bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019‒06‒23
75 papers selected by
Gavin McStay
Staffordshire University
  1. Theaflavic acid from black tea protects PC12 cells against ROS-mediated mitochondrial apoptosis induced by OGD/R via activating Nrf2/ARE signaling pathway.
  2. Rutin attenuates vancomycin-induced renal tubular cell apoptosis via suppression of apoptosis, mitochondrial dysfunction, and oxidative stress.
  3. Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of coptisine against oxidative stress-induced DNA damage and apoptosis in HaCaT keratinocytes.
  4. Methylmercury, cadmium and arsenic(III)-induced toxicity, oxidative stress and apoptosis in Pacific red snapper leukocytes.
  5. Protective effect of anisodamine in rats with glycerol-induced acute kidney injury.
  6. NADPH Oxidase Hyperactivity Contributes to Cardiac Dysfunction and Apoptosis in Rats with Severe Experimental Pancreatitis through ROS-Mediated MAPK Signaling Pathway.
  7. Tetramethylpyrazine Prevents Contrast-Induced Nephropathy via Modulating Tubular Cell Mitophagy and Suppressing Mitochondrial Fragmentation, CCL2/CCR2-Mediated Inflammation, and Intestinal Injury.
  8. ROS-Mediated Cancer Cell Killing through Dietary Phytochemicals.
  9. A novel polysaccharide from Lentinus edodes mycelia protects MIN6 cells against high glucose-induced damage via the MAPKs and Nrf2 pathways.
  10. Celecoxib, indomethacin, and ibuprofen prevent 6-hydroxydopamine-induced PC12 cell death through the inhibition of NFκB and SAPK/JNK pathways.
  11. Ultraviolet B irradiation induced Nrf2 degradation occurs via activation of TRPV1 channels in human dermal fibroblasts.
  12. BA6 Induces Apoptosis via Stimulation of Reactive Oxygen Species and Inhibition of Oxidative Phosphorylation in Human Lung Cancer Cells.
  13. Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs alone and in combination with N-acetyl cysteine in tumor-bearing mice.
  14. Aloe-Emodin Attenuates Myocardial Infarction and Apoptosis Via Up-Regulating MiR-133 Expression.
  15. MARVELD1 attenuates arsenic trioxide-induced apoptosis in liver cancer cells by inhibiting reactive oxygen species production.
  16. Antitumor Effects of 8-Deoxylactucin in RB355 Human Retinoblastoma Cells Are Mediated via Apoptosis Induction, Reactive Oxygen Species Production, and Cell Cycle Arrest.
  17. β-caryophyllene, a dietary phytocannabinoid attenuates oxidative stress, inflammation, apoptosis and prevents structural alterations of the myocardium against doxorubicin-induced acute cardiotoxicity in rats: An in vitro and in vivo study.
  18. Bullfrog oil (Rana catesbeiana Shaw) induces apoptosis, in A2058 human melanoma cells by mitochondrial dysfunction triggered by oxidative stress.
  19. Yellow Wine Polyphenolic Compounds prevents Doxorubicin-induced cardiotoxicity through activation of the Nrf2 signalling pathway.
  20. The biochemical and molecular mechanisms involved in the role of micro-tumor environment stress in development of drug resistance.
  21. Protocatechuic acid inhibits testicular and epididymal toxicity associated with methotrexate in rats.
  22. Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion.
  23. Protective effects of Ganoderma lucidum triterpenoids on oxidative stress and apoptosis in the spleen of chickens induced by cadmium.
  24. Coordination between NADPH oxidase and vascular peroxidase 1 promotes dysfunctions of endothelial progenitor cells in hypoxia-induced pulmonary hypertensive rats.
  25. Chronic Alcohol Exposure Induced Neuroapoptosis: Diminishing Effect of Ethyl Acetate Fraction from Aralia elata.
  26. Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling.
  27. Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach.
  28. Induction of apoptosis by piperine in human cervical adenocarcinoma via ROS mediated mitochondrial pathway and caspase-3 activation.
  29. Studies of anticancer activity in vitro and in vivo of iridium(III) polypyridyl complexes-loaded liposomes as drug delivery system.
  30. FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT.
  31. Paeoniflorin protects spiral ganglion neurons from cisplatin-induced ototoxicity: Possible relation to PINK1/BAD pathway.
  32. DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2.
  33. Calotropis gigantea extract induces apoptosis through extrinsic/intrinsic pathways and reactive oxygen species generation in A549 and NCI-H1299 non-small cell lung cancer cells.
  34. Anticancer effect of inactivated Sendai virus strain Tianjin on human osteosarcoma HOS cells.
  35. Toxic effects of 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal on the maturation and subsequent development of murine oocyte.
  36. Microcystin-LR promotes necroptosis in primary mouse hepatocytes by overproducing reactive oxygen species.
  37. Mst1 deletion reduces hyperglycemia-mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway.
  38. Cytotoxicity and apoptogenic properties of the standardized extract of Portulaca oleracea on glioblastoma multiforme cancer cell line (U-87): a mechanistic study.
  39. Lycopene Protects Cortical Neurons via Oxidative Stress-mediated ΔN-Bcl-xL Formation (FS05-08-19).
  40. Tempol Protects Against Acetaminophen Induced Acute Hepatotoxicity by Inhibiting Oxidative Stress and Apoptosis.
  41. Abnormal Ribosome Biogenesis Partly Induced p53-Dependent Aortic Medial Smooth Muscle Cell Apoptosis and Oxidative Stress.
  42. CARD9 inhibits mitochondria-dependent apoptosis of cardiomyocytes under oxidative stress via interacting with Apaf-1.
  43. Mitophagy in Yeast.
  44. Hepatoprotective Effect of Curcumin on Hepatocellular Carcinoma Through Autophagic and Apoptic Pathways.
  45. Effects of cyclophosphamide on the phenotypes and functions of THP-1 cells.
  46. Stress Hormone and Oxidative Stress Biomarkers Link Obesity and Diabetes with Reduced Fertility Potential.
  47. Synergistic antibacterial activity of gold nanoparticles caused by apoptosis-like death.
  48. Comparison of the effects of adipose tissue mesenchymal stromal cell-derived exosomes with conditioned media on neutrophil function and apoptosis.
  49. Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway.
  50. NANOG Alleviates the Damage of Human Hair Follicle Mesenchymal Stem Cells Caused by H2O2 through Activation of AKT Pathway.
  51. Hepatic DNA Damage Induced by Electronic Cigarette Exposure Is Associated With the Modulation of NAD+/PARP1/SIRT1 Axis.
  52. 6-shogaol, a active constiuents of ginger prevents UVB radiation mediated inflammation and oxidative stress through modulating NrF2 signaling in human epidermal keratinocytes (HaCaT cells).
  53. Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy.
  54. Additives migrating from 3D-printed plastic induce developmental toxicity and neuro-behavioural alterations in early life zebrafish (Danio rerio).
  55. Complex I and MDM2: hit me baby one more time.
  56. Huangqi decoction inhibits hyperglycemia-induced podocyte apoptosis by down-regulated Nox4/p53/Bax signaling in vitro and in vivo.
  57. Global gene expression revealed an increase of HMGB1 and APEX1 proteins and their involvement in oxidative stress, apoptosis and inflammation pathways among beta-thalassaemia intermedia and major phenotypes.
  58. Cell Stress - a new journal for cellular pathophysiology.
  59. Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells.
  60. Neuroprotective effect of omega-3 fatty acids on spinal cord injury induced rats.
  61. Gasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis.
  62. Early and Synergistic Recovery Effect of Herbal Combination on Surgically Corrected Varicocele.
  63. Effects of Dietary Zearalenone on Oxidative Stress, Cell Apoptosis, and Tight Junction in the Intestine of Juvenile Grass Carp (Ctenopharyngodon idella).
  64. Melatonin Abrogates the Anti-Developmental Effect of the AKT Inhibitor SH6 in Bovine Oocytes and Embryos.
  65. Cortisol Excess-Mediated Mitochondrial Damage Induced Hippocampal Neuronal Apoptosis in Mice Following Cold Exposure.
  66. Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells.
  67. Doxorubicin and siRNA-PD-L1 co-delivery with T7 modified ROS-sensitive nanoparticles for tumor chemoimmunotherapy.
  68. The Roles of Environmental Factors in Regulation of Oxidative Stress in Plant.
  69. Dark Sweet Cherry phenolics as Dietary Chemopreventive/therapeutic Compounds for Aggressive Breast Cancer Cell Growth with No Toxicity to Normal Breast Cells (FS13-03-19).
  70. Isoflavone ME-344 disrupts redox homeostasis and mitochondrial function by targeting Heme Oxygenase 1.
  71. Neuroprotective mechanism of low-dose sodium nitrite in oxygen-glucose deprivation model of cerebral ischemic stroke in PC12 cells.
  72. Mitochondrial Division Inhibitor 1 Attenuates Mitophagy in a Rat Model of Acute Lung Injury.
  73. Enrichment of novel quinazoline derivatives with high antitumor activity in mitochondria tracked by its self-fluorescence.
  74. Epimedin C protects H2O2-induced peroxidation injury by enhancing the function of endothelial progenitor HUVEC populations.
  75. L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70.
  1. J Nat Med. 2019 Jun 21.
    Theaflavic acid from black tea protects PC12 cells against ROS-mediated mitochondrial apoptosis induced by OGD/R via activating Nrf2/ARE signaling pathway.
    Yan Li, Jing Shi, Xinting Sun, Yafeng Li, Yinyin Duan, Huankai Yao.
      Cerebral ischemic stroke is a severe disease afflicting people worldwide. Phytochemicals play a pivotal role in the discovery of novel therapeutic approaches for the prevention of ischemic stroke. In our continual search for bioactive natural products for the treatment of ischemic stroke, we have evaluated the protective effects of theaflavic acid (TFA) from black tea using PC12 cells injured by oxygen and glucose deprivation/restoration (OGD/R), and investigated the possible mechanisms. The results showed that TFA can protect PC12 cells against OGD/R through increasing cell viability and decreasing intracellular lactate dehydrogenase (LDH) release. Further investigations found that TFA could inhibit the overproduction of intracellular reactive oxygen species (ROS), reduce malondialdehyde content, and elevate superoxide dismutase activity, which implied that TFA suppresses oxidative stress in PC12 cells induced by OGD/R. In addition, overload of intracellular calcium and collapse of the mitochondrial membrane potential were improved in the presence of TFA, and the activity of caspase-3 was significantly reduced by TFA. Western blot analysis showed that the expression of Bcl-2 was up-regulated while Bax was down-regulated. Therefore, it can be concluded that TFA can inhibit mitochondria-dependent apoptosis of PC12 cells induced by OGD/R. In addition, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway was explored to elucidate the mechanism by which TFA inhibits ROS-mediated apoptosis in PC12 cells. The results revealed that TFA promoted the translocation of Nrf2 into nuclei, enhanced the transcriptional activity of ARE, and up-regulated expression of downstream HO-1, which indicates that the Nrf2/ARE signaling pathway is involved in the protection by TFA of PC12 cells injured by OGD/R.
    Keywords:  Apoptosis; Ischemic stroke; Nrf2/ARE signaling pathway; Oxidative stress; PC12 cells; Theaflavic acid
    DOI:  https://doi.org/10.1007/s11418-019-01333-4
  2. Phytother Res. 2019 Jun 17.
    Rutin attenuates vancomycin-induced renal tubular cell apoptosis via suppression of apoptosis, mitochondrial dysfunction, and oxidative stress.
    Shaoqi Qu, Cunchun Dai, Hui Guo, Cuncai Wang, Zhihui Hao, Qihe Tang, Haixia Wang, Yanping Zhang.
      Vancomycin is a glycopeptide antibiotic widely used to treat infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is a major adverse side effect, and the development of effective nephroprotective agents remains a priority in antimicrobial chemotherapy. In this study, we investigated the cell protective effects of the flavonol glycoside rutin against vancomycin-induced toxicity. Vancomycin added to porcine renal tubular LLC-PK1 cells caused an increase of production of intracellular reactive oxygen species and subsequent apoptotic cell death. Pretreatment of LLC-PK1 cells with rutin at 5, 10, and 20 μM for 2 hr prior to 2-mM vancomycin exposure for 24 hr significantly decreased intracellular reactive oxygen species and increased superoxide dismutase and catalase activities. Rutin pretreatment also protected cells from vancomycin-induced caspase activation, mitochondrial membrane depolarization, and subsequent apoptosis. This study demonstrates a protective effect of rutin and suggests that rutin coadministration is an alternative therapy for treatment of vancomycin-induced nephrotoxicity.
    Keywords:  apoptosis; nephrotoxicity; rutin; vancomycin
    DOI:  https://doi.org/10.1002/ptr.6391
  3. Gen Physiol Biophys. 2019 Jun 20.
    Activation of the Nrf2/HO-1 signaling pathway contributes to the protective effects of coptisine against oxidative stress-induced DNA damage and apoptosis in HaCaT keratinocytes.
    Yung Hyun Choi.
      In this study, the protective effect of coptisine on the oxidative damage-mediated apoptosis was evaluated in cultured human HaCaT keratinocytes. The results demonstrate that preincubation of cells with coptisine prior to H2O2 stimulation resulted in significant inhibition of cytotoxicity and DNA damage associated with the inhibition of reactive oxygen species (ROS) accumulation. Coptisine also restored H2O2-induced mitochondrial dysfunction and decrease of ATP production, and prevented apoptosis by inhibiting Bax/Bcl-2 ratio, caspase-3 activity, and poly(ADP-ribose) polymerase degradation. Interestingly, the expressions of nuclear factor-erythroid-2-related factor 2 (Nrf2) and its active form, phosphorylated Nrf2, were strikingly promoted by coptisine in the presence of H2O2, which was associated with a marked increase in the expression of heme oxygenase-1 (HO-1). However, coptisine-induced HO-1 expression was completely abrogated by Nrf2-specific small interfering RNA (Nrf2-siRNA), which suggests that the increased expression of HO-1 by coptisine is Nrf2-dependent. In addition, Nrf2-siRNA transfection significantly eliminated the protective effect of coptisine on H2O2-induced cytotoxicity, and this effect was similar to that by zinc protoporphyrin IX (ZnPP), an HO-1 specific inhibitor. Furthermore, the protective effects of coptisine against H2O2-induced cytotoxicity were abolished by ZnPP, indicating that coptisine protects keratinocytes against oxidative stress-induced injury through activation of the Nrf2/HO-1 signaling pathway.
    DOI:  https://doi.org/10.4149/gpb_2019014
  4. Aquat Toxicol. 2019 Jun 11. pii: S0166-445X(19)30327-3. [Epub ahead of print]213 105223
    Methylmercury, cadmium and arsenic(III)-induced toxicity, oxidative stress and apoptosis in Pacific red snapper leukocytes.
    Martha Reyes-Becerril, Carlos Angulo, Veronica Sanchez, Alberto Cuesta, Ariel Cruz.
      Methylmercury (MeHg), cadmium (Cd) and arsenic (As(III)) are among the most toxic metals in aquatic systems that have been associated with multiple animal and human health problems. This study investigated cytotoxic, oxidative stress, and apoptosis effects on fish leukocytes following their exposure to metals. A preliminary study indicated that leukocytes exposed to MeHg at a concentration of 0.01 mM, Cd at 0.05 mM, and As(III) at 2 mM showed a time-dependent cell viability reduction (around 40%), so they were selected for further experiments. To evaluate the effect of MeHg, Cd and As(III) on Pacific red snapper Lutjanus peru, we measured cytotoxicity, reactive oxygen species, antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT)), nitric oxide production, apoptosis-related and immune-related genes on head-kidney and spleen leukocytes following exposure to MeHg (0.01 mM), Cd (0.05 mM) and As(III) (2 mM) for 30 min and 2 h. Reactive oxygen species (ROS) generation highly increased in time-dependent doses in head-kidney leukocytes compared with the control group. Regarding antioxidant activity, SOD increased significantly in leukocytes exposed to any heavy metals after two h. Expressly, CAT activity decreased in those leukocytes exposed to Cd and As(III). Apoptotic function genes (Casp-2, Casp-3, and Casp-7) strongly up-regulated after heavy metal exposure, but Cd was more toxic. Finally, granzyme A and perforin 1 strongly up-regulated in leukocytes exposed to MeHg and As(III) compared with the control group. Our data showed that MeHg, Cd, and As(III) might have been cytotoxic and induced oxidative stress and apoptosis with possible biological consequences in fish.
    Keywords:  Apoptosis; Leukocytes; Metals; Oxidative stress; Pacific red snapper; Toxicity
    DOI:  https://doi.org/10.1016/j.aquatox.2019.105223
  5. BMC Nephrol. 2019 Jun 17. 20(1): 223
    Protective effect of anisodamine in rats with glycerol-induced acute kidney injury.
    Yun-Feng Li, Bing-Yuan Xu, Ran An, Xin-Fang Du, Kun Yu, Jia-Hua Sun, Guo-Hong Zhang, Wei Wang, Li-Ping An, Guang-Li Wu.
      BACKGROUND: Anisodamine is used for the treatment of reperfusion injury in various organs. In this study, we investigated the effectiveness and mechanisms of action of anisodamine in promoting recovery from glycerol-induced acute kidney injury (AKI).METHODS: We compared the protective effects of atropine and anisodamine in the rat model of glycerol-induced AKI. We examined signaling pathways involved in oxidative stress, inflammation and apoptosis, as well as expression of kidney injury molecule-1 (KIM-1). Renal injury was assessed by measuring serum creatinine and urea, and by histologic analysis. Rhabdomyolysis was evaluated by measuring creatine kinase levels, and oxidative stress was assessed by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) levels in kidney tissues. Inflammation was assessed by quantifying interleukin 6 (IL-6) and CD45 expression. Apoptosis and necrosis were evaluated by measuring caspase-3 (including cleaved caspase 3) and RIP3 levels, respectively.
    RESULTS: Glycerol administration resulted in a higher mean histologic damage score, as well as increases in serum creatinine, urea, creatine kinase, reactive oxygen species (ROS), MDA, IL-6, caspase-3 and KIM-1 levels. Furthermore, glycerol reduced kidney tissue SOD activity. All of these markers were significantly improved by anisodamine and atropine. However, the mean histologic damage score and levels of urea, serum creatinine, creatine kinase, ROS and IL-6 were lower in the anisodamine treatment group compared with the atropine treatment group.
    CONCLUSION: Pretreatment with anisodamine ameliorates renal dysfunction in the rat model of glycerol-induced rhabdomyolytic kidney injury by reducing oxidative stress, the inflammatory response and cell death.
    Keywords:  Acute kidney injury; Anisodamine; Atropine; Rhabdomyolysis
    DOI:  https://doi.org/10.1186/s12882-019-1394-y
  6. Oxid Med Cell Longev. 2019 ;2019 4578175
    NADPH Oxidase Hyperactivity Contributes to Cardiac Dysfunction and Apoptosis in Rats with Severe Experimental Pancreatitis through ROS-Mediated MAPK Signaling Pathway.
    Yi Wen, Ruohong Liu, Ning Lin, Hao Luo, Jiajia Tang, Qilin Huang, Hongyu Sun, Lijun Tang.
      NADPH oxidase (Nox) is considered a major source of reactive oxygen species (ROS) in the heart in normal and pathological conditions. However, the role of Nox in severe acute pancreatitis- (SAP-) associated cardiac injury remains unclear. Therefore, we aim to investigate the contribution of Nox to SAP-associated cardiac injury and to explore the underlying molecular mechanisms. Apocynin, a Nox inhibitor, was given at 20 mg/kg for 30 min before SAP induction by a retrograde pancreatic duct injection of 5% sodium taurocholate. Histopathological staining, Nox activity and protein expression, oxidative stress markers, apoptosis and associated proteins, cardiac-related enzyme indexes, and cardiac function were assessed in the myocardium in SAP rats. The redox-sensitive MAPK signaling molecules were also examined by western blotting. SAP rats exhibited significant cardiac impairment along with increased Nox activity and protein expression, ROS production, cell apoptosis, and proapoptotic Bax and cleaved caspase-3 protein levels. Notably, Nox inhibition with apocynin prevented SAP-associated cardiac injury evidenced by a decreased histopathologic score, cardiac-related enzymes, and cardiac function through the reduction of ROS production and cell apoptosis. This protective role was further confirmed by a simulation experiment in vitro. Moreover, we found that SAP-induced activation in MAPK signaling molecules in cardiomyocytes was significantly attenuated by Nox inhibition. Our data provide the first evidence that Nox hyperactivation acts as the main source of ROS production in the myocardium, increases oxidative stress, and promotes cell apoptosis via activating the MAPK pathway, which ultimately results in cardiac injury in SAP.
    DOI:  https://doi.org/10.1155/2019/4578175
  7. Oxid Med Cell Longev. 2019 ;2019 7096912
    Tetramethylpyrazine Prevents Contrast-Induced Nephropathy via Modulating Tubular Cell Mitophagy and Suppressing Mitochondrial Fragmentation, CCL2/CCR2-Mediated Inflammation, and Intestinal Injury.
    Xuezhong Gong, Yiru Duan, Junli Zheng, Zi Ye, Tom K Hei.
      Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI), but detailed pathogenesis and effectual remedy remain elusive. Here, we tested the hypothesis that contrast media (CM) impaired mitochondrial quality control (MQC) in tubules, including mitochondrial fragmentation and mitophagy, induced systemic inflammation, and intestinal injury. Since we previously demonstrated that the natural antioxidant 2,3,5,6-tetramethylpyrazine (TMP) can be a protectant against CIN, we moreover investigated the involved renoprotective mechanisms of TMP. In a well-established CIN rat model, renal functions, urinary AKI biomarkers, and renal reactive oxygen species (ROS) production were measured. Mitochondrial damage and mitophagy were detected by transmission electron microscopy (TEM) and western blot. The abundance of Drp1 and Mfn2 by western blot and immunohistochemistry (IHC) was used to evaluate mitochondrial fragmentation. TUNEL staining, TEM, and the abundance of cleaved-caspase 3 and procaspase 9 were used to assay apoptosis. We demonstrated that increased mitophagy, mitochondrial fragmentation, ROS generation, autophagy, and apoptosis occurred in renal tubular cells. These phenomena were accompanied by renal dysfunction and an increased excretion of urinary AKI biomarkers. Meanwhile, CM exposure resulted in concurrent small intestinal injury and villous capillary endothelial apoptosis. The abundance of the inflammatory cytokines CCL2 and CCR2 markedly increased in the renal tubules of CIN rats, accompanied by increased concentrations of IL-6 and TNF-α in the kidneys and the serum. Interestingly, TMP efficiently prevented CM-induced kidney injury in vivo by reversing these pathological processes. Mechanistically, TMP inhibited the CM-induced activation of the CCL2/CCR2 pathway, ameliorated renal oxidative stress and aberrant mitochondrial dynamics, and modulated mitophagy in tubular cells. In summary, this study demonstrated novel pathological mechanisms of CIN, that is, impairing MQC, inducing CCL2/CCR2-mediated inflammation and small intestinal injury, and provided novel renoprotective mechanisms of TMP; thus, TMP may be a promising therapeutic agent for CIN.
    DOI:  https://doi.org/10.1155/2019/7096912
  8. Oxid Med Cell Longev. 2019 ;2019 9051542
    ROS-Mediated Cancer Cell Killing through Dietary Phytochemicals.
    Saranya NavaneethaKrishnan, Jesusa L Rosales, Ki-Young Lee.
      Reactive oxygen species (ROS) promote carcinogenesis by inducing genetic mutations, activating oncogenes, and raising oxidative stress, which all influence cell proliferation, survival, and apoptosis. Cancer cells display redox imbalance due to increased ROS level compared to normal cells. This unique feature in cancer cells may, therefore, be exploited for targeted therapy. Over the past few decades, natural compounds have attracted attention as potential cancer therapies because of their ability to maintain cellular redox homeostasis with minimal toxicity. Preclinical studies show that bioactive dietary polyphenols exert antitumor effects by inducing ROS-mediated cytotoxicity in cancer cells. These bioactive compounds also regulate cell proliferation, survival, and apoptotic and antiapoptotic signalling pathways. In this review, we discuss (i) how ROS is generated and (ii) regulated and (iii) the cell signalling pathways affected by ROS. We also discuss (iv) the various dietary phytochemicals that have been implicated to have cancer therapeutic effects through their ROS-related functions.
    DOI:  https://doi.org/10.1155/2019/9051542
  9. Food Nutr Res. 2019 ;63
    A novel polysaccharide from Lentinus edodes mycelia protects MIN6 cells against high glucose-induced damage via the MAPKs and Nrf2 pathways.
    Xiangyu Cao, Dan Liu, Ying Xia, Tiange Cai, Yin He, Jianli Liu.
      Background: Diabetes mellitus is one of the most widespread diseases in the world, high glucose can damage islet cells, it is important to discover new natural products to inhibit high glucose damage. The protective effects and mechanisms of a novel Lentinus edodes mycelia polysaccharide (LMP) against damage induced by high glucose in MIN6 cells were explored.Methods: Cell viability, malondialdehyde (MDA) inhibition, lactate dehydrogenase (LDH) release and the activity of superoxide dismutase (SOD) were evaluated under 40 mM glucose with or without LMP for 48 h. Cell signaling pathway analysis was performed to investigate the possible mechanisms of the protective effects of LMP in MIN6 cells.
    Results: The results showed that LMP could increase cell viability and the activity of SOD, decrease the reactive oxygen species ( ROS) production, and reduce the MDA content and LDH release in high glucose-induced MIN6 cells. Moreover, LMP prevented high glucose-induced apoptosis by decreasing the expression of Bax and the activation of caspase-1 and caspase-3. Cell signaling pathway analysis showed that p38 mitogen-activated protein kinase (MAPK) and JNK pathways were inhibited and the Nrf2 pathway was activated after treated with LMP.
    Conclusion: The protective effects of LMP against MIN6 cells damage induced by high glucose might rely on the regulation of the MAPK and Nrf2 pathways. These results indicated that LMP had great potential as a therapeutic agent for the treatment of diabetes mellitus.
    Keywords:  LMP; MAPK; MIN6 cells; Nrf2; Oxidative stress; ROS
    DOI:  https://doi.org/10.29219/fnr.v63.1598
  10. Iran J Basic Med Sci. 2019 May;22(5): 477-484
    Celecoxib, indomethacin, and ibuprofen prevent 6-hydroxydopamine-induced PC12 cell death through the inhibition of NFκB and SAPK/JNK pathways.
    Elham Ramazani, Zahra Tayarani-Najaran, Masoud Fereidoni.
      Objectives: The possible action of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of reactive oxygen species (ROS) and also as anti-apoptotic agents may suggest them as putative agents for the treatment of neurodegenerative diseases. This study was designed to explore some pathways alterations induced by NSAIDs following 6-hydroxydopamine (6-OHDA)-induced cell death in PC12 cells as an in vitro model of Parkinson's disease (PD) and to compare the effects of celecoxib, indomethacin and ibuprofen.Materials and Methods: The cell viability, ROS content, glutathione (GSH) level, and apoptosis were measured using resazurin, dichlorofluorescein diacetate (DCFH-DA), 5,5'-dithiobis-2-nitrobenzoic acid (DTNB), propidium iodide (PI) and flowcytometry, real-time PCR and western blot.
    Results: Based on the results, pretreatment with celecoxib, indomethacin and ibuprofen for 24 hr significantly induced concentration and time-dependent protection against 6-OHDA-induced PC12 cell death. Cell viability (P<0.001), GSH level (P<0.01) and cytoplasmic content of nuclear factor kappa B (NFκB) (P<0.01) were increased, also ROS content (P<0.001) and apoptosis biomarkers such as the cleaved caspase-3 (P<0.001), Bax (P<0.01), phospho- stress-activated protein kinases / c-Jun N-terminal kinases (P-SAPK/JNK) (P<0.01) and cleaved poly ADP ribose polymerase (PARP) (P<0.001) protein levels were all decreased after pretreatment of cells with NSAIDs in 6-OHDA-induced PC12 cells.
    Conclusion: It is suggested that NFκB and SAPK/JNK pathways have an important role in 6-OHDA-induced cell injury. Overall, it seems that pretreatment with NSAIDs protect dopaminergic cells and may have the potential to slow the progression of PD.
    Keywords:  Apoptosis; Glutathione; NSAIDs; PC12 cells; Parkinson's disease; ROS
    DOI:  https://doi.org/10.22038/IJBMS.2019.34011.8091
  11. Free Radic Biol Med. 2019 Jun 17. pii: S0891-5849(18)32230-5. [Epub ahead of print]
    Ultraviolet B irradiation induced Nrf2 degradation occurs via activation of TRPV1 channels in human dermal fibroblasts.
    Kuo-Feng Huang, Kuo-Hsing Ma, Tian-You Jhap, Pei-Shan Liu, Sheau-Huei Chueh.
      Ultraviolet (UV) irradiation causes cellular oxidative stress. Under redox imbalance, Keap1-dependent Nrf2 degradation is minimal. In this study, we examined the role of Ca2+ in Nrf2 homeostasis after UVB irradiation using human dermal fibroblasts. UVB irradiation stimulates 12-lipoxygenase and the product 12-hydroxyeicosatetraenoic acid then activates TRPV1 increasing the cell's cytosolic Ca2+ concentration. UVB irradiation induced reactive oxygen species generation and apoptosis are inhibited in the absence of Ca2+ or in the presence of either a 12-lipoxygenase inhibitor or a TRPV1 inhibitor during and after UVB irradiation. Thus, the Ca2+ increase via TRPV1 is a critical factor in UVB irradiation induced oxidative stress. UVB irradiation induces a Ca2+ dependent Nrf2 degradation and thus activation of TRPV1 with 12-hydroxyeicosatetraenoic acid also decreasing Nrf2 levels. UVB irradiation induced Nrf2 degradation is inhibited by co-treatment of cells with W-7, cyclosporin A, SB-216763 or MG-132, which are inhibitors of calmodulin, calcineurin, GSK3β and the proteasome, respectively. Furthermore, UVB irradiation in parallel induces GSK3β dephosphorylation in a Ca2+ dependent manner. Co-immunoprecipitation showed that UVB irradiation induces an increase in Nrf2 phosphorylation, an increase in the binding of β-TrCP and Nrf2, and an increase in Nrf2 ubiquitination; these effects are all Ca2+ dependent. These findings suggest that UVB irradiation induced GSK3β activation in a Ca2+ dependent manner, which then stimulates the phosphorylation and ubiquitination of Nrf2 via β-TrCP. Indeed, silencing of β-TrCP was found to inhibit UVB irradiation-induced oxidative stress, Nrf2 degradation and apoptosis, while it had no effect on the Ca2+ increase. Taken together, our results suggest that a Ca2+ influx via TRPV1 is responsible for UVB irradiation-induced Nrf2 degradation and that modulation of the Ca2+-calmodulin-calcineurin-GSK3β-Nrf2-β-TrCP-Cullin-1 pathway may explain Ca2+ dependent Nrf2 degradation.
    Keywords:  Beta-TrCP; Cytosolic calcium increase; Glycogen synthase kinase 3 beta; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.06.020
  12. Oxid Med Cell Longev. 2019 ;2019 6342104
    BA6 Induces Apoptosis via Stimulation of Reactive Oxygen Species and Inhibition of Oxidative Phosphorylation in Human Lung Cancer Cells.
    Meng-Hsuan Cheng, Hung-Ling Huang, Yen-You Lin, Kuan-Hao Tsui, Pei-Chin Chen, Shu-Yu Cheng, Inn-Wen Chong, Ping-Jyun Sung, Ming-Hong Tai, Zhi-Hong Wen, Nan-Fu Chen, Hsiao-Mei Kuo.
      Lung cancer is the leading cause of cancer deaths in the world, with a five-year survival rate of less than 30%. Clinically effective chemotherapeutic treatments at the initial stage may eventually face the dilemma of no drug being effective due to drug resistance; therefore, finding new effective drugs for lung cancer treatment is a necessary and important issue. Compounds capable of further increasing the oxidative stress of cancer cells are considered to have anticancer potential because they possessed the ability to induce apoptosis. This study mainly investigated the effects of BA6 (heteronemin), the marine sponge sesterterpene, on lung cancer cell apoptosis, via modulation of mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS). BA6 has cellular cytotoxic activities against a variety of cancer cell lines, but it has no effect on nontumor cells. The BA6-treated lung cancer cells show a significant increase in both cellular ROS and mtROS, which in turn caused the loss of mitochondrial membrane potential (MMP). The increase of oxidative stress in lung cancer cells treated with BA6 was accompanied by a decrease in the expression of antioxidant enzymes Cu/Zn SOD, MnSOD, and catalase. In addition, OXPHOS performed in the mitochondria and glycolysis in the cytoplasm were inhibited, which subsequently reduced downstream ATP production. Pretreatment with mitochondria-targeted antioxidant MitoTEMPO reduced BA6-induced apoptosis through the mitochondria-dependent apoptotic pathway, which was accompanied by increased cell viability, decreased mtROS, enhanced MMP, and suppressed expression of cleaved caspase-3 and caspase-9 proteins. In conclusion, the results of this study clarify the mechanism of BA6-induced apoptosis in lung cancer cells via the mitochondrial apoptotic pathway, suggesting that it is a potentially innovative alternative to the treatment of human lung cancer.
    DOI:  https://doi.org/10.1155/2019/6342104
  13. Int J Nanomedicine. 2019 ;14 3911-3928
    Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs alone and in combination with N-acetyl cysteine in tumor-bearing mice.
    Haidan M El-Shorbagy, Shaymaa M Eissa, Salwa Sabet, Akmal A El-Ghor.
      Background: Several in vitro studies have revealed that zinc oxide nanoparticles (ZnO-NPs) were able to target cancerous cells selectively with minimal damage to healthy cells. Purpose: In the current study, we aimed to evaluate the antitumor activity of ZnO-NPs in Ehrlich solid carcinoma (ESC) bearing mice by measuring their effect on the expression levels of P53, Bax and Bcl2 genes as indicators of apoptotic induction in tumor tissues. Also, we assessed the potential ameliorative or potentiation effect of 100 mg/kg N-acetyl cysteine (NAC) in combination with ZnO-NPs. Materials and methods: ESC bearing mice were gavaged with three different doses of ZnO-NPs (50, 300 and 500 mg/kg body weight) alone or in combination with NAC for seven consecutive days. In addition to measuring the tumor size, pathological changes, zinc content, oxidative stress biomarkers and DNA damage in ESC, normal muscle, liver and kidney tissues were assessed. Results: Data revealed a significant reduction in tumor size with a significant increase in p53 and Bax and decrease in Bcl2 expression levels in the tissues of ZnO-NPs treated ESC bearing mice. Moreover, a significant elevation of MDA accompanied with a significant reduction of CAT and GST. Also, a marked increase in all comet assay parameters was detected in ZnO-NPs treated groups. On the other hand, the combined treatment with ZnO-NPs and NAC significantly reduced reactive oxygen species production and DNA damage in liver and kidney tissues in all ZnO-NPs treated groups. Conclusion: ZnO-NPs exhibited a promising anticancer efficacy in ESC, this could serve as a foundation for developing new cancer therapeutics. Meanwhile, the combined treatment with ZnO-NPs and NAC could act as a protective method for the healthy normal tissue against ZnO-NPs toxicity, without affecting its antitumor activity.
    Keywords:  DNA damage; Ehrlich solid carcinoma; N-acetyl cysteine; ZnO-NPs; antitumor; oxidative stress
    DOI:  https://doi.org/10.2147/IJN.S204757
  14. Pharmacol Res. 2019 Jun 14. pii: S1043-6618(19)30559-6. [Epub ahead of print] 104315
    Aloe-Emodin Attenuates Myocardial Infarction and Apoptosis Via Up-Regulating MiR-133 Expression.
    Yang Yu, Huibin Liu, Di Yang, Fang He, Ye Yuan, Jing Guo, Juan Hu, Jie Yu, Xiuqing Yan, Shuo Wang, Zhimin Du.
      Aloe-emodin (AE) is an anthraquinone derived from rhubarb and has a variety of pharmacological actions. However, the role of AE in regulating ischemic heart diseases is still unclear. The present study investigated the effect of AE on cardiac injuries induced by myocardial infarction (MI) in vivo and oxidative insults in vitro and explored the mechanisms involved. TUNEL and Flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect expression of Bcl-2, Bax and Caspase-3 proteins. Real-time PCR was used to quantify the microRNAs levels. Our data showed that AE protected neonatal rat ventricular myocytes (NRVMs) from hydrogen peroxide (H2O2) induced apoptosis and significantly inhibited H2O2-induced reactive oxygen species (ROS) elevation. Furthermore, AE treatment significantly reversed H2O2-induced upregulation of Bax/Bcl-2 and the loss of mitochondrial membrane potential. In vivo, AE treatment significantly reduced infarct size, ameliorated impaired cardiac function and obviously decreased cardiac apoptosis and oxidative stress in MI mice heart. Meanwhile, AE restored H2O2-induced downregulation of miR-133, and transfection with miR-133 inhibitor abolished the anti-apoptotic and anti-oxidative effects of AE. Moreover, AE prevented H2O2-induced increase in caspase-3 activity, which was diminished by application of miR-133 inhibitor. Our results indicate that AE protectes against myocardial infarction via the upregulation of miR-133, inhibition of ROS production and suppression of caspase-3 apoptotic signaling pathway.
    Keywords:  Aloe-emodin; Apoptosis; Caspase-3; MicroRNA-133; Myocardial infarction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.phrs.2019.104315
  15. Ann Transl Med. 2019 May;7(9): 200
    MARVELD1 attenuates arsenic trioxide-induced apoptosis in liver cancer cells by inhibiting reactive oxygen species production.
    Wenping Ma, Haiyang Shen, Qian Li, Hao Song, Yanyan Guo, Fangrong Li, Xingang Zhou, Xinwu Guo, Jingdong Shi, Qi Cui, Jinhao Xing, Jinhai Deng, Youtao Yu, Wenjie Liu, Hongshan Zhao.
      Background: Arsenic trioxide (As2O3) is widely used for the treatment of acute promyelocytic leukemia (APL), and more recently, has also been applied to solid tumors. However, there are a fraction of patients with solid tumors, such as liver cancer, who respond to As2O3 treatment poorly. The underlying mechanisms for this remain unclear.Methods: We determined the suitable concentration of drugs by IC50. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to analyze the apoptosis. Morphological changes of the cells were observed by laser scanning confocal microscopy. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Quantitative polymerase chain reaction (qPCR) and Western blot tests were conducted to detect the mRNA and protein levels in different groups. Finally, a xenograft tumor assay and histopathological analysis were performed to evaluate the MARVELD1 function in cell proliferation and apoptosis.
    Results: Here, we show that MARVELD1 enhances the therapeutic effects of epirubicin, while inducing the strong resistance of liver cancer cells to As2O3 treatment. We further demonstrate that the As2O3-induced apoptosis was inhibited by MARVELD1 overexpression (24 h Vector vs. MARVELD1 =30.58% vs. 17.41%, P<0.01; 48 h Vector vs. MARVELD1 =46.50% vs. 21.02%, P<0.01), possibly through inhibiting ROS production by enhancing TRXR1 expression. In vivo, we found a significantly increased size (Vector vs. MARVELD1 =203.90±21.92 vs. 675.70±37.84 mm3, P<0.001) and weight (Vector vs. MARVELD1 =0.19±0.02 vs. 0.58±0.05 g, P<0.001) of tumors with high expression of MARVELD1 after As2O3 treatment. Consistently, a higher expression of MARVELD1 predicted a poor prognosis for liver cancer patients.
    Conclusions: Our data identified a unique role of MARVELD1 in As2O3-induced apoptosis and As2O3 cancer therapy resistance.
    Keywords:  Arsenic trioxide (As2O3); MARVELD1; apoptosis; reactive oxygen species (ROS); therapy
    DOI:  https://doi.org/10.21037/atm.2019.04.38
  16. Med Sci Monit. 2019 Jun 20. 25 4575-4582
    Antitumor Effects of 8-Deoxylactucin in RB355 Human Retinoblastoma Cells Are Mediated via Apoptosis Induction, Reactive Oxygen Species Production, and Cell Cycle Arrest.
    Tan Guiying, Li Yue, Xiong Chao, Yu Jinhai, Xu Qihua.
      BACKGROUND Retinoblastoma is a rare malignancy arising from the immature cells of the retina, generally in children up to the age of 3 years. Here, we assessed the anticancer effects of a natural sesquiterpene lactone - 8-deoxylactucin - on the growth of the retinoblastoma RB355 and normal RPE cells. MATERIAL AND METHODS Cell viability was assessed by 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was assessed by DAPI staining and annexin V/propidium iodide (PI) assay. Reactive oxygen species (ROS) levels were determined by fluorescence microscopy. Flow cytometry was used to determine the cell cycle distribution. Protein expression was determined by Western blot analysis. RESULTS The results showed that 8-deoxylactucin exerted selective and potent anticancer effects on the RB355 cells and exhibited an IC50 of 25 µM. Nonetheless, the cytotoxic effects of 8-deoxylactucin on the normal RPF cells were comparatively lower, as evident from the IC₅₀ of 65 µM. 8-Deoxylactucin increased the production of ROS and triggering apoptosis of RB355 cells. The induction of 8-deoxylactucin-induced apoptosis was also accompanied with increased cleavage of caspase 3, upregulation of Bax, and downregulation of Bcl-2. The 8-deoxylactucin-induced cell cycle arrest of RB355 cells was also associated with inhibition of cyclin A and B1 expression, as well as the inhibition of Cdc2 phosphorylation. CONCLUSIONS 8-Deoxylactucin inhibits the growth of RB355 cells by apoptosis, cell cycle arrest, and increased production of ROS.
    DOI:  https://doi.org/10.12659/MSM.914242
  17. Eur J Pharmacol. 2019 Jun 16. pii: S0014-2999(19)30419-4. [Epub ahead of print] 172467
    β-caryophyllene, a dietary phytocannabinoid attenuates oxidative stress, inflammation, apoptosis and prevents structural alterations of the myocardium against doxorubicin-induced acute cardiotoxicity in rats: An in vitro and in vivo study.
    Hasan Al-Taee, Sheikh Azimullah, M F Nagoor Meeran, Mahra Khamis Alaraj Almehiri, Rehab Abdulla Al Jasmi, Saeed Tariq, Moien Ab Khan, Ernest Adeghate, Shreesh Ojha.
      The present study investigates the cardioprotective effect of β-caryophyllene against doxorubicin-induced acute cardiotoxicity in rats. Doxorubicin (12.5 mg/kg) and β-caryophyllene (25, 50 or 100 mg/kg) were administered intraperitoneally to male albino Wistar rats. Doxorubicin-injected rats showed elevated levels of creatine kinase-MB in serum and oxidative stress in the myocardium as evidenced by decreased superoxide dismutase, catalase and glutathione with a concomitant rise in malondialdehyde levels. Doxorubicin also induced pro-inflammatory cytokines release following activation of the nuclear factor kappa-B and elevated expressions of inducible nitric oxide synthase and cyclooxygenase-2 in the myocardium. Additionally, doxorubicin also increased expression of γ-H2AX, a marker of DNA damage as well as increased expression of proapoptotic (Bax, p53, and active caspase-3) proteins along with the decreased expression of anti-apoptotic protein, Bcl2 in the myocardium. The histological and ultrastructural studies further revealed edema, inflammation and structural degeneration of cardiomyocytes following doxorubicin injection. However, treatment with β-caryophyllene showed significant cardioprotective effects as evidenced by favorable improvement of biochemical and molecular parameters along with remarkable preservation of cardiomyocytes in histological and ultrastructural studies. Results of the present study demonstrate that β-caryophyllene has potential to protect heart against doxorubicin-induced acute cardiotoxicity in rats. Moreover, the antioxidant and free radical scavenging properties of β-caryophyllene was confirmed by in vitro assays. Provided the anticancer and chemosensitizing properties of β-caryophyllene, the cardioprotective effects of β-caryophyllene are suggestive of its multiple properties that afford an additional basis of its possible therapeutic application in chemotherapy-associated cardiotoxicity.
    Keywords:  Acute cardiotoxicity; Cardioprotection; DNA damage and apoptosis; Doxorubicin; Inflammation; β-Caryophyllene
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172467
  18. Biomed Pharmacother. 2019 Jun 13. pii: S0753-3322(19)30901-1. [Epub ahead of print]117 109103
    Bullfrog oil (Rana catesbeiana Shaw) induces apoptosis, in A2058 human melanoma cells by mitochondrial dysfunction triggered by oxidative stress.
    Lucas Amaral-Machado, Wógenes N Oliveira, Éverton N Alencar, Ana Katarina M Cruz, Hugo Alexandre O Rocha, Kareem Ebeid, Aliasger K Salem, Eryvaldo Sócrates T Egito.
      Bullfrog oil, an animal oil extracted from the adipose tissue of Rana catesbeiana Shaw, showed promising cytotoxic activity against melanoma cells and, therefore, has the potential to become a pharmaceutical active compound. However, there is a lack of information regarding the pathways involved in its pharmacological activity. Thus, the aim of this study was to investigate and elucidate the cytotoxic effect of this oil against A2058 human melanoma cells. The cytotoxic potential was evaluated by the MTT assay, the cell cycle analysis and the cell death assay. In addition, the apoptotic potential was investigated by (i) the DNA fragmentation using propidium iodide staining analysis, (ii) the evaluation of mitochondrial membrane potential and (iii) the determination of intracellular Reactive Oxygen Species (ROS) level. The results showed that the bullfrog oil was able to promote a time-dependent cytotoxic effect, decreasing cell viability to 38% after 72 h of treatment without affecting the cell cycle. Additionally, the bullfrog oil induced the apoptosis in A2058 cells, increasing up to 50 ± 13% of the intracellular ROS level, maintaining the DNA integrity and promoting an approximate decrease of 35 ± 5% in the mitochondrial membrane potential. It can be concluded that the in vitro cytotoxic effect of the bullfrog oil in A2058 human melanoma cells is mediated by oxidative stress that induces mitochondrial dysfunction, triggering the apoptosis. These unprecedented results highlight the pharmacological potential of bullfrog oil and provide important information to support studies on the development of new pharmaceutical products for complementary and alternative treatments for melanoma.
    Keywords:  Apoptosis; Bullfrog oil; Cytotoxicity; Melanoma; Natural products
    DOI:  https://doi.org/10.1016/j.biopha.2019.109103
  19. J Cell Mol Med. 2019 Jun 21.
    Yellow Wine Polyphenolic Compounds prevents Doxorubicin-induced cardiotoxicity through activation of the Nrf2 signalling pathway.
    Hui Lin, Jie Zhang, Tingjuan Ni, Na Lin, Liping Meng, Feidan Gao, Hangqi Luo, Xiatian Liu, Jufang Chi, Hangyuan Guo.
      Doxorubicin (DOX) is considered as the major culprit in chemotherapy-induced cardiotoxicity. Yellow wine polyphenolic compounds (YWPC), which are full of polyphenols, have beneficial effects on cardiovascular disease. However, their role in DOX-induced cardiotoxicity is poorly understood. Due to their antioxidant property, we have been suggested that YWPC could prevent DOX-induced cardiotoxicity. In this study, we found that YWPC treatment (30 mg/kg/day) significantly improved DOX-induced cardiac hypertrophy and cardiac dysfunction. YWPC alleviated DOX-induced increase in oxidative stress levels, reduction in endogenous antioxidant enzyme activities and inflammatory response. Besides, administration of YWPC could prevent DOX-induced mitochondria-mediated cardiac apoptosis. Mechanistically, we found that YWPC attenuated DOX-induced reactive oxygen species (ROS) and down-regulation of transforming growth factor beta 1 (TGF-β1)/smad3 pathway by promoting nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nucleus translocation in cultured H9C2 cardiomyocytes. Additionally, YWPC against DOX-induced TGF-β1 up-regulation were abolished by Nrf2 knockdown. Further studies revealed that YWPC could inhibit DOX-induced cardiac fibrosis through inhibiting TGF-β/smad3-mediated ECM synthesis. Collectively, our results revealed that YWPC might be effective in mitigating DOX-induced cardiotoxicity by Nrf2-dependent down-regulation of the TGF-β/smad3 pathway.
    Keywords:  Nrf2; cardiotoxicity; doxorubicin; oxidative stress; polyphenols
    DOI:  https://doi.org/10.1111/jcmm.14466
  20. Biochim Biophys Acta Gen Subj. 2019 Jun 13. pii: S0304-4165(19)30156-4. [Epub ahead of print]
    The biochemical and molecular mechanisms involved in the role of micro-tumor environment stress in development of drug resistance.
    Lina Al-Akra, Dong-Hun Bae, Lionel L Leck, Des R Richardson, Patric J Jansson.
      BACKGROUND: Multi-drug resistance (MDR) is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Moreover, the tumor microenvironment is essential to the formation of drug resistant cancers. Recent evidence indicates that the tumor microenvironment is a critical regulator of cancer progression, distant metastasis and acquired resistance of tumors to various therapies. Despite significant advances in chemotherapy and radiotherapy, the development of therapeutic resistance leads to reduced drug efficacy.SCOPE OF REVIEW: This review highlights mechanistic aspects of the biochemistry of the tumor microenviroment, such as the hypoglycaemia, reactive oxygen species (ROS), hypoxia and their effects in propagating MDR. This is achieved through: (A) increased survival via autophagy and failure of apoptosis; (B) altered metabolic processing; and (C) reduction in drug delivery and uptake or increased drug efflux.
    MAJOR CONCLUSIONS: The development of MDR in cancer has been demonstrated to be majorly influenced by naturally occurring stressors within the tumor microenvironment, as well as chemotherapeutics. Thus, the tumor microenvironment is currently emerging as a major focus of research which needs to be carefully addressed before cancer can be successfully treated.
    GENERAL SIGNIFICANCE: Elucidating the biochemical mechanisms which promote MDR is essential in development of effective therapeutics that can overcome these acquired defences in cancer cells.
    Keywords:  Apoptosis; Autophagy; Hypoxia; Metabolism; Multi-drug resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbagen.2019.06.007
  21. Andrologia. 2019 Jun 17. e13350
    Protocatechuic acid inhibits testicular and epididymal toxicity associated with methotrexate in rats.
    Solomon E Owumi, Samuel E Ochaoga, Oyeronke A Odunola, Ebenezer O Farombi.
      We examined the effect of protocatechuic acid (PCA) on methotrexate (MTX)-induced testicular and epididymal toxicity in Wistar rats, treated with MTX (20 mg/kg) alone or in combination with PCA (25 and 50 mg/kg) body weight for a week. PCA significantly abated MTX-mediated increase in reactive oxygen and nitrogen species generation and lipid peroxidation as well as enhances glutathione balance and antioxidant enzymes in the testes and epididymis of treated animals. PCA suppressed MTX-mediated increases in interleukin-1β, tumour necrosis factor alpha and caspase-3 activity in treated animals. Additionally, PCA treatment mediated increases in luteinising and follicle-stimulating hormones, prolactin and testosterone levels with marker enzymes of testicular function, accompanied with increase in sperm functionality in treated animals. Conclusively, PCA may serve as potential supplementation, enhancing reproductive health in males undergoing MTX therapy.
    Keywords:  apoptosis; methotrexate; oxido-inflammation; protocatechuic acid; reproductive toxicity
    DOI:  https://doi.org/10.1111/and.13350
  22. Am J Transl Res. 2019 ;11(5): 3140-3149
    Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion.
    Weiting Cheng, Wei Xiang, Shan Wang, Kai Xu.
      Peripheral neurotoxicity is a common adverse reaction in cancer patients undergoing chemotherapy. The neuropathologic changes were partly associated with mitochondrial dysfunction and autophagy. Tanshinone IIA, a compound extracted from the medicinal herb Salvia miltiorrhiza, has been shown to exhibit neuroprotective effects. The present study investigated the effects of tanshinone IIA on chemotherapy-induced neurotoxicity and to study the underlying mechanism. Neuroma cell line N2a and rats were treated with oxaliplatin and/or tanshinone IIA. The effects on neurotoxicity were evaluated using cell viability assay, flow cytometry detection of apoptosis, measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Ψm), autophagy detection, nerve function assessment, and behavior assessment. The results showed that tanshinone IIA prevented oxaliplatin-induced inhibition of cell viability and reduced apoptosis. Tanshinone IIA also prevented excessive oxidative stress, as demonstrated by decreased ROS levels and reduced Ψm loss. Lastly, treatment with tanshinone IIA promoted autophagy through the PI3K/Akt/mTOR signaling pathway. The in vivo experiment showed that tanshinone IIA ameliorated oxaliplatin-induced allodynia and sciatic nerve dysfunction. An increase in serum nerve growth factor level was observed. In conclusion, the results of the study suggested a protective role of tanshinone IIA in neurotoxicity induced by oxaliplatin via mitochondrial protection and autophagy promotion.
    Keywords:  Autophagy; chemotherapy; neurotoxicity; tanshinone IIA
  23. Environ Sci Pollut Res Int. 2019 Jun 20.
    Protective effects of Ganoderma lucidum triterpenoids on oxidative stress and apoptosis in the spleen of chickens induced by cadmium.
    Xiangqi Teng, Weiqian Zhang, Yangyang Song, Haibin Wang, Ming Ge, Ruili Zhang.
      Cadmium (Cd) is a heavy metal that poses a huge potential threat to human and animal health. Therefore, it is necessary to study its damage mechanism. In the present study, we have examined the protective effects of Ganoderma lucidum triterpenoids on oxidative stress and apoptosis in the spleen of chickens induced by Cd. One hundred and twenty healthy Hailan white chickens (7-day-old) were randomly divided into the following four groups: control group, Cd group, triterpenoid group, and Cd-triterpenoid group. The chickens were euthanized on the 20th, 40th, and 60th days, and the spleens were removed. Cd and malondialdehyde (MDA) content, antioxidant enzyme (superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)) activities, and inflammatory factor (tumor necrosis factor alpha (TNF-α) and interleukin (IL-1β and IL-6)) and apoptotic factor (caspase-3, BAX, and Bcl-2) expressions were detected. The results showed that Ganoderma lucidum triterpenoids could reduce the content of Cd and MDA; increase the antioxidant enzyme activities (SOD and GSH-Px); decrease the expression of inflammatory factors (TNF-α) and interleukin (IL-1β and IL-6); increase the expression of apoptotic factor (Bcl-2); and decrease the expression of apoptotic factors (caspase-3 and Bax). It showed that the triterpenoids of Ganoderma lucidum had significant protective effects on oxidative stress and apoptosis of chicken spleen, which provided a theoretical basis for further prevention and treatment of cadmium poisoning.
    Keywords:  Antioxidant; Apoptosis; Cadmium; Ganoderma lucidum triterpenoids; Spleen
    DOI:  https://doi.org/10.1007/s11356-019-05638-5
  24. Eur J Pharmacol. 2019 Jun 16. pii: S0014-2999(19)30411-X. [Epub ahead of print] 172459
    Coordination between NADPH oxidase and vascular peroxidase 1 promotes dysfunctions of endothelial progenitor cells in hypoxia-induced pulmonary hypertensive rats.
    E-Li Wang, Miao-Miao Jia, Fang-Mei Luo, Tao Li, Jing-Jie Peng, Xiu-Ju Luo, Feng-Lin Song, Jin-Fu Yang, Jun Peng, Bin Liu.
      Previous studies have demonstrated that NADPH oxidase (NOX)/vascular peroxidase (VPO1) pathway - mediated oxidative stress plays an important role in the pathogenesis of multiple cardiovascular diseases. This study aims to evaluate the correlation between NOX/VPO1 pathway and endothelial progenitor cells (EPCs) dysfunctions in hypoxia-induced pulmonary hypertension (PH). The rats were exposed to 10% hypoxia for 3 weeks to establish a PH model, which showed increases in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, acceleration in apoptosis and impairment in functions of the peripheral blood derived - EPCs (the reduced abilities in adhesion, migration and tube formation), accompanied by up-regulation of NOX (NOX2 and NOX4) and VPO1. Next, normal EPCs were cultured under hypoxia to induce apoptosis in vitro. Consistent with the in vivo findings, hypoxia enhanced the apoptosis and dysfunctions of EPCs concomitant with an increase in NOX and VPO1 expression, hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) production; these phenomena were attenuated by NOX2 or NOX4 siRNA. Knockdown of VPO1 showed similar results to that of NOX siRNA except no effect on NOX expression and H2O2 production. Based on these observations, we conclude that NOX/VPO1 pathway-derived reactive oxygen species promote the oxidative injury and dysfunctions of EPCs in PH, which may contribute to endothelial dysfunctions in PH.
    Keywords:  Dysfunction; Endothelial progenitor cells; Hypoxia; NADPH oxidase; Pulmonary hypertension; Vascular peroxidase 1
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172459
  25. Oxid Med Cell Longev. 2019 ;2019 7849876
    Chronic Alcohol Exposure Induced Neuroapoptosis: Diminishing Effect of Ethyl Acetate Fraction from Aralia elata.
    Bong Seok Kwon, Jong Min Kim, Seon Kyeong Park, Jin Yong Kang, Jeong Eun Kang, Chang Jun Lee, Sang Hyun Park, Su Bin Park, Seul Ki Yoo, Uk Lee, Dae-Ok Kim, Ho Jin Heo.
      An ethyl acetate fraction from Aralia elata (AEEF) was investigated to confirm its neuronal cell protective effect on ethanol-induced cytotoxicity in MC-IXC cells and its ameliorating effect on neurodegeneration in chronic alcohol-induced mice. The neuroprotective effect was examined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) and 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) assays. As a result, AEEF reduced alcohol-induced cytotoxicity and oxidative stress. To evaluate the improvement of learning, memory ability, and spatial cognition, Y-maze, passive avoidance, and Morris water maze tests were conducted. The AEEF groups showed an alleviation of the decrease in cognitive function in alcohol-treated mice. Then, malondialdehyde (MDA) levels and the superoxide dismutase (SOD) content were measured to evaluate the antioxidant effect of AEEF in the brain tissue. Treatment with AEEF showed a considerable ameliorating effect on biomarkers such as SOD and MDA content in alcohol-induced mice. To assess the cerebral cholinergic system involved in neuronal signaling, acetylcholinesterase (AChE) activity and acetylcholine (ACh) content were measured. The AEEF groups showed increased ACh levels and decreased AChE activities. In addition, AEEF prevented alcohol-induced neuronal apoptosis via improvement of mitochondrial activity, including reactive oxygen species levels, mitochondrial membrane potential, and adenosine triphosphate content. AEEF inhibited apoptotic signals by regulating phosphorylated c-Jun N-terminal kinases (p-JNK), phosphorylated protein kinase B (p-Akt), Bcl-2-associated X protein (BAX), and phosphorylated Tau (p-Tau). Finally, the bioactive compounds of AEEF were identified as caffeoylquinic acid (CQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and chikusetsusaponin IVa using the UPLC-Q-TOF-MS system.
    DOI:  https://doi.org/10.1155/2019/7849876
  26. Oxid Med Cell Longev. 2019 ;2019 9056845
    Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling.
    Chien-Ta Wu, Jeng-Shyan Deng, Wen-Chin Huang, Po-Chou Shieh, Mei-Ing Chung, Guan-Jhong Huang.
      Acetaminophen (APAP) overdose is one of the most common causes of drug-induced acute liver failure in humans. To investigate the hepatoprotective effect of salvianolic acid C (SAC) on APAP-induced hepatic damage, SAC was administered by daily intraperitoneal (i.p.) injection for 6 days before the APAP administration in mice. SAC prevented the elevation of serum biochemical parameters and lipid profile including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), total cholesterol (TC), and triacylglycerol (TG) against acute liver failure. Additionally, SAC reduced the content of malondialdehyde (MDA), the cytochrome P450 2E1 (CYP2E1), and the histopathological alterations and inhibited the production of proinflammatory cytokines in APAP-induced hepatotoxicity. Importantly, SAC effectively diminished APAP-induced liver injury by inhibiting nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinases (MAPKs) activation signaling pathway. Moreover, SAC enhanced the levels of hepatic activities of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in APAP-induced mice. SAC mainly inhibited the activation of apoptotic pathways by reduction of cytochrome c, Bax, and caspase-3 protein expression. Taken together, we provide the molecular evidence that SAC protected the hepatocytes from APAP-induced damage by mitigating mitochondrial oxidative stress, inflammatory response, and caspase-mediated antiapoptotic effect through inhibition of the Keap1/Nrf2/HO-1 signaling axis.
    DOI:  https://doi.org/10.1155/2019/9056845
  27. Chemosphere. 2019 Jun 10. pii: S0045-6535(19)31244-5. [Epub ahead of print]234 139-147
    Elucidating cylindrospermopsin toxicity via synthetic analogues: An in vitro approach.
    Daniel M Evans, Jack Hughes, Leigh F Jones, Patrick J Murphy, Halina Falfushynska, Oksana Horyn, Inna M Sokolova, Jeppe Christensen, Simon J Coles, Piotr Rzymski.
      Cylindrospermopsin (CYN) is an alkaloid biosynthesized by selected cyanobacteria, the cyto- and genotoxic properties of which have been studied extensively by in vitro and in vivo experimental models. Various studies have separately established the role of uracil, guanidine and hydroxyl groups in CYN-induced toxicity. In the present study, we have prepared five synthetic analogues that all possess a uracil group but had variations in the other functionality found in CYN. We compared the in vitro toxicity of these analogues in common carp hepatocytes by assessing oxidative stress markers, DNA fragmentation and apoptosis. All the analogues tested induced generation of reactive oxygen species, lipid peroxidation (LPO) and DNA fragmentation. However, the greatest increase in LPO and increase in caspase-3 activity, an apoptosis marker, was demonstrated by an analogue containing guanidine, hydroxyl and uracil functionalities similar to those found in CYN but lacking the complex tricyclic structure of CYN. We also report a crystal structure of an analogue lacking the hydroxyl group found in CYN which does not show intramolecular H-bonding interactions between the guanidine and the uracil functionalities. The observations made in this work supports the hypothesis that CYN toxicity is a result of an interplay between both of the uracil, hydroxyl and guanidine functional groups.
    Keywords:  Cyanobacteria; Cylindrospermopsin; DNA damage; Hepatocytes; Mechanism of action; Oxidative stress
    DOI:  https://doi.org/10.1016/j.chemosphere.2019.06.021
  28. EXCLI J. 2019 ;18 154-164
    Induction of apoptosis by piperine in human cervical adenocarcinoma via ROS mediated mitochondrial pathway and caspase-3 activation.
    Asif Jafri, Sahabjada Siddiqui, Juhi Rais, Md Sultan Ahmad, Sudhir Kumar, Tabrez Jafar, Mohammad Afzal, Md Arshad.
      Piperine (1-piperoylpeperdine), a nitrogenous pungent substance, is present in the fruits of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.). It possesses several pharmacological properties and has been extensively explored for its anti-cancerous activities. The mechanism underlying its anti-cancer potential in human cervical adenocarcinoma (HeLa) cells is not well interpreted. The anti-proliferative effect and the mode of action of piperine were investigated through some potent markers of apoptosis viz.reactive oxygen species (ROS) generation, cellular apoptosis and loss of mitochondrial membrane potential (MMP). DNA fragmentation, cell cycle kinetics, caspase-3 activity and cell migration assays were also conducted to observe the efficacy of piperine against HeLa cells. The results showed that piperine exposure induces apoptosis significantly in a dose-dependent manner and inhibits the growth of HeLa cells with an increase in ROS generation, nuclear condensation and delayed wound healing. In addition, piperine also encourages cell death by the loss of MMP, DNA fragmentation and the activation of caspase-3. Growth inhibition of HeLa cells was found to be associated with G2/M phase arrest and sub-G1 accumulation. The present study provides useful insight into the apoptotic potential of piperine and further in vivo and clinical studies will be needed for its validation and in the finding of more effective and least toxic regimens against cervical cancer.
    Keywords:  ROS; anti-tumor; caspase-3; cell cycle kinetics; piperine
    DOI:  https://doi.org/10.17179/excli2018-1928
  29. Eur J Med Chem. 2019 Jun 04. pii: S0223-5234(19)30525-2. [Epub ahead of print]178 390-400
    Studies of anticancer activity in vitro and in vivo of iridium(III) polypyridyl complexes-loaded liposomes as drug delivery system.
    Wen-Yao Zhang, Fan Du, Miao He, Lan Bai, Yi-Ying Gu, Lin-Lin Yang, Yun-Jun Liu.
      Two iridium(III) polypyridyl complexes [Ir(ppy)2(HPIP)](PF6) (Ir-1), [Ir(ppy)2(BHPIP)](PF6) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC50 values range from 5.2 ± 0.8 to 22.3 ± 1.8 μM. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca2+ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase.
    Keywords:  Cytotoxicity in vitro and in vivo assays; Iridium(III) polypyridyl complexes; Liposomes; Microtubules; ROS
    DOI:  https://doi.org/10.1016/j.ejmech.2019.06.009
  30. Cell Death Differ. 2019 Jun 17.
    FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT.
    Xin Zhang, Can Hu, Chun-Yan Kong, Peng Song, Hai-Ming Wu, Si-Chi Xu, Yu-Pei Yuan, Wei Deng, Zhen-Guo Ma, Qi-Zhu Tang.
      Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
    DOI:  https://doi.org/10.1038/s41418-019-0372-z
  31. J Cell Mol Med. 2019 Jun 17.
    Paeoniflorin protects spiral ganglion neurons from cisplatin-induced ototoxicity: Possible relation to PINK1/BAD pathway.
    Xiaoyu Yu, Rongjun Man, Yanan Li, Qianqian Yang, Hongrui Li, Huiming Yang, Xiaohui Bai, Haiyan Yin, Jianfeng Li, Haibo Wang.
      The objective of this study was to elucidate whether paeoniflorin (PF) exerted an effect on cisplatin-induced spiral ganglion neuron (SGN) damage, with special attention given to the role of PINK1/BAD pathway in this process. Middle cochlear turn culture and C57BL/6 mice were utilized to identify the character of PF in vitro and in vivo. We found that cisplatin treatment led to SGN damage, in which reactive oxygen species (ROS) generation increased, PINK1 expression decreased, BAD accumulation on mitochondria raised and mitochondrial apoptotic pathway activated. Conversely, we demonstrated that PF pre-treatment obviously mitigated cisplatin-induced SGN damage. Mechanistic studies showed that PF could reduce ROS levels, increase PINK1 expression, decrease the BAD accumulation on mitochondria and, thus, alleviate the activated mitochondrial apoptosis in SGNs caused by cisplatin. Overall, the findings from this work reveal the important role of PF and provide another strategy against cisplatin-induced ototoxicity.
    Keywords:  BAD; PINK1; ROS; paeoniflorin; spiral ganglion neuron
    DOI:  https://doi.org/10.1111/jcmm.14379
  32. Cancer Manag Res. 2019 ;11 4797-4808
    DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2.
    Yuanyuan Kong, Bo Li, Shuaikang Chang, Lu Gao, Zhijian Xu, Wan He, Guang Yang, Bingqian Xie, Gege Chen, Liangning Hu, Kang Lu, Yingcong Wang, Xiaosong Wu, Weiliang Zhu, Jumei Shi.
      Purpose: The present study investigates the effect of DCZ0814 in multiple myeloma (MM) cells, and determines the molecular mechanism of its antitumor activity against MM. Methods: The effects of DCZ0814 were evaluated in vitro using human MM cell lines (ARP1 and OCI-MY5) and in vivo in a murine xenograft MM model. Cell viability was measured with the CCK-8 assay and mitochondrial membrane potential (MMP) was assessed with the JC-1 dye. Apoptosis and cell cycle distribution were examined by flow cytometry. Inhibition of mTORC1 and mTORC2 was assessed by western blot analysis, and the synergistic effect of DCZ0814 and known MM drugs was assessed by calculating the combination index value, using the CalcuSyn software. Results: DCZ0814 effectively inhibited proliferation in MM cells, an effect that was associated with the induction of apoptosis, G0/G1 cell cycle arrest, MMP reduction and reactive oxygen species (ROS) generation. Meanwhile, DCZ0814 repressed the mTOR signaling via dual mTORC1/C2 inhibition and overcame the protective effect of the bone marrow (BM) microenvironment in myeloma cells. In addition, co-treatment with DCZ0814 and other anti-MM agents induced synergistic effects. Finally, the efficacy of the DCZ0814 treatment was confirmed in an MM xenograft mouse model. Conclusion: DCZ0814 exhibits potent anti-MM activity and abrogates the activation of the mTOR/Akt signaling pathway mediated by the BM stroma-derived cytokines. Our results provide a theoretical basis for the development of novel therapeutic strategies in MM using DCZ0814 as a natural product combination compound.
    Keywords:  DCZ0814; apoptosis; bone marrow microenvironment; mTOR; multiple myeloma
    DOI:  https://doi.org/10.2147/CMAR.S194202
  33. BMC Complement Altern Med. 2019 Jun 18. 19(1): 134
    Calotropis gigantea extract induces apoptosis through extrinsic/intrinsic pathways and reactive oxygen species generation in A549 and NCI-H1299 non-small cell lung cancer cells.
    Jiyon Lee, Hui-Ju Jang, Hyunwoo Chun, Thu-Huyen Pham, Yesol Bak, Jong-Woon Shin, Hang Jin, Yong-In Kim, Hyung Won Ryu, Sei Ryang Oh, Do-Young Yoon.
      BACKGROUND: Calotropis gigantea (CG) is a tall and waxy flower that is used as a traditional remedy for fever, indigestion, rheumatism, leprosy, and leukoderma. However, the precise mechanisms of its anticancer effects have not yet been examined in human non-small cell lung cancer (NSCLC) cells. In this study, we investigated whether CG extract exerted an apoptotic effect in A549 and NCI-H1299 NSCLC cells.METHODS: The ethanol extract of CG was prepared, and its apoptotic effects on A549 and NCI-H1299 NSCLC cells were assessed by using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining, cell cycle analysis, real-time polymerase chain reaction (RT-PCR), western blotting, JC-1 staining, and ROS detection assay.
    RESULTS: The CG extract induced apoptosis through the stimulation of intrinsic and extrinsic signaling pathways in A549 and NCI-H1299 lung cancer cells. Cell cycle arrest was induced by the CG extract in both cell lines. Reactive oxygen species (ROS), which can induce cell death, were also generated in the CG-treated A549 and NCI-H1299 cells.
    CONCLUSIONS: These data confirmed that CG caused apoptosis through the activation of extrinsic and intrinsic pathways, cell cycle arrest, and ROS generation in A549 and NCI-H1299 lung cancer cells. Thus, CG can be suggested as a potential agent for lung cancer therapy.
    Keywords:  Anti-cancer; Apoptosis; Calotropis gigantea; Non-small cell lung cancer cell; ROS
    DOI:  https://doi.org/10.1186/s12906-019-2561-1
  34. Gen Physiol Biophys. 2019 Jun 20.
    Anticancer effect of inactivated Sendai virus strain Tianjin on human osteosarcoma HOS cells.
    Qing Li, Huachong Ma, Shuya Sun, Liying Shi.
      Ultraviolet-inactivated Sendai virus strain Tianjin (UV-Tianjin) has been proved to have antitumor effects in many kinds of tumor cells. Here, we investigated the anticancer properties of UV-Tianjin on human osteosarcoma HOS cells and the underlying molecular mechanism. Apoptosis, intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential were determined by flow cytometry analysis. The expression levels of apoptosis-related proteins were tested by western blotting. The results showed that UV-Tianjin concentration-dependently induced apoptosis in HOS cells. UV-Tianjin-induced apoptosis was mediated by the mitochondrial pathway, which was confirmed by mitochondrial dysfunction, downregulation of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-xL (Bcl-xL) and myeloid cell leukemia-1 (Mcl-1), upregulation of B-cell lymphoma 2 associated X protein (Bax) and Bcl-2 Homologous Antagonist/Killer (Bak), as well as the cleavage of caspase-9 and -3. Further analysis showed that UV-Tianjin augmented the phosphorylation of c-Jun N-terminal kinase, the extracellular-regulated kinase and p38, the major components of mitogen-activated protein kinase (MAPK) pathways, as well as the generation of ROS. Moreover, UV-Tianjin-induced apoptosis was remarkably attenuated by MAPK inhibitors and ROS inhibitor. Taken together, our results indicated that UV-Tianjin exerts antitumor effects by inducing mitochondria-dependent apoptosis involving ROS generation and MAPK pathway in human osteosarcoma HOS cells.
    DOI:  https://doi.org/10.4149/gpb_2019015
  35. Ecotoxicol Environ Saf. 2019 Jun 15. pii: S0147-6513(19)30634-7. [Epub ahead of print]181 370-380
    Toxic effects of 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal on the maturation and subsequent development of murine oocyte.
    Huage Liu, Zhiqiang Liu, Tengfei Lu, Luyao Zhang, Jinmei Cheng, Xiangwei Fu, Yunpeng Hou.
      Cigarette smoke can cause follicle destruction and oocyte dysfunction and increase the risks of spontaneous abortion, stillbirth, and tubal ectopic pregnancy, affecting female reproductive health. Third-hand smoke (THS) is residual tobacco smoke existing in the environment long after cigarettes are extinguished, which can react with other compounds in the environment to produce secondary pollutants. However, the effects of THS on the female reproductive system, particularly the maturation of the oocyte, remain unclear. 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA), a component of THS, is a logical biomarker of THS exposure. Thus, this study aims to investigate the toxic effects of NNA on the maturation of murine oocytes and subsequent developmental competence. Herein, murine oocytes were exposed to 0 (control group), 0.1, 1.0, 10, and 50 μM NNA for 24 h. Our results showed that NNA exposure reduced the polar body extrusion rate by causing 8-oxo-deoxyguanosine (8-OHdG) to increase and disrupting the meiotic spindle morphology by inhibiting ERK1/2 activation during in vitro maturation. Additionally, NNA exposure resulted in cleavage and blastocyst rate reduction by altering DNA and histone methylations by reducing 5 mC and H3K4me2 levels and by inducing apoptosis caused by mitochondrial dysfunction and reactive oxygen species accumulation, as shown by the increased superoxide dismutase mRNA level and by the decreased Bcl-x mRNA level. Collectively, our results demonstrate that NNA exposure reduces the maturation and developmental capability of murine oocytes by increasing the risk of DNA damage and abnormal spindle morphology, altering epigenetic modifications, and inducing apoptosis, suggesting the toxic effect of NNA on mammalian productive health.
    Keywords:  1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal; Apoptosis; DNA; Damage; Epigenetic modifications; Murine oocyte; Spindle damage
    DOI:  https://doi.org/10.1016/j.ecoenv.2019.06.006
  36. Toxicol Appl Pharmacol. 2019 Jun 12. pii: S0041-008X(19)30234-0. [Epub ahead of print] 114626
    Microcystin-LR promotes necroptosis in primary mouse hepatocytes by overproducing reactive oxygen species.
    Yun-Li Wu, Yun He, Jia-Jian Shi, Tian-Xiu Zheng, Xin-Jian Lin, Xu Lin.
      Microcystin-LR (MC-LR) is a type of cyclic heptapeptide toxin produced by cyanobacteria during bloom events. MC-LR-induced cell death is critically involved in its potent specific hepatotoxicity. Many studies have demonstrated that prototypical apoptosis as a form of programmed cell death after MC-LR is associated with liver injury. However, whether another form of programmed cell death exists and the underlying mechanism have not been reported. Here, we demonstrate that MC-LR can induce necroptosis via ROS overactivation in primary mouse hepatocytes. Various potential pathways of programmed cell death induced by MC-LR were evaluated by annexin V/PI dual staining for flow cytometric analysis, image-based PI staining analysis and western blot analysis. Cell viability was determined by the CCK8 assay. Rupture of the plasma membrane was indicated by lactate dehydrogenase release. ROS was evaluated with the carboxy-H2DCFDA fluorescent probe. It was found that in MC-LR-treated cells, as the plasma membrane was damaged, annexin V/PI-stained double-positive cells were significantly induced and PI-stained nuclei were more diffuse. Western blot analysis showed that MC-LR treatment significantly upregulated the expression of necroptotic and apoptotic proteins. Mechanistically, MC-LR induced ROS overproduction by dysregulating the expression and activity of the pro-oxidants SOD1, MAOA, and NOX4 and the antioxidant GPX1. These results indicate the presence of a novel mechanism for MC-LR-mediated liver injury and present a novel target in the treatment of MC-LR-exposed patients.
    Keywords:  Apoptosis; Cyanbacteria; Eutrophication; Liver injury; Microcystins; Necroptosis
    DOI:  https://doi.org/10.1016/j.taap.2019.114626
  37. J Cell Physiol. 2019 Jun 17.
    Mst1 deletion reduces hyperglycemia-mediated vascular dysfunction via attenuating mitochondrial fission and modulating the JNK signaling pathway.
    Ruijie Qin, Dong Lin, Lina Zhang, Fei Xiao, Lixin Guo.
      Diabetes is a leading cause of microvascular complications, such as nephropathy and retinopathy. Recent studies have proposed that hyperglycemia-induced endothelial cell dysfunction is modulated by mitochondrial stress. Therefore, our experiment was to detect the upstream mediator of mitochondrial stress in hyperglycemia-treated endothelial cells with a focus on macrophage-stimulating 1 (Mst1) and mitochondrial fission. Our data illuminated that hyperglycemia incubation reduced cell viability, as well as increased apoptosis ratio in endothelial cell, and this alteration seemed to be associated with Mst1 upregulation. Inhibition of Mst1 via transfection of Mst1 siRNA into an endothelial cell could sustain cell viability and maintain mitochondrial function. At the molecular levels, endothelial cell death was accompanied with the activation of mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial fission. Genetic ablation of Mst1 could reduce mitochondrial oxidative injury, block mitochondrial apoptosis, and repress mitochondrial fission. Besides, we also found Mst1 triggered mitochondrial dysfunction as well as endothelial cell damage through augmenting JNK pathway. Suppression of JNK largely ameliorated the protective actions of Mst1 silencing on hyperglycemia-treated endothelial cells and sustain mitochondrial function. The present study identifies Mst1 as a primary key mediator for hyperglycemia-induced mitochondrial damage and endothelial cell dysfunction. Increased Mst1 impairs mitochondrial function and activates endothelial cell death via opening mitochondrial death pathway through JNK.
    Keywords:  JNK pathway; Mst1; endothelial cells; hyperglycemia; mitochondria
    DOI:  https://doi.org/10.1002/jcp.28969
  38. EXCLI J. 2019 ;18 165-186
    Cytotoxicity and apoptogenic properties of the standardized extract of Portulaca oleracea on glioblastoma multiforme cancer cell line (U-87): a mechanistic study.
    Vafa Baradaran Rahimi, Seyed Hadi Mousavi, Soroush Haghighi, Sina Soheili-Far, Vahid Reza Askari.
      The traditional uses of Portulaca oleracea L. (PO) with anti-inflammatory and anti-cancer activity as well as antioxidants properties were expressed previously. Glioma is considered the most common primary brain tumor and its malignant form is the most lethal adult brain tumor, that glioblastoma covers about 50 % of glioma tumors. The present study was aimed to evaluate the cytotoxicity and apoptogenic effects of the hydro-ethanolic extract of PO on human glioblastoma cancer cell line (U-87) and the role of NF-κB. Cytotoxicity of the extract in the presence or absence of Vitamin C was evaluated using MTT assay, and the following hypotonic PI and SubG1 peak were performed. Moreover, the reactive oxygen species (ROS), the level of NF-κB protein and nitric oxide (NO) production were investigated. The extract had cytotoxicity and apoptogenic effects on U-87 cells in both the concentration and time-dependent manners. The mechanism of cytotoxicity and apoptosis induction of the extract at the first hours of incubation and low concentrations were dependent on ROS. However, the toxicity was replaced with NO pathway with time-lapse and higher concentrations. Results also indicated that the extract acts as an NF-κB inhibitor with concentration and time-dependent manners. The present study may suggest the anti-NF-κB activity of PO along with two upstream ROS and NO mechanisms. Furthermore, the extract as ethnobotanical may be used as adjunctive anti-cancer therapy against glioblastoma multiforme.
    Keywords:  NF-kappaB; Portulaca oleracea; ROS; U-87 cell; glioblastoma multiforme (GBM); nitric oxide
    DOI:  https://doi.org/10.17179/excli2019-1063
  39. Curr Dev Nutr. 2019 Jun;pii: nzz052.FS05-08-19. [Epub ahead of print]3(Suppl 1):
    Lycopene Protects Cortical Neurons via Oxidative Stress-mediated ΔN-Bcl-xL Formation (FS05-08-19).
    Allison Stumpf, Katheryn Broman, Katelyn Senkus, Libo Tan, Kristi Crowe-White, Han-A Park.
      Objectives: B-cell lymphoma-extra large (Bcl-xL) is a protein found in the mitochondrial membrane with anti-apoptotic properties. Bcl-xL has demonstrated neuroprotective effects by enhancing mitochondrial function. However, during oxidative stress, Bcl-xL undergoes cleavage to form pro-cell death ∆N-Bcl-xL. Accumulation of ∆N-Bcl-xL causes abnormal mitochondrial channel activity associated with neuronal death. Therefore, strategies that prevent formation of ∆N-Bcl-xL protect the brain. In this study, we hypothesize that cleavage of Bcl-xL can be controlled by nutritional intervention. We test if treatment with lycopene, a potent antioxidant with neuroprotective effects, can protect primary neurons via improving intracellular redox status by reducing production of ∆N-Bcl-xL.Methods: Primary cortical neurons were treated with lycopene, hydrogen peroxide (a ROS donor), or both. Levels of superoxide, cell viability and cytotoxicity, and protein levels of Bcl-xL and ∆N-Bcl-xL were quantified.
    Results: Hydrogen peroxide increased cytotoxicity while treatment with lycopene protected oxidative stress-induced cortical death. Lycopene prevented N-terminal cleavage of Bcl-xL and thus inhibited formation of ∆N-Bcl-xL.
    Conclusions: These data show that the formation of ∆N-Bcl-xL is induced in part by reactive oxygen species and high levels of oxidative stress. The antioxidant properties of lycopene help reduce oxidative stress and prevent cleavage of Bcl-xL to ∆N-Bcl-xL, thus maintaining an anti-apoptotic environment.
    Funding Sources: RG14811.
    DOI:  https://doi.org/10.1093/cdn/nzz052.FS05-08-19
  40. Front Physiol. 2019 ;10 660
    Tempol Protects Against Acetaminophen Induced Acute Hepatotoxicity by Inhibiting Oxidative Stress and Apoptosis.
    Zheng Ge, Chenyu Wang, Junjie Zhang, Xiwang Li, Junhong Hu.
      Acetaminophen (APAP)-induced acute hepatotoxicity is the leading cause of drug-induced acute liver failure. The aim of this study was to evaluate the effects of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) on the protection of APAP-induced hepatotoxicity in mice. Mice were pretreated with a single dose of tempol (20 mg/kg per day) orally for 7 days. On the seventh day, mice were injected with a single dose of APAP (300 mg/kg) to induce acute hepatotoxicity. Our results showed that tempol treatment markedly improved liver functions with alleviations of histopathological damage induced by APAP. Tempol treatment upregulated levels of antioxidant proteins, including superoxide dismutase, catalase, and glutathione. Also, phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) and protein expression of nuclear factor erythroid 2-related factor (Nrf 2) and heme oxygense-1 (HO-1) were all increased by tempol, which indicated tempol protected against APAP-induced hepatotoxicity via the PI3K/Akt/Nrf2 pathway. Moreover, tempol treatment decreased pro-apoptotic protein expressions (cleaved caspase-3 and Bax) and increased anti-apoptotic Bcl-2 in liver, as well as reducing apoptotic cells of TUNEL staining, which suggested apoptotic effects of tempol treatment. Overall, we found that tempol normalizes liver function in APAP-induced acute hepatotoxicity mice via activating PI3K/Akt/Nrf2 pathway, thus enhancing antioxidant response and inhibiting hepatic apoptosis.
    Keywords:  acetaminophen; acute hepatotoxicity; apoptosis; oxidative stress; tempol
    DOI:  https://doi.org/10.3389/fphys.2019.00660
  41. Oxid Med Cell Longev. 2019 ;2019 7064319
    Abnormal Ribosome Biogenesis Partly Induced p53-Dependent Aortic Medial Smooth Muscle Cell Apoptosis and Oxidative Stress.
    Qi Wu, Junmou Hong, Zhiwei Wang, Junxia Hu, Ruoshi Chen, Zhipeng Hu, Bowen Li, Xiaoping Hu, Zhengpei Zhang, Yongle Ruan.
      Ribosome biogenesis is a crucial biological process related to cell proliferation, redox balance, and muscle contractility. Aortic smooth muscle cells (ASMCs) show inhibition of proliferation and apoptosis, along with high levels of oxidative stress in aortic dissection (AD). Theoretically, ribosome biogenesis should be enhanced in the ASMCs at its proliferative state but suppressed during apoptosis and oxidative stress. However, the exact status and role of ribosome biogenesis in AD are unknown. We therefore analyzed the expression levels of BOP1, a component of the PeBoW complex which is crucial to ribosome biogenesis, in AD patients and a murine AD model and its influence on the ASMCs. BOP1 was downregulated in the aortic tissues of AD patients compared to healthy donors. In addition, overexpression of BOP1 in human aortic smooth muscle cells (HASMCs) inhibited apoptosis and accumulation of p53 under hypoxic conditions, while knockdown of BOP1 decreased the protein synthesis rate and motility of HASMCs. The RNA polymerase I inhibitor cx-5461 induced apoptosis, ROS production, and proliferative inhibition in the HASMCs, which was partly attenuated by p53 knockout. Furthermore, cx-5461 aggravated the severity of AD in vivo, but a p53-/- background extended the life-span and lowered AD incidence in the mice. Taken together, decreased ribosome biogenesis in ASMCs resulting in p53-dependent proliferative inhibition, oxidative stress, and apoptosis is one of the underlying mechanisms of AD.
    DOI:  https://doi.org/10.1155/2019/7064319
  42. Free Radic Biol Med. 2019 Jun 15. pii: S0891-5849(19)30532-5. [Epub ahead of print]
    CARD9 inhibits mitochondria-dependent apoptosis of cardiomyocytes under oxidative stress via interacting with Apaf-1.
    Yuanbin Li, Pengfei Liang, Bimei Jiang, Yuting Tang, Qinglan Lv, Hong Hao, Zhenguo Liu, Xianzhong Xiao.
      Cardiomyocyte apoptosis is known to contribute to myocardial ischemia/reperfusion (I/R) injury. Caspase recruitment domain-containing protein 9 (CARD9) play a role in cardiac fibrosis and dysfunction. However, the role of CARD9 in apoptosis of cardiomyocytes in myocardial I/R injury and its underlying mechanisms are still unclear. In this study, CARD9 expression was found to increase in H9c2 cells in response to hydrogen peroxide. Loss of CARD9 significantly increased caspase-3 activation and cardiomyocyte death following oxidative stress in vitro. Conversely, CARD9 overexpression decreased apoptosis as evidenced by a reduction in caspase-3 activation and the apoptotic rate. The caspase recruitment domain (CARD) of CARD9 was necessary for the protective effect of CARD9 against oxidative stress in cardiomyocytes. CARD9 suppressed the activation of caspase-9 by interacting with Apaf-1 via its CARD domain in H9c2 cells exposed to H2O2. Ablation of caspase-9 activity by z-lehd-fmk effectively prevented the detrimental effect of CARD9 deficiency on cardiomyocytes. Wild-type (WT) and CARD9-/- mice were subjected to 30 min of left ascending coronary (LAD) ischemia and 12 h of reperfusion. TdT-mediated dUTP nick end labeling (TUNEL) staining analysis showed that CARD9-/- mice exhibited a significantly higher number of apoptotic-positive cells after myocardial I/R injury than the WT mice. These results suggest that CARD9 protects cardiomyocytes from apoptosis by interacting with Apaf-1 and interfering with apoptosome formation following myocardial I/R injury in vivo and in vitro.
    Keywords:  Apaf-1; Apoptosis; CARD9; Caspase-9; Myocardial I/R injury; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.06.017
  43. Biochemistry (Mosc). 2019 Jan;84(Suppl 1): S225-S232
    Mitophagy in Yeast.
    D V Mamaev, R A Zvyagilskaya.
      Mitochondria play a crucial role in energy production, general cell metabolism, cell signaling, and apoptosis. Mitochondria are also the main source of reactive oxygen species, especially in the case of their dysfunction. Therefore, damaged or even superfluous mitochondria not required for normal cell functioning represent risk factors and should be removed in order to maintain cell homeostasis. Mitochondria removal occurs via mitophagy, a type of selective autophagy (from Greek autos, self and phagein, to eat) that takes place in parallel with mitochondrial biogenesis and other processes. This review outlines general views on autophagy and mitophagy and summarizes information on the autophagy-related (Atg) proteins and their complexes involved in these processes. Yeast, especially Saccharomyces cerevisiae, is a convenient model system for studying molecular mechanisms of mitophagy because yeast genome, transcriptome, and proteome have been well characterized and because genetic manipulations with yeast are relatively simple and fast. Furthermore, yeast contain a number of orthologs of human proteins. Mitophagy in yeast is promoted by various factors, such as starvation, aging, oxidative stress, mitochondrial dysfunction, signaling proteins, and modification of mitochondrial proteins. In this review, we discuss molecular mechanisms underlying mitophagy and its regulation in yeast and present examples of relationships between mitophagy and ubiquitination-deubiquitination processes, as well as between mitophagy and other types of autophagy.
    DOI:  https://doi.org/10.1134/S000629791914013X
  44. Ann Hepatol. 2017 Jul - Aug;16(4):pii: S1665-2681(19)31099-3. [Epub ahead of print]16(4): 607-618
    Hepatoprotective Effect of Curcumin on Hepatocellular Carcinoma Through Autophagic and Apoptic Pathways.
    Ahmed M Elmansi, Amro A El-Karef, Mamdouh M El-Shishtawy, Laila A Eissa.
      BACKGROUND AND RATIONALE: Microtubule-associated protein light chain 3-II (LC3-II), and Sequestosome-1 (SQSTM1) are proteins that can be used as markers for autophagic pathway. Bcl-2 protein is reported to be inversely correlated with apoptosis. We aimed to investigate the effects of curcumin on liver inflammation and fibrosis up to the first dysplastic stage of Hepatocellular carcinoma (HCC) induced by Thioacetamide (TAA) in rats and to clarify the effects of curcumin on LC3-II, SQSTM1, and Bcl-2. Male Sprague-Dawley rats were randomized into four groups: Control group, TAA group, Curcumin low-dose group, and Curcumin highdose group. The last three groups received TAA 200 mg/kg i.p. twice weekly for 18 weeks. Oxidative stress markers as hepatic malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity were measured by colorimetric methods. Hepatic SQSTM1 concentration was measured by ELISA, and gene expression levels of Bcl-2, and LC3-II were measured by RT-PCR.We also investigated the in vitro effect of curcumin on HepG2 cells viability through MTT assay, and the involvement of autophagy in this effect.RESULTS: Curcumin increased the survival percent in rats, decreased -fetoprotein (AFP) concentration, and serum aspartate aminotransferase (AST) activity, and increased serum albumin concentration. Curcumin also significantly reduced oxidative stress in liver, inhibited apoptosis, and induced autophagy. In vitro, curcumin (50 μM) decreased HepG2 cells viabilityand the concentration of SQSTM1.
    CONCLUSIONS: Curcumin leads to protection against TAA induced HCC up to the first dysplastic stage through activating autophagic pathway and inhibiting apoptosis. Also, the antioxidant activity of curcumin almost prevents liver fibrosis.
    Keywords:  Bcl-2; LC3-II; Liver fibrosis; ROS; SQSTM1
    DOI:  https://doi.org/10.5604/01.3001.0010.0307
  45. Environ Toxicol Pharmacol. 2019 Jun 08. pii: S1382-6689(19)30067-5. [Epub ahead of print]70 103201
    Effects of cyclophosphamide on the phenotypes and functions of THP-1 cells.
    Youliang Zhao, Changfu Hao, Ruonan Zhai, Lei Bao, Di Wang, Yiping Li, Xinghao Yu, Ruoxuan Huang, Wu Yao.
      Early and accurate evaluation of immunotoxicity is crucial. However, there are few in vitro models for immunosuppressive evaluation. THP-1 cells has long been used for in vitro sensitivity evaluation. Whether it can be used for immunosuppressive evaluation remains unclear. In this study, effects of immunosuppressant cyclophosphamide (CY) on THP-1 cells were observed while 2, 4-Dinitrochlorobenzene (DNCB) was used as a control. The phenotypes of THP-1 cells, the ability to activate naïve T cells, intracellular reactive oxygen species (ROS) level, gene markers, phagocytic ability and cell apoptosis were detected after THP-1 cells being exposed to different concentrations of CY and DNCB. Both CY and DNCB were able to activate THP-1 cells, but there were a lot of differences in their effects on THP-1 cells, such as the changes in phenotypes, in the ability to activate naïve T cells, in ROS production and in marker gene expression. Firstly, CY down-regulated the expression of CD86 on THP-1 cells while DNCB up-regulated its expression. Secondly, the ability of THP-1 cells to activate naïve T cells was enhanced by CY and suppressed by DNCB. Thirdly, CY raised rapid and transient elevation of ROS level in THP-1 cells, while the effects of DNCB were slower and longer-lasting. Finally, only CY could lead to an increase in heme oxygenase 1 (HMOX1) expression. Taken all these results into account, we suggested that THP-1 cell line possesses the potency to be an in vitro model of immunosuppressive evaluation. And the surface molecule CD86, the ability to activate naïve T cells, the ROS production and the gene marker HMOX1 of THP-1 cells are promising markers.
    Keywords:  Cyclophosphamide; Immunosuppressive; Immunotoxicity; In vitro evaluation; THP-1
    DOI:  https://doi.org/10.1016/j.etap.2019.103201
  46. Cell J. 2019 Oct;21(3): 307-313
    Stress Hormone and Oxidative Stress Biomarkers Link Obesity and Diabetes with Reduced Fertility Potential.
    S Hima Abbasihormozi, Vahab Babapour, Azam Kouhkan, Amir Niasari Naslji, Kaveh Afraz, Zahra Zolfaghary, Abdol Hossein Shahverdi.
      Objective: Tilting the balance in favor of antioxidant agents could increase infertility problems in obese and diabetic individuals. The aim of this study was to evaluate oxidative stress status in semen of men with type 2 diabetes and obesity to investigate whether excessive amounts of oxidative stress, as a result of diabetes and obesity, influence infertility potential.Materials and Methods: A case-control study was conducted in men (n=150) attending the Infertility Center of Royan Institute between December 2016 and February 2017. Participants were categorized into four groups; normal weight (BMI<25 kg/m2) and non-type-2 diabetic (control=40), obese and non- type-2 diabetic (obese=40), non-obese and type- 2 diabetic (Nob-DM=35), and obese and type-2 diabetic (Ob-DM=35). The semen analysis was performed according to the World Health Organization criteria. Oxidative stress, DNA fragmentation, sperm apoptosis, and total antioxidant capacity (TAC) were evaluated in semen samples of men. Serum glucose, HbA1c, cortisol, and testosterone levels were determined using the enzyme-linked immunosorbent assay (ELISA) method.
    Results: Compared with the control group, sperm motility, progressive motility, and normal morphology were significantly decreased in the obese, Nob-DM, and Ob-DM groups (P<0.01). The obese, Nob-DM, and Ob-DM groups showed significantly lower levels of TAC and higher amounts of oxidative stress, early apoptotic sperm, and the percentage of DNA fragmentation as compared with the control group (P<0.05). Testosterone concentration was decreased in the obese, Nob-DM, and Ob-DM groups when compared with healthy individuals (P<0.05), whereas the cortisol level was significantly increased in the Nob-DM and Ob-DM groups in comparison to the obese and control group (P<0.01).
    Conclusion: Increased amount of reactive oxygen species (ROS) levels and DNA fragmentation in men affected by either diabetes or obesity could be considered prognostic factors in sub-fertile patients, alerting physicians to an early screen of male patients to avoid the development of infertility in prone patients.
    Keywords:  Antioxidants; Diabetes; Male Infertility; Obesity; Reactive Oxygen Species
    DOI:  https://doi.org/10.22074/cellj.2019.6339
  47. J Appl Microbiol. 2019 Jun 19.
    Synergistic antibacterial activity of gold nanoparticles caused by apoptosis-like death.
    Bin Lee, Dong Gun Lee.
      AIMS: Metal nanoparticles are promising materials for the management of infectious diseases as known to have various antimicrobial activities in pathogenic microorganisms. Among them, gold nanoparticles (AuNPs) are used in a wide range of fields such as photodynamic therapy, molecular diagnostics, and drug delivery because of their unique physicochemical properties. However, little is known about the synergistic antibacterial activity and mechanism of AuNPs on pathogenic bacteria.METHOD AND RESULT: Combinations of AuNPs and cefotaxime and ciprofloxacin showed synergistic interaction against all Salmonella species, however the combination with kanamycin exhibited no interaction. We determined that AuNPs and in combinations with antibiotics exert its antibacterial effect through bacterial apoptosis-like death. AuNPs caused collapse of intracellular divalent cation homeostasis, and conventional antibiotics caused accumulation of reactive oxygen species, which induced apoptotic hallmarks such as membrane depolarization, caspase-like protein activation, cell filamentation, and phosphatidylserine externalization.
    CONCLUSIONS: The cation homeostasis disruption by AuNPs and the accumulation of ROS by conventional antibiotics synergistically affected bacterial cell death and induced apoptosis-like death in Salmonella cells SIGNIFICANCE AND IMPACT OF STUDY: The synergistic activity between AuNPs and antibiotics propose that the AuNPs are a potential antibacterial agent and adjuvant for antimicrobial chemotherapy.
    Keywords:  Antibacterial activity; Apoptosis-like death; Gold nanoparticles; Salmonella species; Synergistic effect
    DOI:  https://doi.org/10.1111/jam.14357
  48. Int Immunopharmacol. 2019 Jun 14. pii: S1567-5769(19)30696-4. [Epub ahead of print]74 105689
    Comparison of the effects of adipose tissue mesenchymal stromal cell-derived exosomes with conditioned media on neutrophil function and apoptosis.
    Mohammad Mahmoudi, Mahsa Taghavi-Farahabadi, Nima Rezaei, Seyed Mahmoud Hashemi.
      BACKGROUND: Neutrophils are short-lived cells of the innate immune system that have an important role in defending against pathogens by producing reactive oxygen species (ROS). Therefore, effective strategies for increasing neutrophil's viability and function may be beneficial, especially in many conditions such as infections and immunodeficiency diseases. Some studies suggest using multipotent mesenchymal stromal cells (MSCs) and MSC-conditioned media (MSC-CM) for this aim. But, there is no study on using MSC-derived exosomes for improving neutrophil's viability and function. So, we examined the effects of MSC-exosomes and also MSC-CM on neutrophil's function and survival and compared them with each other.METHODS: Exosomes and CM were isolated from human adipose tissue MSCs. Exosomes were characterized, and the protein content of them was determined. Neutrophils were isolated from five healthy donors, and the effects of the two independent treatments (exosomes and conditioned media) on neutrophil's apoptosis were measured by Annexin V-PI method, then neutrophil's function was evaluated using NBT and phagocytosis assays.
    RESULTS: It was recognized that exosomes decreased neutrophils apoptosis and increased their phagocytosis capacity. The conditioned media augmented neutrophil's phagocytosis and reactive oxygen species (ROS) production, but it couldn't decrease neutrophil's apoptosis.
    DISCUSSION: Briefly, we concluded that MSC-exosomes augment neutrophil's viability more than their function while MSC-CM increase neutrophil's function more than the survival. This report showed that the use of MSC-exosomes and CM might be useful for increasing immunity by improving neutrophil's function and survival.
    Keywords:  Apoptosis; Conditioned media (CM); Exosomes; Mesenchymal stromal cells; Neutrophils; Phagocytosis
    DOI:  https://doi.org/10.1016/j.intimp.2019.105689
  49. Oxid Med Cell Longev. 2019 ;2019 9549506
    Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway.
    Qianqian Zhang, Yanqiu Lai, Jielin Deng, Menglong Wang, Zhenya Wang, Meng Wang, Yifeng Zhang, Xiaomeng Yang, Xiaoya Zhou, Hong Jiang.
      It has been demonstrated that vagus nerve stimulation (VNS) plays a protective role in ischemia/reperfusion (I/R) injury of various organs. The present study investigates the protective effect of VNS on hepatic I/R injury and the potential mechanisms. Male Sprague-Dawley rats were randomly allocated into three groups: the sham operation group (Sham; n = 6, sham surgery with sham VNS); the I/R group (n = 6, hepatic I/R surgery with sham VNS); and the VNS group (n = 6, hepatic I/R surgery plus VNS). The I/R model was established by 1 hour of 70% hepatic ischemia. Tissue samples and blood samples were collected after 6 hours of reperfusion. The left cervical vagus nerve was separated and stimulated throughout the whole I/R process. The stimulus intensity was standardized to the voltage level that slowed the sinus rate by 10%. VNS significantly reduced the necrotic area and cell death in I/R tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were also decreased by VNS. In addition, VNS suppressed inflammation, oxidative stress, and apoptosis in I/R tissues. VNS significantly increased the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) in the liver. These data indicated that VNS may attenuate hepatic I/R injury by inhibiting inflammation, oxidative stress, and apoptosis possibly via the Nrf2/HO-1 pathway.
    DOI:  https://doi.org/10.1155/2019/9549506
  50. Biomed Environ Sci. 2019 Apr;32(4): 272-280
    NANOG Alleviates the Damage of Human Hair Follicle Mesenchymal Stem Cells Caused by H2O2 through Activation of AKT Pathway.
    Jia Hong Shi, Kui Yang Zuo, Ying Yao Zhang, Bo Wang, Xing Han, Ao Bo Lian, Jin Yu Liu.
      OBJECTIVE: To explore the protective effect of NANOG against hydrogen peroxide (H2O2) -induced cell damage in the human hair follicle mesenchymal stem cells (hHF-MSCs).METHODS: NANOG was expressed from a lentiviral vector, pLVX-IRES-ZsGreen. NANOG hHF-MSCs and vector hHF-MSCs were treated with 400 μmol/L hydrogen peroxide (H2O2) for 2 h, the cell survival rate, cell morphology, ROS production, apoptosis and expression of AKT, ERK, and p21 were determined and compared.
    RESULTS: Our results showed that NANOG could activate AKT and upregulate the expression of p-AKT, but not p-ERK. When treated with 400 μmol/L H2O2, NANOG hHF-MSCs showed higher cell survival rate, lower ROS production and apoptosis, higher expression of p-AKT, higher ratio of p-AKT/AKT.
    CONCLUSION: Our results suggest that NANOG could protect hHF-MSCs against cell damage caused by H2O2 through activating AKT signaling pathway.
    Keywords:  AKT; Hair follicles; Hydrogen peroxide; Mesenchymal stem cells; NANOG homeobox protein
    DOI:  https://doi.org/10.3967/bes2019.037
  51. Front Endocrinol (Lausanne). 2019 ;10 320
    Hepatic DNA Damage Induced by Electronic Cigarette Exposure Is Associated With the Modulation of NAD+/PARP1/SIRT1 Axis.
    Jorge Espinoza-Derout, Xuesi M Shao, Emmanuel Bankole, Kamrul M Hasan, Norma Mtume, Yanjun Liu, Amiya P Sinha-Hikim, Theodore C Friedman.
      The prevalence of electronic cigarette (e-cigarettes) use has rapidly increased worldwide. Use of tobacco products has been associated with DNA damage and metabolic syndrome. Using Apolipoprotein E knockout (ApoE-/-) mice on a western diet (WD), a mouse model of non-alcoholic fatty liver disease (NAFLD), we recently demonstrated that nicotine in e-cigarettes activates hepatocyte apoptosis, and causes hepatic steatosis. This study examines the harmful effects of e-cigarettes on the liver with a special emphasis on DNA damage and mitochondrial dysfunction. ApoE-/- mice were exposed to saline, e-cigarettes without nicotine or e-cigarettes with 2.4% nicotine for 12 weeks using our newly developed mouse e-cigarette exposure model system that delivers nicotine to mice leading to equivalent serum cotinine levels found in human cigarette users. Mice exposed to e-cigarette (2.4% nicotine) had increased apurinic/apyrimidinic (AP) sites, a manifestation of DNA damage. Additionally, e-cigarette (2.4% nicotine) produced a decrease in NAD+/NADH ratio and increased oxidative stress in hepatic cells, in comparison with saline and e-cigarette (0%). Western blot analysis showed that mice treated with e-cigarette (2.4% nicotine) had increased poly (ADP ribose) polymerase (PARP1) activity associated with reduced levels of Sirtuin 1 (SIRT1). Furthermore, mitochondrial DNA mutations and PTEN-induced kinase 1 (PINK1) were increased in mice treated with e-cigarette (2.4% nicotine). Transmission electron microscopy revealed that hepatocytes of mice treated with e-cigarette (2.4% nicotine) exhibited increased vacuolization of the mitochondria and a reduction in cellular organelles. These results demonstrate the adverse effects of e-cigarettes exposure leading to NAD+ deficiency which may suggest a mechanistic link between e-cigarette-induced hepatic DNA damage and mitochondrial dysfunction.
    Keywords:  DNA damage; NAD+; hepatic metabolism; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3389/fendo.2019.00320
  52. J Photochem Photobiol B. 2019 May 31. pii: S1011-1344(19)30231-3. [Epub ahead of print]197 111518
    6-shogaol, a active constiuents of ginger prevents UVB radiation mediated inflammation and oxidative stress through modulating NrF2 signaling in human epidermal keratinocytes (HaCaT cells).
    Feng Chen, Ying Tang, Yujia Sun, Vishnu Priya Veeraraghavan, Surapaneni Krishna Mohan, Chuanxin Cui.
      Disclosure of ultraviolet (UV) radiation is the key feature from environment to cause redness of the skin, inflammation, photoaging and skin cancer. 6-Shogaol, a spicy compound secluded from ginger, which shows anti-inflammatory effects. Present study was demonstrated the role of 6-Shogaol on UVB induced oxidative stress and photoaging signaling in human epidermal keratinocytes (HaCaT cells). In this study, UVB-irratiation (180 mJ/cm2) significantly elevated the intracellular ROS levels, depletion of antioxidants resulted in apoptotic HaCaT cells. MAPKs signaling are concerned in oxidative stress; these signaling events are measured as differentiation. We found that 6-shogaol prevents over expression of MAPKs (ERK1, JNK1 & p38), in disclosure of UVB in HaCaT cells. Moreover, 6-shogaol infringed Bax and Bcl-2 in which 20 μg 6-shogaol influenced apoptosis in HaCaT cells by investigating augmented appearance of Bax and condensed appearance of Bcl-2 in contrast to control HaCaT cells. These results suggest that 6-shogaol could be a successful healing agent provides fortification against UVB-induced provocative and oxidative skin reimbursement.
    Keywords:  6-shogaol; Bcl-2; HaCaT cells; MAPKs; UVB
    DOI:  https://doi.org/10.1016/j.jphotobiol.2019.111518
  53. Mol Cell Endocrinol. 2019 Jun 14. pii: S0303-7207(19)30192-3. [Epub ahead of print] 110490
    Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy.
    Wei Jiang, Tangli Xiao, Wenhao Han, Jiachuan Xiong, Ting He, Yong Liu, Yinghui Huang, Ke Yang, Xianjin Bi, Xinli Xu, Yanlin Yu, Yan Li, Jun Gu, Jingbo Zhang, Yunjian Huang, Bo Zhang, Jinghong Zhao.
      Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in podocyte injury, protein kinase C isoform α (PKCα) was reported to regulate the phosphorylation of p66SHC. However, the role of PKCα/p66SHC in DN remains unknown. Klotho, an anti-aging protein with critical roles in protecting kidney, is expressed predominantly in the kidney and secreted in the blood. Nonetheless, the mechanism underlying amelioration of podocyte injury by Klotho in DN remains unclear. Our data showed that Klotho was decreased in STZ-treated mice and was further declined in diabetic KL± mice. As expected, Klotho deficiency aggravated diabetes-induced proteinuria and podocyte injury, accompanied by the activation of PKCα and p66SHC. In contrast, overexpression of Klotho partially ameliorated PKCα/p66SHC-mediated podocyte injury and proteinuria. In addition, in vitro experiments showed that activation of PKCα and subsequently increased intracellular reactive oxygen species (ROS) was involved in podocytic apoptosis induced by high glucose (HG), which could be partially reversed by Klotho. Hence, we conclude that Klotho might inhibit PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy.
    Keywords:  Diabetic nephropathy; Klotho; PKCα; Podocyte; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.mce.2019.110490
  54. Aquat Toxicol. 2019 Jun 13. pii: S0166-445X(19)30190-0. [Epub ahead of print]213 105227
    Additives migrating from 3D-printed plastic induce developmental toxicity and neuro-behavioural alterations in early life zebrafish (Danio rerio).
    Milanga Walpitagama, Megan Carve, Alon M Douek, Charlene Trestrail, Yutao Bai, Jan Kaslin, Donald Wlodkowic.
      The environmental impact of exposure to 3D-printed plastics as well as potential migration of toxic chemicals from 3D-printed plastics remains largely unexplored. In this work we applied leachates from plastics fabricated using a stereolithography (SLA) process to early developmental stages of zebrafish (Danio rerio) to investigate developmental toxicity and neurotoxicity. Migration of unpolymerized photoinitiator, 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) from a plastic solid phase to aqueous media at up to 200 mg/L in the first 24 h was detected using gas chromatography-mass spectrometry. Both plastic extracts (LC50 22.25% v/v) and 1-HCHPK (LC50 60 mg/L) induced mortality and teratogenicity within 48 h of exposure. Developmental toxicity correlated with in situ generation of reactive oxygen species (ROS), an increase in lipid peroxidation and protein carbonylation markers and enhanced activity of superoxide dismutase (SOD) and glutathione-S-transferase (GST) in embryos exposed to concentrations as low as 20% v/v for plastic extracts and 16 mg/L for 1-HCHPK. ROS-induced cellular damage led to induction of caspase-dependent apoptosis which could be pharmacologically inhibited with both antioxidant ascorbic acid and a pan-caspase inhibitor. Neuro-behavioral analysis showed that exposure to plastic leachates reduced spontaneous embryonic movement in 24-36 hpf embryos. Plastic extracts in concentrations above 20% v/v induced rapid retardation of locomotion, changes in photomotor response and habituation to photic stimuli with progressive paralysis in 120 hpf larvae. Significantly decreased acetylcholinesterase (AChE) activity with lack of any CNS-specific apoptotic phenotypes as well as lack of changes in motor neuron density, axonal growth, muscle segment integrity or presence of myoseptal defects were detected upon exposure to plastic extracts during embryogenesis. Considering implications of the results for environmental risk assessment and the growing usage of 3D-printing technologies, we speculate that some 3D-printed plastic waste may represent a significant and yet very poorly uncharacterized environmental hazard that merits further investigation on a range of aquatic and terrestrial species.
    Keywords:  3D printing; Apoptosis; Behaviour; Development; Plastic; Toxicity; Zebrafish
    DOI:  https://doi.org/10.1016/j.aquatox.2019.105227
  55. Mol Cell Oncol. 2019 ;6(4): 1607457
    Complex I and MDM2: hit me baby one more time.
    Jerry Edward Chipuk.
      MDM2 (mouse double minute 2) functions as both a tumor suppressor and oncogene, yet little is known if MDM2 regulates cancer cell biology by altering cellular metabolism. We recently found that MDM2 binds NDUFS1 (NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1), a key protein involved in Complex I assembly, function, and efficiency. The MDM2⋅NDUFS1 interaction promotes reactive oxygen species production, DNA damage, and apoptosis.
    Keywords:  Apoptosis; Complex I; MDM2; NDUFS1; mitochondria
    DOI:  https://doi.org/10.1080/23723556.2019.1607457
  56. Am J Transl Res. 2019 ;11(5): 3195-3212
    Huangqi decoction inhibits hyperglycemia-induced podocyte apoptosis by down-regulated Nox4/p53/Bax signaling in vitro and in vivo.
    Zezheng Li, Wenjuan Deng, Aili Cao, Yingjun Zang, Yunman Wang, Hao Wang, Li Wang, Wen Peng.
      BACKGROUND: Podocyte dysfunction is associated with the progression of diabetic nephropathy (DN). Huangqi decoction (HQD), a traditional Chinese medical formula, has been used to improve diabetes-related syndrome in China. The present study was to investigate the protective effect of HQD on podocyte apoptosis and the underlying molecular mechanism.METHODS: Podocyte was used to measure the efficacy of HQD on cell apoptosis, activities of NADPH oxidases, ROS generation and mitochondrial membrane potential (MMP), and the activation of Nox4/p53/Bax signaling pathway with HQD treatment were also investigated in vitro. Renal pathological morphology, renal function, podocyte apoptosis and Nox4/p53/Bax signaling pathway were investigated with STZ-induced diabetic mice in vivo.
    RESULTS: HQD increased the cell proliferation and MMP level, while the ROS production and activities of NADPH oxidases were decreased. Meanwhile, Nox4/p53/Bax signaling was down-regulated. Contrarily, overexpression of Nox4 or p53 significantly abolished those efficacies of HQD. Accordingly, in vivo study showed that the progressive albuminuria, glomerulosclerosis and loss of podocytes were significantly alleviated with HQD treatment in diabetic mice, which paralleled by the marked inhibition of Nox4/p53/Bax signaling.
    CONCLUSION: Collectively, we provide further evidence that HQD had a renoprotective effect in preventing podocyte apoptosis, which was mediated at least in part by down-regulation of Nox4/p53/Bax signaling.
    Keywords:  Huangqi decoction; Nox4/p53/Bax signaling; diabetic nephropathy; mitochondrial dysfunction; oxidative stress; podocytes apoptosis
  57. Br J Haematol. 2019 Jun 19.
    Global gene expression revealed an increase of HMGB1 and APEX1 proteins and their involvement in oxidative stress, apoptosis and inflammation pathways among beta-thalassaemia intermedia and major phenotypes.
    João Pedro Maia de Oliveira da Silva, Ana Flávia Brugnerotto, Karen S Romanello, Karina K L Teixeira, Carolina Lanaro, Adriana S Duarte, Gustavo G L Costa, Aderson da Silva Araújo, Marcos André C Bezerra, Igor de Farias Domingos, Diego A Pereira Martins, Iran Malavazi, Fernando F Costa, Anderson F da Cunha.
      Beta-thalassaemia (BT) is classified according to blood transfusion requirement as minor (BTMi), intermedia (BTI) and major (BTM). BTM is the most severe form, requiring regular transfusions while transfusion need is only occasional in BTI. Differential gene expression between patients has not been assessed so far. Here, we evaluated the global gene expression profiles during differentiation of human erythroid cells of two patients carrying the same mutation [CD39, (C → T)], though displaying different phenotypes (BTI and BTM). Considering the role of reactive oxygen species (ROS) in the pathophysiology of thalassaemia, we focused on differentially expressed genes involved in metabolic pathways triggered by ROS, such as inflammation and apoptosis, and, from these, we selected the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) and High Mobility Group Box1 (HMGB1) genes, whose role in BT is not well established. An in-depth expression analysis of transcriptional and protein levels in patients carrying a range of mutations associated with BT phenotypes indicated that APEX1 was increased in both BTI and BTM. Furthermore, higher amounts of HMGB1 was found in the plasma of BTI patients. Our findings suggest that these proteins have important roles in BT and could represent new targets for further studies aiming to improve the management of the disease.
    Keywords:  APEX1; Beta-thalassaemia; HMGB1; haemolytic anaemia; oxidative stress
    DOI:  https://doi.org/10.1111/bjh.16062
  58. Cell Stress. 2017 Oct 01. 1(1): 1-3
    Cell Stress - a new journal for cellular pathophysiology.
    Andreas Zimmermann, Christoph Ruckenstuhl, Katharina Kainz, Sebastian Hofer, Frank Madeo, Didac Carmona-Gutierrez, Guido Kroemer.
      
    Keywords:  DNA damage; aging; apoptosis; autophagy; bacterial and viral infections; cancer; cell death; cellular stress; genome instability; heat shock response; immune response; inflammation; lipotoxicity; mitochondria; necrosis; neurodegeneration; open access; oxidative stress; protein misfolding; radiation; systems biology; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.15698/cst2017.10.101
  59. Oxid Med Cell Longev. 2019 ;2019 3685817
    Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells.
    Kun Chen, Houqiang Xu, Jiafu Zhao.
      Purpose: Prostate cancer (PC) is a common malignant tumor and a leading cause of cancer-related death in men worldwide. In order to design new therapeutic interventions for PC, an understanding of the molecular events underlying PC tumorigenesis is required. Bloom syndrome protein (BLM) is a RecQ-like helicase, which helps maintain genetic stability. BLM dysfunction has been implicated in tumor development, most recently during PC tumorigenesis. However, the molecular basis for BLM-induced PC progression remains poorly characterized. In this study, we investigated whether BLM modulates the phosphorylation of an array of prooncogenic signaling pathways to promote PC progression.Methods: We analyzed differentially expressed proteins (DEPs) using iTRAQ technology. Site-directed knockout of BLM in PC-3 prostate cancer cells was performed using CRISPR/Cas9-mediated homologous recombination gene editing to confirm the effects of BLM on DEPs. PathScan® Antibody Array Kits were used to analyze the phosphorylation of nodal proteins in PC tissue. Immunohistochemistry and automated western blot (WES) analyses were used to validate these findings.
    Results: We found that silencing BLM in PC-3 cells significantly reduced their proliferative capacity. In addition, BLM downregulation significantly reduced levels of phosphorylated protein kinase B (AKT (Ser473)) and proline-rich AKT substrate of 40 kDa (PRAS40 (Thr246)), and this was accompanied by enhanced ROS (reactive oxygen species) levels. In addition, we found that AKT and PRAS40 inhibition reduced BLM, increased ROS levels, and induced PC cell apoptosis.
    Conclusions: We demonstrated that BLM activates AKT and PRAS40 to promote PC cell proliferation and survival. We further propose that ROS act in concert with BLM to facilitate PC oncogenesis, potentially via further enhancing AKT signaling and downregulating PTEN expression. Importantly, inhibiting the BLM-AKT-PRAS40 axis induced PC cell apoptosis. Thus, we highlight new avenues for novel anti-PC treatments.
    DOI:  https://doi.org/10.1155/2019/3685817
  60. Brain Behav. 2019 Jun 21. e01339
    Neuroprotective effect of omega-3 fatty acids on spinal cord injury induced rats.
    Jiaqi Bi, Chong Chen, Peiyu Sun, Haining Tan, Fan Feng, Jianxiong Shen.
      INTRODUCTION: In this study, the effects of omega-3 fatty acids were examined in a rat model of spinal cord injury.METHODS: The rats were classified into sham, control, spinal cord injury plus 50 mg/kg Omega-3 fatty acids and spinal cord injury plus 100 mg/kg Omega-3 fatty acids. The levels of oxidative, apoptotic, and inflammatory markers were examined in each of these groups.
    RESULTS: Altered lipid peroxidation, reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and catalase were normalized. Omega-3 fatty acid supplementation decreased tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels by >50%. TNF-α and IL-6 mRNA expression were reduced. Caspase-3, p53, bax, and pro-NGF mRNA expression levels were increased by 1.3-, 1.4-, 1.2-, and 0.9-fold, respectively, whereas bcl-2 mRNA expression was decreased by 0.77-fold in control rats. Omega-3 fatty acid supplementation decreased p53, caspase-3, bax, and pro-NGF mRNA expression by >40%, while the level of bcl-2 mRNA expression was increased by 286.9%. Omega-3 fatty acid supplementation decreased caspase-3 and p53 protein expression by >30%.
    CONCLUSION: Taken together, our results suggested that omega-3 fatty acid supplementation reduced oxidative stress, apoptosis, and the levels of inflammatory markers in ischemia-reperfusion-induced rats.
    Keywords:  apoptosis; inflammation; omega-3 fatty acid; oxidative stress; rat
    DOI:  https://doi.org/10.1002/brb3.1339
  61. Cell Death Dis. 2019 Jun 17. 10(7): 481
    Gasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis.
    Chenxuan Yang, Ping Sun, Meihong Deng, Patricia Loughran, Wenbo Li, Zhongjie Yi, Shilai Li, Xianghong Zhang, Jie Fan, Timothy R Billiar, Melanie J Scott.
      Gasdermin D (GsdmD) was recently identified as the executioner of pyroptotic inflammatory cell death, and is a substrate for caspases-1 and 11. GsdmD is detrimental in lethal endotoxemia but protective in bacterial sepsis. However, little is known about its role during noninfectious/sterile injuries. In this study, we examined the contribution of GsdmD using WT and GsdmD-/- mice in two models of noninfectious liver injury: hemorrhagic shock with resuscitation (HS/R) and acetaminophen (APAP) overdose. GsdmD-/- mice had significantly increased liver damage at 6 h after HS/R or APAP vs WT, shown by significantly elevated ALT level and extended areas of cell death in liver. Caspase-8, a mediator of multiple cell death pathways, was highly elevated in GsdmD-/- mice after injury. Significantly increased cleavage of caspase-8 and subsequent high levels of apoptosis were found in livers of GsdmD-/- mice after HS/R, a relatively mild ROS-induced liver injury. However, during more severe APAP-mediated ROS-induced liver injury, caspase-8 cleavage in GsdmD-/- liver was inhibited compared with WT, resulting in accumulation of pro-caspase-8 and increased levels of necroptosis. Our findings indicate a novel hepatoprotective role for GsdmD in noninfectious inflammation models via regulation of caspase-8 expression and downstream cell death pathways. The effects of GsdmD protection are likely injury specific and may also depend on injury severity and levels of ROS produced. These data suggest modulation of GsdmD/caspase-8 may be a novel therapeutic option in ROS-mediated liver injury.
    DOI:  https://doi.org/10.1038/s41419-019-1719-6
  62. Altern Ther Health Med. 2019 Jun 01. pii: AT5711. [Epub ahead of print]
    Early and Synergistic Recovery Effect of Herbal Combination on Surgically Corrected Varicocele.
    Su Jin Kim, Seung Hwan Jeon, Eun Bi Kwon, Hyun Cheol Jeong, Sae Woong Choi, Woong Jin Bae, Hyuk Jin Cho, U-Syn Ha, Sung Hoo Hong, Ji Youl Lee, Sung Yeoun Hwang, Sae Woong.
      Context: Not all men presenting varicocele-associated infertility exhibit improved sperm quality or achieve pregnancy following varicocelectomy. Some combinations of specific natural herbs have been shown empirically to reduce oxidative stress and improve sperm quality.Objective: We conducted a study to determine the effects of an herbal combination on sperm quality in varicocele-induced rats following varicocelectomy, hoping to find a new treatment approach to restore sperm quality following varicocelectomy.
    Design: The research team designed an animal study.
    Setting: The study took place in the Department of Urology at Seoul St. Mary's Hospital (Seoul, Republic of Korea).
    Animals: Fifty white, male, Sprague-Dawley rats weighing 250 to 300 g each were used in the study.
    Intervention: The rats were randomly assigned to 5 groups: (1) a control group (n = 10), (2) varicocele group (n = 10), (3) rats with varicocele and receiving varicocelectomy only (varicocelectomy group, n = 10), (4) rats with varicocele received varicocelectomy and oral administration with 200 mg/kg of an herbal combination for 4 wk (varicocelectomy + 200 mg/kg group, n = 10), and (5) rats with varicocele received varicocelectomy and oral administration with 400 mg/kg of an herbal com for 4 wk (varicocelectomy + 400 mg/kg group, n = 10).
    Outcome Measures: The study measured (1) sperm concentration and motility, (2) levels of reactive oxygen species (ROS), (3) concentrations of interleukin 6, interleukin 1β, and tumor necrosis factor alpha (TNF-α), (4) apoptotic change, and (5) levels of heat shock protein (HSP).
    Results: The sperm concentrations and motilities recovered after treatment in the varicocelectomy, varicocelectomy + 200 mg/kg, and varicocelectomy + 400 mg/kg groups. Significantly increased SOD and decreased ROS and cytokine levels were also observed. The apoptosis in the testes also was significantly decreased compared with the varicocele group. HSP70 in groups received varicocelectomy and administered with herbal combination was significantly decreased compared with the varicocelectomy group.
    Conclusions: The herbal combination was found to improve the sperm qualities, oxidative stress, and inflammation after varicocelectomy. Therefore, the herbal combination may provide a new and additional treatment for varicocele-associated infertility. For clinical application, further studies are needed to identify active ingredients in each herb and the mechanism by which each ingredient works, to standardize the herbal combination.
  63. Toxins (Basel). 2019 Jun 12. pii: E333. [Epub ahead of print]11(6):
    Effects of Dietary Zearalenone on Oxidative Stress, Cell Apoptosis, and Tight Junction in the Intestine of Juvenile Grass Carp (Ctenopharyngodon idella).
    Ya-Li Wang, Xiao-Qiu Zhou, Wei-Dan Jiang, Pei Wu, Yang Liu, Jun Jiang, Shang-Wen Wang, Sheng-Yao Kuang, Ling Tang, Lin Feng.
      Zearalenone (ZEA) is a prevalent mycotoxin with high toxicity in animals. In order to study its effect on juvenile grass carp (Ctenopharyngodon idella), six diets supplemented with different levels of ZEA (0, 535, 1041, 1548, 2002, and 2507 μg/kg diet) for 10 weeks were studied to assess its toxicity on intestinal structural integrity and potential mechanisms of action. Our report firstly proved that ZEA led to growth retardation and body deformity, and impaired the intestinal structural integrity of juvenile grass carp, as revealed by the following findings: (1) ZEA accumulated in the intestine and caused histopathological lesions; (2) ZEA resulted in oxidative injury, apoptosis, and breached tight junctions in the fish intestine, which were probably associated with Nuclear factor-erythroid 2-related factor 2 (Nrf2), p38 mitogen activated protein kinases (p38MAPK), and myosin light chain kinase (MLCK) signaling pathways, respectively. ZEA had no influence on the antioxidant gene levels of Kelch-like ECH associating protein 1 (Keap1)b (rather than Keap1a), glutathione-S-transferase (GST)P1, GSTP2 (not in the distal intestine (DI)), tight junctions occludin, claudin-c (not in the proximal intestine (PI)), or claudin-3c (not in the mid intestine (MI) or DI).
    Keywords:  apoptosis; intestine; oxidative injury; tight junctions; zearalenone
    DOI:  https://doi.org/10.3390/toxins11060333
  64. Int J Mol Sci. 2019 Jun 17. pii: E2956. [Epub ahead of print]20(12):
    Melatonin Abrogates the Anti-Developmental Effect of the AKT Inhibitor SH6 in Bovine Oocytes and Embryos.
    Marwa El Sheikh, Ayman Mesalam, Ahmed Atef Mesalam, Muhammad Idrees, Kyeong-Lim Lee, Il-Keun Kong.
      Melatonin, a nighttime-secreted antioxidant hormone produced by the pineal gland, and AKT, a serine/threonine-specific protein kinase, have been identified as regulators for several cellular processes essential for reproduction. The current study aimed to investigate the potential interplay between melatonin and AKT in bovine oocytes in the context of embryo development. Results showed that the inclusion of SH6, a specific AKT inhibitor, during in vitro maturation (IVM) significantly reduced oocyte maturation, cumulus cell expansion, cleavage, and blastocyst development that were rescued upon addition of melatonin. Oocytes treated with SH6 in the presence of melatonin showed lower levels of reactive oxygen species (ROS) and blastocysts developed exhibited low apoptosis while the mitochondrial profile was significantly improved compared to the SH6-treated group. The RT-qPCR results showed up-regulation of the mRNA of maturation-, mitochondrial-, and cumulus expansion-related genes including GDF-9, BMP-15, MARF1, ATPase, ATP5F1E, POLG2, HAS2, TNFAIP6, and PTGS2 and down-regulation of Bcl-2 associated X apoptosis regulator (BAX), caspase 3, and p21 involved in apoptosis and cell cycle arrest in melatonin-SH6 co-treated group compared to SH6 sole treatment. The immunofluorescence showed high levels of caspase 3 and caspase 9, and low AKT phosphorylation in the SH6-treated group compared to the control and melatonin-SH6 co-treatment. Taken together, our results showed the importance of both melatonin and AKT for overall embryonic developmental processes and, for the first time, we report that melatonin could neutralize the deleterious consequences of AKT inhibition, suggesting a potential role in regulation of AKT signaling in bovine oocytes.
    Keywords:  AKT; SH6; bovine; embryo; in vitro maturation; melatonin; oocyte
    DOI:  https://doi.org/10.3390/ijms20122956
  65. Cells. 2019 Jun 18. pii: E612. [Epub ahead of print]8(6):
    Cortisol Excess-Mediated Mitochondrial Damage Induced Hippocampal Neuronal Apoptosis in Mice Following Cold Exposure.
    Bin Xu, Li-Min Lang, Shi-Ze Li, Jing-Ru Guo, Jian-Fa Wang, Di Wang, Li-Ping Zhang, Huan-Min Yang, Shuai Lian.
      Cold stress can induce neuronal apoptosis in the hippocampus, but the internal mechanism involving neuronal loss induced by cold stress is not clear. In vivo, male and female C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week. In vitro, HT22 cells were treated with different concentrations of cortisol (CORT) for 3 h. In vivo, CORT levels in the hippocampus were measured using ELISA, western blotting, and immunohistochemistry to assess the neuronal population and oxidation of the hippocampus. In vitro, western blotting, immunofluorescence, flow cytometry, transmission electron microscopy, and other methods were used to characterize the mechanism of mitochondrial damage induced by CORT. The phenomena of excessive CORT-mediated oxidation stress and neuronal apoptosis were shown in mouse hippocampus tissue following cold exposure, involving mitochondrial oxidative stress and endogenous apoptotic pathway activation. These processes were mediated by acetylation of lysine 9 of histone 3, resulting in upregulation involving Adenosine 5'-monophosphate (AMP)-activated protein kinase (APMK) phosphorylation and translocation of Nrf2 to the nucleus. In addition, oxidation in male mice was more severe. These findings provide a new understanding of the underlying mechanisms of the cold stress response and explain the apoptosis process induced by CORT, which may influence the selection of animal models in future stress-related studies.
    Keywords:  CORT excess; cold stress; hippocampus oxidation stress; neuronal apoptosis
    DOI:  https://doi.org/10.3390/cells8060612
  66. Oxid Med Cell Longev. 2019 ;2019 2654910
    Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells.
    Xiurui Yan, Xue Fu, Yuanyuan Jia, Xiaona Ma, Jin Tao, Tingting Yang, Haibin Ma, Xueyun Liang, Xiaoming Liu, Jiali Yang, Jun Wei.
      The oxidative stresses are a major insult in pulmonary injury such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), two clinical manifestations of acute respiratory failure with substantially high morbidity and mortality. Mesenchymal stem cells (MSCs) hold a promise in treatments of many human diseases, mainly owing to their capacities of immunoregulation and antioxidative activity. The strong immunoregulatory role of human placental MSCs of fetal origin (hfPMSCs) has been previously demonstrated; their antioxidant activity, however, has yet been interrogated. In this report, we examined the antioxidative activity of hfPMSCs by accessing the ability to scavenge oxidants and radicals and to protect alveolar epithelial cells from antioxidative injury using both a cell coculture model and a conditioned culture medium (CM) of hfPMSCs. Results showed a comparable antioxidative capacity of the CM with 100 μM of vitamin C (VC) in terms of the total antioxidant capacity (T-AOC), scavenging abilities of free radicals DPPH, hydroxyl radical (·OH), and superoxide anion radical (O2 -), as well as activities of antioxidant enzymes of SOD and GSH-PX. Importantly, both of the CM alone and cocultures of hfPMSCs displayed a protection of A549 alveolar epithelial cells from oxidative injury of 600 μM hydrogen peroxide (H2O2) exposure, as determined in monolayer and transwell coculture models, respectively. Mechanistically, hfPMSCs and their CM could significantly reduce the apoptotic cell fraction of alveolar epithelial A549 cells exposed to H2O2, accompanied with an increased expression of antiapoptotic proteins Bcl-2, Mcl-1, Nrf-2, and HO-1 and decreased proapoptotic proteins Bax, caspase 3, and Keap1, in comparison with naïve controls. Furthermore, hfPMSCs-CM (passage 3) collected from cultures exposed an inhibition of the Nrf2/Keap1/ARE signaling pathway which led to a significant reduction in caspase 3 expression in A549 cells, although the addition of Nrf2 inhibitor ML385 had no effect on the antioxidative activity of hfPMSCs-CM. These data clearly suggested that hfPMSCs protected the H2O2-induced cell oxidative injury at least in part by regulating the Nrf2-Keap1-ARE signaling-mediated cell apoptosis. Our study thus provided a new insight into the antioxidative mechanism and novel functions of hfPMSCs as antioxidants in disease treatments, which is warranted for further investigations.
    DOI:  https://doi.org/10.1155/2019/2654910
  67. Int J Pharm. 2019 Jun 15. pii: S0378-5173(19)30473-9. [Epub ahead of print]
    Doxorubicin and siRNA-PD-L1 co-delivery with T7 modified ROS-sensitive nanoparticles for tumor chemoimmunotherapy.
    Wen-Jun Wan, Chen-Xi Qu, Ye-Juan Zhou, Liang Zhang, Meng-Tian Chen, Yang Liu, Ben-Gang You, Fang Li, Dan-Dan Wang, Xue-Nong Zhang.
      Tumor cells avoid immunosurveillance during the tumorigenesis, metastasis and recurrence periods thanks to the overexpressed immunosuppressive molecules on their surface. For instance, the programmed cell death 1 ligand (PD-L1) binds with the T-cells' programmed cell death receptor 1 (PD-1) impairing the anti-tumor activity of the host T cells. In this study, a new reactive oxygen species (ROS) responsive nanoparticle (NP), modified with the HAIYPRH (T7) peptide, was developed for the co-delivery of siRNA-PD-L1 and doxorubicin (Dox). These NPs can block the inhibitory signal responding to T cells and enhance cytotoxicity of Dox against tumor cells. The T7 modification binds to the overexpressed transferrin receptor on tumor cells facilitating its cellular uptake. Dox rapid release is then triggered by the high tumor cells cytoplasmic concentration of ROS, leading to cell apoptosis. Our results demonstrated these NPs exhibited a T7-mediated cellular uptake and an intracellular ROS-triggered payloads release in vitro. They also suggested an improved in vivo 4T1 tumor targeting efficiency and chemoimmunotherapy. Most notably, the co-delivery system exhibited a significantly enhanced antitumor effect over Dox-only loaded NPs following prompting the proliferation of T cells by siRNA-PD-L1. In conclusion, these ROS-responsive NPs provided a promising strategy to combine siRNA-PD-L1 immunotherapy and Dox chemotherapy.
    Keywords:  Doxorubicin; HAIYPRH peptide; Nanoparticle; Reactive oxygen species; chemoimmunotherapy; siRNA-PD-L1
    DOI:  https://doi.org/10.1016/j.ijpharm.2019.06.030
  68. Biomed Res Int. 2019 ;2019 9732325
    The Roles of Environmental Factors in Regulation of Oxidative Stress in Plant.
    Xiulan Xie, Zhouqing He, Nifan Chen, Zizhong Tang, Qiang Wang, Yi Cai.
      Exposure to a variety of environmental factors such as salinity, drought, metal toxicity, extreme temperature, air pollutants, ultraviolet-B (UV-B) radiation, pesticides, and pathogen infection leads to subject oxidative stress in plants, which in turn affects multiple biological processes via reactive oxygen species (ROS) generation. ROS include hydroxyl radicals, singlet oxygen, and hydrogen peroxide in the plant cells and activates signaling pathways leading to some changes of physiological, biochemical, and molecular mechanisms in cellular metabolism. Excessive ROS, however, cause oxidative stress, a state of imbalance between the production of ROS and the neutralization of free radicals by antioxidants, resulting in damage of cellular components including lipids, nucleic acids, metabolites, and proteins, which finally leads to the death of cells in plants. Thus, maintaining a physiological level of ROS is crucial for aerobic organisms, which relies on the combined operation of enzymatic and nonenzymatic antioxidants. In order to improve plants' tolerance towards the harsh environment, it is vital to reinforce the comprehension of oxidative stress and antioxidant systems. In this review, recent findings on the metabolism of ROS as well as the antioxidative defense machinery are briefly updated. The latest findings on differential regulation of antioxidants at multiple levels under adverse environment are also discussed here.
    DOI:  https://doi.org/10.1155/2019/9732325
  69. Curr Dev Nutr. 2019 Jun;pii: nzz030.FS13-03-19. [Epub ahead of print]3(Suppl 1):
    Dark Sweet Cherry phenolics as Dietary Chemopreventive/therapeutic Compounds for Aggressive Breast Cancer Cell Growth with No Toxicity to Normal Breast Cells (FS13-03-19).
    Marjorie Anne Layosa, Nara Lage, Susanne Talcott, Stephen Talcott, Maria Pedrosa, Boon Chew, Giuliana Noratto.
      Objectives: Dark sweet cherries (DSC) (Prunus avium) contain phenolic compounds with chemopreventive and chemotherapeutic potential. This study aimed to evaluate the effect of DSC extracts in inhibiting the most aggressive breast cancer subtypes without toxicity to normal cells.Methods: DSC phenolic extracts (WE) or its fractions enriched in phenolic acids (F1), anthocyanins (F2), flavonols (F3) or procyanidins (F4) were assessed for their antiproliferative activity against the most aggressive breast cancer BT-474, MDA-MB-453, and MDA-MB-231 cell lines, and MCF-10A noncancer breast epithelial cells using the resazurin assay. Cell levels of oxidative stress were assessed with fluorescein derivative H2DFFDA. Expression of genes linked to cell growth, apoptosis, and metastasis was assessed.
    Results: DSC phenolics in whole extract (WE) and fractions enriched in phenolic acids (F1), flavonols (F3) and procyanidins (F4) inhibited MDA-MB-453 with higher potency (lower IC50values) compared to the other cell lines tested (P < 0.05) followed by MDA-MB-231 ∼ BT-474, without toxicity to MCF-10A cells. F3 inhibited BT-474 and MCF-10A cells with similar potency (P > 0.05). F2 inhibited all assessed breast cancer cell lines with similar potencies without toxicity to MCF-10A cells. Mechanisms for WE, F2 and F4 inhibitory activity on MDA-MB-453 cells were mediated by reduction of ROS (down to 28%, 56%, and 58% of control, respectively); which mediate proliferation and other events required for tumor progression. This was accompanied by downregulation of Akt/mTOR, p38, and survivin mRNA, suggesting antiproliferative and apoptotic mechanisms. An enhanced chemopreventive/chemotherapeutic potential of DSC anthocyanins is suggested because mRNA levels of invasive/metastatic biomarkers Sp1, Sp4, and VCAM-1 were downregulated only by F2.
    Conclusions: These results demonstrate the chemopreventive/chemotherapeutic potential of DSC phenolics and fractions enriched in anthocyanins and procyanidins as natural compounds to target cell pathways linked to proliferation, apoptosis and invasion in breast cancer. The underlying molecular mechanisms are currently under investigation.
    Funding Sources: This work was supported by the Northwest Cherry Growers.
    DOI:  https://doi.org/10.1093/cdn/nzz030.FS13-03-19
  70. Cancer Res. 2019 Jun 21. pii: canres.3503.2018. [Epub ahead of print]
    Isoflavone ME-344 disrupts redox homeostasis and mitochondrial function by targeting Heme Oxygenase 1.
    Leilei Zhang, Jie Zhang, Zhiwei Ye, Yefim Manevich, Lauren E Ball, Jennifer R Bethard, Yu-Lin Jiang, Ann-Marie Broome, Annamarie C Dalton, Gavin Y Wang, Danyelle M Townsend, Kenneth D Tew.
      ME-344 is a second generation isoflavone with unusual cytotoxic properties that is in clinical testing in cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used lung cancer cell lines that are naturally sensitive or resistant to ME-344. Drug-induced apoptosis was linked with enhanced levels of reactive oxygen species (ROS) and this initiated an Nrf2 (Nuclear erythroid factor 2-like 2) signaling response, downstream of which, heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by ME-344. ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts, with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance (SPR) technology and through interaction with a clickable ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of ME-344 with HO-1. Proteomic analysis showed that clusters of mitochondrial proteins, including voltage-dependent anion-selective channels (VDACs), were also impacted by ME-344. Human lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared to normal tissues. Overall, our data show that ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other mitochondrial proteins are also affected resulting in interference in tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of ME-344.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-3503
  71. EXCLI J. 2019 ;18 229-242
    Neuroprotective mechanism of low-dose sodium nitrite in oxygen-glucose deprivation model of cerebral ischemic stroke in PC12 cells.
    Nader Shakib, Mohammad Hassan Khadem Ansari, Pouran Karimi, Yousef Rasmi.
      The purpose of this study was to clarify the mechanisms of the protective effects of low-dose sodium nitrite (SN) on oxygen and glucose deprivation (OGD)-induced endoplasmic reticulum (ER) stress in PC12 cells. The PC12 cells were exposed to 4 h of OGD and treated with 100 μmol SN. The expression and activity of ER stress markers, including PKR-like endoplasmic reticulum kinase (PERK), transcription factor 6 (ATF6), CCAAT/enhancer binding protein homologous protein (CHOP), as well as caspase-12 and -3, were detected by immunoblotting assay. Fluorescence staining was used to detect the levels of reactive oxygen species (ROS) and Ca2+ release from the ER. Cell viability was also evaluated by MTT assay. It was found that SN significantly inhibited ROS production and Ca2+ release from the ER in OGD-injured PC12 cells. Moreover, ER stress marker expression and cleaved fragments of caspase-3 and -12 in OGD-injured PC12 cells were decreased after SN treatment. These findings were accompanied by a significant increase in cell viability. It seems that SN exerts a neuroprotective effect at least partially through reduction of ROS-mediated ER stress caused by OGD insult.
    Keywords:  Ca2+ release; PC12 cells; endoplasmic reticulum stress; oxygen and glucose deprivation; sodium nitrite
    DOI:  https://doi.org/10.17179/excli2018-1947
  72. Biomed Res Int. 2019 ;2019 2193706
    Mitochondrial Division Inhibitor 1 Attenuates Mitophagy in a Rat Model of Acute Lung Injury.
    Xu Luo, Ruimeng Liu, Zhihao Zhang, Zhugui Chen, Jian He, Youtan Liu.
      The regulation of intracellular mitochondria degradation is mediated by mitophagy. While studies have shown that mitophagy can lead to mitochondrial dysfunction and cell damage, the role of Mdivi-1 and mitophagy remains unclear in acute lung injury (ALI) pathogenesis. In this study, we demonstrated that Mdivi-1, which is widely used as an inhibitor of mitophagy, ameliorated acute lung injury assessed by HE staining, pulmonary microvascular permeability assay, measurement of wet/dry weight (W/D) ratio, and oxygenation index (PaO2/FiO2) analysis. Then, the mitophagy related proteins were evaluated by western blot. The results indicated that LPS-induced activation of mitophagy was inhibited by Mdivi-1 treatment. In addition, we found that Mdivi-1 protected A549 cells against LPS-induced mitochondrial dysfunction. We also found that Mdivi-1 reduced pulmonary cell apoptosis in the LPS-challenged rats and protected pulmonary tissues from oxidative stress (represented by the content of superoxide dismutase, malondialdehyde and lipid peroxides in lung). Moreover, Mdivi-1 treatment ameliorated LPS-induced lung inflammatory response and cells recruitment. These findings indicate that Mdivi-1 mitigates LPS-induced apoptosis, oxidative stress, and inflammation in ALI, which may be associated with mitophagy inhibition. Thus, the inhibition of mitophagy may represent a potential therapy for treating ALI.
    DOI:  https://doi.org/10.1155/2019/2193706
  73. Eur J Med Chem. 2019 Jun 06. pii: S0223-5234(19)30534-3. [Epub ahead of print]178 417-432
    Enrichment of novel quinazoline derivatives with high antitumor activity in mitochondria tracked by its self-fluorescence.
    Yaling Zhang, Qiaoli Hou, Xiabing Li, Jiuling Zhu, Wei Wang, Baolin Li, Lijun Zhao, Haibin Xia.
      In novel synthetic 28 4-arylamino-6-fluoro quinazoline derivatives, compound 3a displayed the most remarkable inhibitory activities against tumor cells (IC50 values ranging between 0.71 and 2.30 μM) in vitro. Importantly, 3a obviously inhibited the proliferation and metastasis of A549 cells in a zebrafish xenograft model, while also mediated cell apoptosis and G0/G1-phase cell cycle arrest in A549 cells. Interestingly, 3a had excellent fluorescence at 439 nm (λex = 375 nm) in DMSO and at 428 nm (λex = 372 nm) in 0.5% DMSO-phosphate buffer, and the self-fluorescent characteristic revealed 3a itself accumulates in the mitochondria of A549 cells, which suggested the antitumor process of 3a may involve the mitochondrial apoptotic pathway. The hypothesis was verified by the increase of the intracellular reactive oxygen species, the decrease of mitochondrial membrane potential, the release of cytochrome C from the mitochondria into the cytoplasm, and the cascade activation of caspase-9 and caspase-3 when A549 cells were treated with 3a. This work has great implications for further development of anticancer agents that can be enriched in mitochondria and can be tracked in real-time in biological systems due to the ideal fluorescence.
    Keywords:  Antitumor activity; Mitochondria; Quinazoline; Self-fluorescence
    DOI:  https://doi.org/10.1016/j.ejmech.2019.06.015
  74. Biol Pharm Bull. 2019 Jun 14.
    Epimedin C protects H2O2-induced peroxidation injury by enhancing the function of endothelial progenitor HUVEC populations.
    Dan-Hong Wei, Jiu-Ling Deng, Rong-Zhen Shi, Li Ma, Jia-Man Shen, Robert Hoffman, Ying-Hong Hu, Hui Wang, Jian-Li Gao.
      Endothelial cell injury and apoptosis induced by oxidative stress serve important roles in many vascular diseases. The repair of endothelial cell vascular injury relies on the function of local endothelial progenitor cells (EPCs). Our previous study indicated that epimedin C, a major flavonoid derived from Herba epimedii (yin yang huo), could promote vascularization by inducing endothelial-like differentiation of mesenchymal stem cells C3H/10T1/2 both in vivo and in vitro. In view of the significant cardiovascular protective effects of Herba epimedii, we detected a protective effect of epimedin C on H2O2-induced peroxidation injury in human umbilical vein endothelial cells (HUVECs) and the role of EPC in this process. The results show that epimedin C increased the expression of the stem cell marker, CD34 and PROM1, and subsequently enhanced the expression and function of vascular endothelial growth factor and MMP-2 in local vascular endothelial cells. In conclusion, epimedin C protects H2O2-induced peroxidation injury by enhancing the function of endothelial progenitor HUVEC populations.
    Keywords:  Chinese herbs; Epimedin C; HUVEC; Herba Epimdii; endothelial progenitor cell; peroxidation injury
    DOI:  https://doi.org/10.1248/bpb.b19-00159
  75. CNS Neurosci Ther. 2019 Jun 20.
    L-glutamine protects mouse brain from ischemic injury via up-regulating heat shock protein 70.
    Long-Long Luo, Yong-Fang Li, Hui-Min Shan, Li-Ping Wang, Fang Yuan, Yuan-Yuan Ma, Wan-Lu Li, Ting-Ting He, Yu-Yang Wang, Mei-Jie Qu, Huai-Bin Liang, Zhi-Jun Zhang, Guo-Yuan Yang, Yao-Hui Tang, Yong-Ting Wang.
      INTRODUCTION: L-glutamine is an antioxidant that plays a role in a variety of biochemical processes. Given that oxidative stress is a key component of stroke pathology, the potential of L-glutamine in the treatment of ischemic stroke is worth exploring.AIMS: In this study, we investigated the effect and mechanisms of action of L-glutamine after cerebral ischemic injury.
    RESULTS: L-glutamine reduced brain infarct volume and promoted neurobehavioral recovery in mice. L-glutamine administration increased the expression of heat-shock protein 70 (HSP70) in astrocytes and endothelial cells. Such effects were abolished by the coadministration of Apoptozole, an inhibitor of the ATPase activity of HSP70. L-glutamine also reduced oxidative stress and neuronal apoptosis, and increased the level of superoxide dismutase, glutathione, and brain-derived neurotrophic factor. Cotreatment with Apoptozole abolished these effects. Cell culture study further revealed that the conditioned medium from astrocytes cultured with L-glutamine reduced the apoptosis of neurons after oxygen-glucose deprivation.
    CONCLUSION: L-glutamine attenuated ischemic brain injury and promoted functional recovery via HSP70, suggesting its potential in ischemic stroke therapy.
    Keywords:  L-glutamine; heat-shock protein 70; ischemic stroke; neuroprotection; oxidative stress
    DOI:  https://doi.org/10.1111/cns.13184
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