatic pathologic morphology was depleted. Activity of superoxide dismutase, catalase, and glutathione peroxidase was recovered to 198.2, 34.5, 236.0 U/mg protein, respectively, while malondialdehyde level was decreased by 76.3% (PHGG, 1000 mg/kg∙day). Co-administration of PHGG induced a 4.4-fold increment of p-AMPK expression, and lipid metabolism was mediated. PHGG alleviated toll-like-receptor-4-mediated inflammation via the signaling cascade of MyD88 and IκBα, decreasing cytokine production. Moreover, mediated expression of Bcl-2 and Bax was responsible for inhibited acute alcohol-induced apoptosis with suppressed cleavage of caspase 3 and PARP. Findings gained suggest that PHGG can be used as functional food supplement for the treatment of acute alcohol-induced liver injury.
    Keywords:  acute alcohol-induced liver injury; antioxidant activity; apoptosis; inflammation; lipid metabolism; partially hydrolyzed guar gum
    DOI:  https://doi.org/10.3390/nu11050963
  41. Biochem Biophys Res Commun. 2019 Apr 30. pii: S0006-291X(19)30805-8. [Epub ahead of print]
    Time-restricted feeding reduces high-fat diet associated placental inflammation and limits adverse effects on fetal organ development.
    Aditya Upadhyay, B Anjum, Nachiket M Godbole, Sangam Rajak, Pooja Shukla, Swasti Tiwari, Rohit A Sinha, Madan M Godbole.
      Maternal nutrition has become a major public health concern over recent years and is a known predictor of adverse long-term metabolic derangement in offspring. Time-restricted feeding (TRF), wherein food consumption is restricted to the metabolically active phase of the day, is a dietary approach that improves metabolic parameters when consuming a high-fat diet (HFD). Here, we tested whether TRF could reduce maternal HFD associated inflammation and thereby mitigate defects in fetal organ developmental. Female rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months prior to mating and continued throughout pregnancy. Rat dams were sacrificed at embryonic day 18.5 (ED18.5) and placental tissues from these rats were processed for the analysis of cellular apoptosis, inflammatory cytokines (TNFα and IL-6), oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Furthermore, fetal hepatic triglyceride (TG) content and fetal lung maturation were assessed at ED18.5. Biochemical analysis revealed that HFD-TRF rat had significantly lower serum TG levels and body weight compared to HFD-AL rats. Additionally, TRF significantly blocked HFD-induced placental apoptosis and inflammation via minimizing cellular stress, and restoring autophagic flux. In addition, fetal hepatosteatosis and delayed fetal lung maturation induced by HFD was significantly ameliorated in HFD-TRF compared to HFD-AL. Collectively, our results suggest that reducing placental inflammation via TRF could prevent adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.
    Keywords:  Autophagy; Hepatosteatosis; Inflammation; Obesity; Oxidative stress; Placenta; Time-restricted feeding
    DOI:  https://doi.org/10.1016/j.bbrc.2019.04.154
  42. Food Funct. 2019 Apr 30.
    Brosimone I, an isoprenoid-substituted flavonoid, induces cell cycle G1 phase arrest and apoptosis through ROS-dependent endoplasmic reticulum stress in HCT116 human colon cancer cells.
    Yueliang Zhao, Yue Zhou, Mingfu Wang.
      Brosimone I is an isoprenoid-substituted flavonoid from Artocarpus heterophyllus. Here, we reported for the first time that brosimone I induced cell cycle G1 phase arrest and apoptosis in HCT116 human colon cancer cells. Brosimone I treatment increased the cytosolic Ca2+ level, and subsequently activated the CaMKKβ-AMPK pathway. STO-609, a CaMKKβ inhibitor, and compound C, an AMPK-specific inhibitor, attenuated brosimone I-induced loss of cell viability in HCT116 cells. Furthermore, brosimone I enhanced ER stress. Salubrinal, an ER stress inhibitor, reduced brosimone I-induced cell growth inhibition. In addition, brosimone I was found to increase ROS generation and the inhibition of ROS formation by NAC, a ROS inhibitor, attenuated brosimone I-induced cell death, cytosolic Ca2+ increase, and ER stress markers. Collectively, our findings reveal that brosimone I induces cell cycle G1 phase arrest and apoptosis via the induction of ROS-mediated increased cytosolic Ca2+, ER stress, and the activation of the CaMKKβ-AMPK signaling pathway.
    DOI:  https://doi.org/10.1039/c8fo02315h
  43. Cell Prolif. 2019 Apr 29. e12609
    Inhibition of PI3K/mTOR increased the sensitivity of hepatocellular carcinoma cells to cisplatin via interference with mitochondrial-lysosomal crosstalk.
    Jiyao Sheng, Luyan Shen, Liankun Sun, Xuewen Zhang, Ranji Cui, Lizhong Wang.
       OBJECTIVES: The genotoxicity of cisplatin towards nuclear DNA is not sufficient to explain the cisplatin resistance of hepatocellular carcinoma (HCC) cells; cisplatin interacts with many organelles, which can influence the sensitivity. Here, we explored the role of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells.
    MATERIALS AND METHODS: Huh7 and HepG2 cells were subjected to different treatments. Flow cytometry was conducted to detect mitochondrial reactive oxygen species, mitochondrial mass, lysosomal function, mitochondrial membrane potential and apoptosis. Western blotting was performed to evaluate protein levels. The oxygen consumption rate was measured to evaluate mitochondrial function.
    RESULTS: Cisplatin activated mitophagy and lysosomal biogenesis, resulting in crosstalk between mitochondria and lysosomes and cisplatin resistance in HCC cells. Furthermore, a combination of cisplatin with the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor PKI-402 induced lysosomal membrane permeabilization. This effect changed the role of the lysosome from a protective one to that of a cell death promoter, completely destroying the mitochondrial-lysosomal crosstalk and significantly enhancing the sensitivity of HCC cells to cisplatin.
    CONCLUSIONS: This is the first evidence of the importance of mitochondrial-lysosomal crosstalk in the cisplatin resistance of HCC cells and of the destruction of this crosstalk by a PI3K/mTOR inhibitor to increase the sensitivity of HCC cells to cisplatin. This mechanism could be developed as a novel target for treatment of HCC in the future.
    Keywords:  chemotherapy resistance; hepatocellular carcinoma; lysosomal biogenesis; mitochondrial-lysosomal crosstalk; mitophagy
    DOI:  https://doi.org/10.1111/cpr.12609
  44. Life Sci. 2019 Apr 29. pii: S0024-3205(19)30329-7. [Epub ahead of print]
    Silymarin protects against radiocontrast-induced nephropathy in mice.
    Verônica de Souza Santos, Beatriz Peters, Larissa Zambom Côco, Gisele Maziero Alves, Arícia Leone Evangelista Monteiro de Assis, Breno Valentim Nogueira, Silvana Santos Meyrelles, Marcella Leite Porto, Elisardo Corral Vasquez, Bianca Prandi Campagnaro, Thiago Melo Costa Pereira.
      Silymarin, an extract from Silybum marianum (milk thistle) containing a standardized mixture of flavonolignans that ameliorates some types of liver disease and, more recently, kidney damage, could be used for the ROS-scavenging effect of these antioxidants. Furthermore, contrast-induced nephropathy (CIN) is an iatrogenic impairment of renal function in patients subjected to angiographic procedures for which there is not yet a successful preventative treatment. Recent evidence has shown that this event is related to tubular/vascular injury activated mainly by oxidative stress. However, whether this bioavailable and pharmacologically safe extract protects against CIN is not clear. We proposed to evaluate the possible protective role of the antioxidant silymarin in an experimental model of CIN. Adult male Swiss mice were separated into 6 groups and pretreated orally with silymarin (50, 200 and 300 mg/kg), N-acetylcysteine (200 mg/kg) or vehicle for 5 days before the CIN and control groups. Renal function was analyzed by plasma creatinine, urea and cystatin C levels. Additionally, blood reactive oxygen species (ROS) were evaluated using ROS bioavailability, protein oxidation and DNA damage. Renal oxidative damage was evaluated using apoptosis/cell viability assays and histological analysis. We showed that silymarin preserved renal function and decreased systemic and renal oxidative damage (antigenotoxic and antiapoptotic properties, respectively) in a dose-dependent manner and was superior to conventional treatment with N-acetylcysteine. Histologically, silymarin treatment also had beneficial effects on renal glomerular and tubular injuries. Therefore, silymarin prophylaxis may be an interesting strategy for the prevention of CIN.
    Keywords:  Apoptosis; Contrast renal toxicity; Contrast-induced nephropathy (CIN); Cystatin C; Oxidative stress; Silymarin
    DOI:  https://doi.org/10.1016/j.lfs.2019.04.061
  45. J Cell Physiol. 2019 May 02.
    GATA-1 isoforms differently contribute to the production and compartmentation of reactive oxygen species in the myeloid leukemia cell line K562.
    Patrizia Riccio, Raffaele Sessa, Sergio de Nicola, Fara Petruzziello, Silvia Trombetti, Giuseppe Menna, Giampiero Pepe, Pasquale Maddalena, Paola Izzo, Michela Grosso.
      Maintenance of a balanced expression of the two isoforms of the transcription factor GATA-1, the full-length protein (GATA-1FL ) and a shorter isoform (GATA-1 S ), contributes to control hematopoiesis, whereas their dysregulation can alter the differentiation/proliferation potential of hematopoietic precursors thereby eventually leading to a variety of hematopoietic disorders. Although it is well established that these isoforms play opposite roles in these remarkable processes, most of the molecular pathways involved remain unknown. Here, we demonstrate that GATA-1FL and GATA-1S are able to differently influence intracellular redox states and reactive oxygen species (ROS) compartmentation in the erythroleukemic K562 cell line, thus shedding novel mechanistic insights into the processes of cell proliferation and apoptosis resistance in myeloid precursors. Furthermore, given the role played by ROS signaling as a strategy to escape apoptosis and evade cell-mediated immunity in myeloid cells, this study highlights a mechanism through which aberrant expression of GATA-1 isoforms could play a role in the leukemogenic process.
    Keywords:  GATA-1; mitochondria remodeling; myeloid leukemia; oxidative stress; succinate dehydrogenase subunit C (SDHC)
    DOI:  https://doi.org/10.1002/jcp.28688
  46. Exp Cell Res. 2019 Apr 28. pii: S0014-4827(19)30212-5. [Epub ahead of print]
    The synthetic tubulysin derivative, tubugi-1, improves the innate immune response by macrophage polarization in addition to its direct cytotoxic effects in a murine melanoma model.
    Dijana Drača, Sanja Mijatović, Tamara Krajnović, Jelena Bogdanović Pristov, Tatjana Đukić, Goran N Kaluđerović, Ludger A Wessjohann, Danijela Maksimović-Ivanić.
      Synthetic tubugis are equally potent but more stable than their natural forms. Their anticancer potential was estimated on a solid melanoma in vitro and in vivo. Tubugi-1 induced the apoptosis in B16 cells accompanied with strong intracellular production of reactive species, subsequently imposing glutathione and thiol group depletion. Paradoxically, membrane lipids were excluded from the cascade of intracellular oxidation, according to malondialdehyde decrease. Although morphologically apoptosis was typical, externalization of phosphatidylserine (PS) as an early apoptotic event was not detected. Even their exposition is pivotal for apoptotic cell eradication, primary macrophages successfully eliminate PS-deficient tubugi-1 induced apoptotic cells. The tumor volume in animals exposed to the drug in therapeutic mode was reduced in comparison to control as well as to paclitaxel-treated animals. Importantly, macrophages isolated from tubugi-1 treated animals possessed conserved phagocytic activity and were functionally and phenotypically recognized as M1. The cytotoxic effect of tubugi-1 is accomplished through its ability to polarize the macrophages toward M1, probably by PS independent apoptotic cell engulfment. The unique potential of tubugi-1 to prime the innate immune response through the induction of a specific pattern of tumor cell apoptosis can be of extraordinary importance from fundamental and applicable aspects.
    Keywords:  Apoptosis; Cancer; Macrophage polarization; Phosphatidylserine; Tubulysin
    DOI:  https://doi.org/10.1016/j.yexcr.2019.04.028
  47. Theranostics. 2019 ;9(6): 1698-1713
    Berberine Protects Glomerular Podocytes via Inhibiting Drp1-Mediated Mitochondrial Fission and Dysfunction.
    Xin Qin, Yan Zhao, Jing Gong, Wenya Huang, Hao Su, Fen Yuan, Ke Fang, Dingkun Wang, Jingbin Li, Xin Zou, Lijun Xu, Hui Dong, Fuer Lu.
      Elevated levels of plasma free fatty acid (FFA) and disturbed mitochondrial dynamics play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, the mechanisms by which FFA leads to mitochondrial damage in glomerular podocytes of DKD and the effects of Berberine (BBR) on podocytes are not fully understood. Methods: Using the db/db diabetic mice model and cultured mouse podocytes, we investigated the molecular mechanism of FFA-induced disturbance of mitochondrial dynamics in podocytes and testified the effects of BBR on regulating mitochondrial dysfunction, podocyte apoptosis and glomerulopathy in the progression of DKD. Results: Intragastric administration of BBR for 8 weeks in db/db mice significantly reversed glucose and lipid metabolism disorders, podocyte damage, basement membrane thickening, mesangial expansion and glomerulosclerosis. BBR strongly inhibited podocyte apoptosis, increased reactive oxygen species (ROS) generation, mitochondrial fragmentation and dysfunction both in vivo and in vitro. Mechanistically, BBR could stabilize mitochondrial morphology in podocytes via abolishing palmitic acid (PA)-induced activation of dynamin-related protein 1 (Drp1). Conclusions: Our study demonstrated for the first time that BBR may have a previously unrecognized role in protecting glomerulus and podocytes via positively regulating Drp1-mediated mitochondrial dynamics. It might serve as a novel therapeutic drug for the treatment of DKD.
    Keywords:  Berberine; diabetic kidney disease; dynamin-related protein 1; mitochondrial fission; podocyte
    DOI:  https://doi.org/10.7150/thno.30640
  48. Molecules. 2019 Apr 29. pii: E1677. [Epub ahead of print]24(9):
    Modulating the Chemical and Biological Properties of Cancer Stem Cell-Potent Copper(II)-Nonsteroidal Anti-Inflammatory Drug Complexes.
    Jimin Shin, Arvin Eskandari, Kogularamanan Suntharalingam.
      Copper(II) complexes bearing nonsteroidal anti-inflammatory drugs (NSAIDs) are known to potently kill cancer stem cells (CSCs), a subpopulation of tumour cells with high metastatic and relapse fidelity. One of the major disadvantages associated to these copper(II) complexes is their instability in the presence of strong cellular reductants (such as ascorbic acid). Here we present a biologically stable copper(II)-NSAID complex containing a bathocuproinedisulfonic acid disodium ligand and two indomethacin moieties, Cu(bathocuproinedisulfonic acid disodium)(indomethacin)2, 2. The copper(II) complex, 2 kills bulk breast cancer cells and breast CSC equally (in the sub-micromolar range) and displays very low toxicity against non-tumorigenic breast and kidney cells (IC50 value > 100 µM). Three-dimensional cell culture studies show that 2 can significantly reduce the number and size of breast CSC mammospheres formed (from single suspensions) to a similar level as salinomycin (an established anti-breast CSC agent). The copper(II) complex, 2 is taken up reasonably by breast CSCs and localises largely in the cytoplasm (>90%). Cytotoxicity studies in the presence of specific inhibitors suggest that 2 induces CSC death via a reactive oxygen species (ROS) and cyclooxygenase isoenzyme-2 (COX-2) dependent apoptosis pathway.
    Keywords:  bioinorganic chemistry; cancer stem cells; copper; metallodrugs
    DOI:  https://doi.org/10.3390/molecules24091677
  49. Mater Sci Eng C Mater Biol Appl. 2019 Aug;pii: S0928-4931(18)31984-2. [Epub ahead of print]101 448-463
    Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics.
    Piyush Kumar Gupta, Sreenath Pappuru, Santosh Gupta, Bamadeb Patra, Debashis Chakraborty, Rama Shanker Verma.
      Recent research has been directed to the use of biocompatible and biodegradable metal-free fully alternating polyester nanomaterial in drug delivery application. The practice of triethyl borane (Et3B)/Bis(triphenylphosphoranylidene)ammonium chloride (PPNCl) Lewis pair as non-metallic catalyst was carried out to synthesize alternating copolymer of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) (poly(tBGE-alt-PA) copolymer) of low Mnvia nearly controlled ring-opening copolymerization (ROCOP) reaction. This biocompatible, hemocompatible, and biodegradable copolymer was used in the fabrication of different nanodrug formulations (NDFs) loaded with doxorubicin (DOX), curcumin (CUR) and their combination. Transmission electron microscope (TEM) imaging showed the spherical shape and core-shell internal structure for all NDFs with an average particle diameter ranging between 200 and 250 nm. X-ray diffraction (XRD) analysis displayed the amorphous nature of both DOX and CUR after their entrapment into the copolymer matrix. Differential scanning colorimetry (DSC) analysis presented no potential chemical interactions between the drug and copolymer. The cellular drug uptake study showed the increased uptake for all NDFs compared to free drug and exhibited higher DOX and CUR accumulation in dual-drug loaded nanoparticles treated pancreatic cancer (MIA PaCa-2) cells. The in vitro drug release kinetic study displayed the slow sustained drug release behavior with anomalous transport for both DOX and CUR in a defined physiological environment. Further, the anti-tumor efficacy of all NDFs was examined on several different cancer cell lines and maximum cytotoxicity was observed in MIA PaCa-2 cells with low inhibitory concentration (IC50) values. These NDFs inhibited the proliferation of MIA PaCa-2 cells due to cell cycle arrest in G2/M phase. In result, MIA PaCa-2 cells underwent apoptosis with significant changes in mitochondrial membrane potential and increased reactive oxygen species (ROS) level. In future, this study will open several novel insights related to the use of such biocompatible and biodegradable metal-free polyesters in targeted drug delivery, tissue engineering and other biomedical applications.
    Keywords:  Alternating copolymer; Cancer theranostics; Drug delivery; Lewis pair; Metal-free polyester
    DOI:  https://doi.org/10.1016/j.msec.2019.03.041
  50. Phytomedicine. 2019 Jan 29. pii: S0944-7113(19)30018-2. [Epub ahead of print]61 152846
    Supercritical CO2 fluid extraction of croton crassifolius Geisel root: Chemical composition and anti-proliferative, autophagic, apoptosis-inducing, and related molecular effects on A549 tumour cells.
    Chao Liu, Rui-Rui Zhang, Yue-Ming Wang, Jing Zhang, Qing Wang, An-Wei Cheng, Xu Guo, Xin-Kun Wang, Jin-Yue Sun.
       BACKGROUND: The use of plant essential oils as pharmaceuticals is a fast-growing market especially in China. Throughout the 20th century, a rapid increase took place in the use of many essential oil-derived products in the medicinal industry as nutraceuticals, medicinal supplements, and pharmaceuticals.
    PURPOSE: The objective of this study was to explore the chemical composition of Croton crassifolius essential oil as well as its potential anti-tumour properties and related anti-proliferative, autophagic, and apoptosis-inducing effects.
    METHODS: Supercritical CO2 fluid extraction technology was used to extract CCEO and the chemical constituents of the essential oil were identified by comparing the retention indices and mass spectra data taken from the NIST library with those calculated based on the C7-C40 n-alkanes standard. The cytotoxic activity and anti-proliferative effects of CCEO were evaluated against five cancer cell lines and one normal human cell line via CCK-8 assays. In addition, flow cytometry was used to detect cell cycle arrest. The efficacy of CCEO treatments in controlling cancer cell proliferation was assessed by cell cycle analysis, clonal formation assays, RT-qPCR, and western blot analysis. Autophagic and apoptosis-inducing effects of oils and the associated molecular mechanisms were assessed by flow cytometry, cell staining, reactive oxygen species assays, RT-qPCR, and western blot analysis.
    CONCLUSION: Forty compounds representing 92.90% of the total oil were identified in CCEO. The results showed that CCEO exerted a measurable selectivity for cancer cell lines, especially for A549 with the lowest IC50 value of 25.00 ± 1.62 μg/mL. Assessment of the anti-proliferative effects of CCEO on A549 cells showed that the oil inhibited cell proliferation and colony formation in a dose- and time-dependent manner. Investigation of the molecular mechanisms of cell cycle regulation confirmed that the oil arrested A549 cells in G2/M phase by decreasing the expression of cyclin B1-CDK1 and cyclin A-CDK1 and increasing the expression of cyclin-dependent kinase inhibitor (CKI) P21 at both the transcriptional and translational levels. Autophagy staining assays and western blot analysis revealed that CCEO promoted the formation of autophagic vacuoles in A549 cells and increased the expression of autophagy-related proteins beclin-1 and LC3-II in a dose-dependent manner. A series of apoptosis analyses indicated that CCEO induces apoptosis through a mitochondria-mediated intrinsic pathway. This study revealed that CCEO is a promising candidate for development into an anti-tumour drug of the future.
    Keywords:  Anti-proliferative; Apoptosis-inducing; Croton crassifolius essential oil; Molecular mechanism
    DOI:  https://doi.org/10.1016/j.phymed.2019.152846
  51. Biochem Biophys Res Commun. 2019 Apr 29. pii: S0006-291X(19)30811-3. [Epub ahead of print]
    Protective effect of the glucagon-like peptide-1 analogue liraglutide on carbon tetrachloride-induced acute liver injury in mice.
    Wen-Yong Zhang, Xiao-Fan Hu, Na Wan, Jin-Feng Zhang, Ping Yang, Qiang Wen, Wei-Jun Chen, Feng Zhu, Ming-Lu Liang, Long-Xian Cheng, Yan-Wen Shu.
      Acute liver injury seriously endangers human health. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has antioxidative effects in addition to being widely used in the treatment of type 2 diabetes and was reported to ameliorate liver diseases. The aim of this study was to evaluate the hepatoprotective effects of liraglutide on carbon tetrachloride (CCl4)-induced acute liver injury in mice and to investigate the mechanisms involved in this protective effect. Male BALB/c mice were pre-treated with liraglutide (200 μg/kg/day) by hypodermic injection for 3 days before a 0.1% (v/v) CCl4 (10 ml/kg, dissolved in olive oil) intraperitoneal injection, or post-treated with liraglutide once immediately after a CCl4 intraperitoneal injection. The experimental data showed that liraglutide treatment significantly decreased the serum ALT and AST levels and ameliorated the liver histopathological changes induced by CCl4. In addition, liraglutide pre-treatment dramatically increased the number of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and significantly reduced hepatocyte apoptosis after CCl4 treatment. As a consequence, liraglutide pre-treatment significantly prevented CCl4-induced malondialdehyde (MDA) production and increased the activity of the antioxidant superoxide dismutase (SOD) enzyme. In addition, liraglutide pre-treatment significantly ameliorated mitochondrial respiratory functions and ultrastructural features. Furthermore, liraglutide pre-treatment enhances the activation of the NRF2/HO-1 signaling pathway. In summary, liraglutide protects against CCl4-induced acute liver injury by protecting mitochondrial functions and inhibiting oxidative stress, which may partly involve the activation of NRF2/HO-1 signaling pathway.
    Keywords:  Acute liver injury; Carbon tetrachloride; Liraglutide; Mitochondria; NRF2/HO-1; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbrc.2019.04.160
  52. Biochem Biophys Res Commun. 2019 Apr 30. pii: S0006-291X(19)30781-8. [Epub ahead of print]
    CircPRKCI-miR-545/589-E2F7 axis dysregulation mediates hydrogen peroxide-induced neuronal cell injury.
    Qiantao Cheng, Xiangyang Cao, Liujun Xue, Lei Xia, Yun Xu.
      Excessive oxidative stress induces significant injury and cytotoxicity to neuronal cells. The current study tested expression and the potential function of the circular RNA PRKCI (circPRKCI) in oxidative stress-injured neuronal cells. In cultured SH-SY5Y neuronal cells, hydrogen peroxide (H2O2) downregulated circPRKCI expression, causing accumulation of miR-545 and miR-589, but reduction of their target, the transcription factor E2F7. Importantly, ectopic overexpression of circPRKCI in SH-SY5Y cells significantly attenuated H2O2-induced cytotoxicity. Conversely, siRNA-mediated knockdown of circPRKCI induced SH-SY5Y cell death and apoptosis. Further studies demonstrated that H2O2-induced cytotoxicity in SH-SY5Y cells was inhibited by miR-545/589 inhibitors, but mimicked by miR-545/589 mimics. Importantly, CRISPR/Cas9-mediated knockout (KO) of E2F7 induced potent SH-SY5Y cell death and apoptosis. Furthermore, transfection of circPRKCI siRNA or miR-545/589 mimics were ineffective in E2F7 KO cells. In the primary human neurons, H2O2 stimulation similarly induced circPRKCI downregulation, miR-545/589 accumulation and E2F7 reduction. Moreover, H2O2-induced death and apoptosis in the primary neurons were significantly inhibited by circPRKCI overexpression or miR-545/589 inhibitors. Taken together, our results show that dysregulation of circPRKCI-miR-545/589-E2F7 axis mediated H2O2-induced neuronal cell injury. Targeting this novel cascade could be a fine strategy to protect neurons from oxidative stress.
    Keywords:  CircPRKCI; E2F7; Hydrogen peroxide; Neurons; miR-545/589
    DOI:  https://doi.org/10.1016/j.bbrc.2019.04.131
  53. Eur J Med Chem. 2019 Apr 16. pii: S0223-5234(19)30330-7. [Epub ahead of print]174 236-251
    Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors.
    Guiping Cai, Wenying Yu, Dongmei Song, Wenda Zhang, Jianpeng Guo, Jiawen Zhu, Yuhao Ren, Lingyi Kong.
      STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.
    Keywords:  Antitumor activity; Benzo[b]thiophene 1, 1-Dioxide; Mitochondrial apoptosis pathway; N, N-Diethyl-7-aminocoumarin fluorophore; STAT3; Ser727 phosphorylation
    DOI:  https://doi.org/10.1016/j.ejmech.2019.04.024
  54. Theranostics. 2019 ;9(6): 1794-1808
    H2Se Induces Reductive Stress in HepG2 Cells and Activates Cell Autophagy by Regulating the Redox of HMGB1 Protein under Hypoxia.
    Xiaohong Pan, Xiaoxiao Song, Cheng Wang, Tingting Cheng, Dongrui Luan, Kehua Xu, Bo Tang.
      Rationale: Selenium has been shown to have chemotherapeutic effects against cancer. However, the anti-cancer mechanism of selenium is not fully understood, and the role of hydrogen selenide (H2Se), which is a common metabolite of dietary selenium compounds, has not been elucidated due to the lack of detection methods. In this study, we revealed a new anti-cancer mechanism of selenite with the help of a H2Se fluorescent probe. Methods: HepG2 cells were cultured under a simulated tumor hypoxic microenvironment. The H2Se and H2O2 levels were detected by fluorescent probes in living cells and in mice. Autophagic and apoptotic proteins were detected by Western blotting. The redox of HMGB1 protein were analyzed by non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis. Results: After pharmacological doses of Na2SeO3 treatment of HepG2 cells under hypoxic conditions, high levels of H2Se were produced before cell death. The H2Se accumulation resulted in reductive stress instead of oxidative stress, which was induced by Na2SeO3 treatment under normoxic conditions. Furthermore, H2Se targeted the HMGB1 protein and induced cell autophagy. H2Se could interrupt the disulfide bond in HMGB1 and promote its secretion. The reduced HMGB1 outside the cells stimulated cell autophagy by inhibiting the Akt/mTOR axis. Here, autophagy played a dual role, i.e., mild autophagy inhibited apoptosis, while excessive autophagy led to autophagy-associated cell death. Conclusions: These results show that H2Se plays a key role during HepG2 cell death induced by selenite. Our findings reveal a new anti-cancer mechanism of selenite and provide a new research area for selenium studies.
    DOI:  https://doi.org/10.7150/thno.31841
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