bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019‒06‒16
fifty-seven papers selected by
Gavin McStay
Staffordshire University
  1. Lycopene alleviates AFB1-induced immunosuppression by inhibiting oxidative stress and apoptosis in the spleen of mice.
  2. Upregulation of UCP2 Expression Protects against LPS-Induced Oxidative Stress and Apoptosis in Cardiomyocytes.
  3. Mitochondrial oxidative stress-induced brain and hippocampus apoptosis decrease through modulation of caspase activity, Ca2+ influx and inflammatory cytokine molecular pathways in the docetaxel-treated mice by melatonin and selenium treatments.
  4. Andrographolide attenuates bupivacaine-induced cytotoxicity in SH-SY5Y cells through preserving Akt/mTOR activity.
  5. The protective effects of glucagon-like peptide-1 on cardiac remodeling by inhibiting oxidative stress through mammalian target of rapamycin complex 1 /p70 ribosomal protein S6 kinase pathway in diabetes mellitus.
  6. Potential Effect of 1,25 Dihydroxyvitamin D3 on Thioacetamide-Induced Hepatotoxicity in Rats.
  7. Cul4a as a New Interaction Protein of PARP1 Inhibits Oxidative Stress-Induced H9c2 Cell Apoptosis.
  8. Cantharidin decreased viable cell number in human osteosarcoma U-2 OS cells through G2/M phase arrest and induction of cell apoptosis.
  9. Dimethyloxalylglycine (DMOG) and the Caspase Inhibitor "Ac-LETD-CHO" Protect Neuronal ND7/23 Cells of Gluocotoxicity.
  10. DL-3-n-butylphthalide protected retinal Müller cells dysfunction from oxidative stress.
  11. Downregulation of Bach1 protects osteoblasts against hydrogen peroxide-induced oxidative damage in vitro by enhancing the activation of Nrf2/ARE signaling.
  12. Follistatin Protects against Glomerular Mesangial Cell Apoptosis and Oxidative Stress to Ameliorate Chronic Kidney Disease.
  13. Dehydroepiandrosterone Prevents H2O2-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways.
  14. Icariin Inhibits AGE-Induced Injury in PC12 Cells by Directly Targeting Apoptosis Regulator Bax.
  15. Antiepileptic Effects of Protein-Rich Extract from Bombyx batryticatus on Mice and Its Protective Effects against H2O2-Induced Oxidative Damage in PC12 Cells via Regulating PI3K/Akt Signaling Pathways.
  16. The protective effects of liraglutide on AD-like neurodegeneration induced by oxidative stress in human neuroblastoma SH-SY5Y cells.
  17. In vitro and in vivo mechanism of hepatocellular carcinoma inhibition by β-TCP nanoparticles.
  18. Diastereoisomer-specific neurotoxicity of hexabromocyclododecane in human SH-SY5Y neuroblastoma cells.
  19. Cyclophilin A Protects Cardiomyocytes against Hypoxia/Reoxygenation-Induced Apoptosis via the AKT/Nox2 Pathway.
  20. Redox-Related Neuronal Death and Crosstalk as Drug Targets: Focus on Epilepsy.
  21. Alantolactone induces gastric cancer BGC-823 cell apoptosis by regulating reactive oxygen species generation and the AKT signaling pathway.
  22. Eclalbasaponin I causes mitophagy to repress oxidative stress-induced apoptosis via activation of p38 and ERK in SH-SY5Y cells.
  23. Callistephin enhances the protective effects of isoflurane on microglial injury through downregulation of inflammation and apoptosis.
  24. A novel NADPH oxidase inhibitor targeting Nox4 in TGFβ-induced lens epithelial to mesenchymal transition.
  25. Cytotoxicity, Oxidative Stress, and Autophagy in Human Alveolar Epithelial Cell Line (A549 Cells) Exposed to Standardized Urban Dust.
  26. Protective Effect of Ginsenoside Rg1 on Oxidative Damage Induced by Hydrogen Peroxide in Chicken Splenic Lymphocytes.
  27. Pro-apoptotic effect of haem oxygenase-1 in human colorectal carcinoma cells via endoplasmic reticular stress.
  28. Protective effect of dexmedetomidine against diabetic hyperglycemia-exacerbated cerebral ischemia/reperfusion injury: An in vivo and in vitro study.
  29. Downregulation of microRNA-302b-3p relieves oxygen-glucose deprivation/re-oxygenation induced injury in murine hippocampal neurons through up-regulating Nrf2 signaling by targeting fibroblast growth factor 15/19.
  30. Baicalin inhibits C2C12 myoblast apoptosis and prevents against skeletal muscle injury.
  31. Role of Cytosolic 2-Cys Prx1 and Prx2 in Redox Signaling.
  32. The protective effect of Korean Red Ginseng against rotenone-induced Parkinson's disease in rat model: modulation of nuclear factor-κβ and caspase-3.
  33. Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-κB inflammatory cascade.
  34. Vagus nerve stimulation protects against acute liver injury induced by renal ischemia reperfusion via antioxidant stress and anti-inflammation.
  35. Resveratrol alleviates inflammatory injury and enhances the apoptosis of fibroblast‑like synoviocytes via mitochondrial dysfunction and ER stress in rats with adjuvant arthritis.
  36. Effect of Baoshenfang Formula on Podocyte Injury via Inhibiting the NOX-4/ROS/p38 Pathway in Diabetic Nephropathy.
  37. Exploring the cytotoxic activity of new phenanthroline salicylaldimine Zn(II) complexes.
  38. Morinda citrifolia and Its Active Principle Scopoletin Mitigate Protein Aggregation and Neuronal Apoptosis through Augmenting the DJ-1/Nrf2/ARE Signaling Pathway.
  39. Small interfering RNA targeting of peroxiredoxinⅡ gene enhances formaldehyde-induced toxicity in bone marrow cells isolated from BALB/c mice.
  40. Increased FoxO3a expression prevents osteoblast differentiation and matrix calcification.
  41. Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells.
  42. Construing the Biochemical and Molecular Mechanism Underlying the In Vivo and In Vitro Chemotherapeutic Efficacy of Ruthenium-Baicalein Complex in Colon Cancer.
  43. The inhibitor of apoptosis protein MoBir1 is involved in the suppression of hydrogen peroxide-induced fungal cell death, reactive oxygen species generation, and pathogenicity of rice blast fungus.
  44. The Neuroprotective Effect of Hemin and the Related Mechanism in Sevoflurane Exposed Neonatal Rats.
  45. Targeting cullin 3 by miR-601 activates Nrf2 signaling to protect retinal pigment epithelium cells from hydrogen peroxide.
  46. Irisin Contributes to the Hepatoprotection of Dexmedetomidine during Intestinal Ischemia/Reperfusion.
  47. Total Extracts of Abelmoschus manihot L. Attenuates Adriamycin-Induced Renal Tubule Injury via Suppression of ROS-ERK1/2-Mediated NLRP3 Inflammasome Activation.
  48. Sex differences in neonatal mouse brain injury after hypoxia ischemia and adaptaquin treatment.
  49. Ligustrazine Attenuates Myocardial Injury Induced by Coronary Microembolization in Rats by Activating the PI3K/Akt Pathway.
  50. Tricetin protects against 6-OHDA-induced neurotoxicity in Parkinson's disease model by activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway.
  51. Apoptosis and cell proliferation in proximal tubular cells exposed to apoptotic bodies. Novel pathophysiological implications in cisplatin-induced renal injury.
  52. Asprosin improves the survival of mesenchymal stromal cells in myocardial infarction by inhibiting apoptosis via the activated ERK1/2-SOD2 pathway.
  53. Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications.
  54. Towards a unified mechanistic theory of aging.
  55. Protective effects of hydrogen inhalation during the warm ischemia phase against lung ischemia-reperfusion injury in rat donors after cardiac death.
  56. Effects of novel antidiabetes agents on apoptotic processes in diabetes and malignancy: Implications for lowering tissue damage.
  57. Time course of cardiomyopathy induced by doxorubicin in rats.
  1. Food Funct. 2019 Jun 11.
    Lycopene alleviates AFB1-induced immunosuppression by inhibiting oxidative stress and apoptosis in the spleen of mice.
    Feibo Xu, Peiyan Wang, Qiucheng Yao, Bing Shao, Hongyan Yu, Kaiyuan Yu, Yanfei Li.
      Lycopene (LYC) has been reported to exhibit antioxidant and immunoprotective activities, and our previous studies confirmed that LYC can alleviate multiple tissue damage induced by aflatoxin B1 (AFB1). However, it is unclear whether LYC could relieve the AFB1-induced immunosuppression. Thus, forty-eight male mice were randomly allocated and treated with LYC (5 mg kg-1) and/or AFB1 (0.75 mg kg-1) by intragastric administration for 30 days. We found that LYC alleviated AFB1-induced immunosuppression by relieving splenic structure injury and increasing the spleen weight, spleen coefficient, T lymphocyte subsets, the contents of IL-2, IFN-γ and TNF-α in serum, as well as the mRNA expression of IL-2, IFN-γ and TNF-α in spleen. Furthermore, LYC inhibited oxidative stress induced by AFB1 via decreasing the levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and malondialdehyde (MDA), while enhancing the total antioxidant capacity (T-AOC) and antioxidant enzyme activities. In addition, LYC also restrained splenic apoptosis through blocking mitochondria-mediated apoptosis in AFB1 intoxicated mice, presenting as the increase of mitochondrial membrane potential, and the decrease of cytoplasmic Cyt-c protein expression, cleaved Caspase-3 protein expression, Caspase-3/9 activities and mRNA expressions, as well as balancing the mitochondrial protein and mRNA expressions of Bax and Bcl-2. These results indicate that LYC can alleviate AFB1-induced immunosuppression by inhibiting oxidative stress and mitochondria-mediated apoptosis of mice spleen.
    DOI:  https://doi.org/10.1039/c8fo02300j
  2. Oxid Med Cell Longev. 2019 ;2019 2758262
    Upregulation of UCP2 Expression Protects against LPS-Induced Oxidative Stress and Apoptosis in Cardiomyocytes.
    Jinda Huang, Wanwan Peng, Yijun Zheng, Hu Hao, Sitao Li, Yu Yao, Yue Ding, Junliang Zhang, Juanjuan Lyu, Qiyi Zeng.
      Uncoupling protein 2 (UCP2) has a cardioprotective role under septic conditions, but the underlying mechanism remains unclear. This study aimed at investigating the effects of UCP2 on the oxidative stress and apoptosis of cardiomyocytes induced by lipopolysaccharide (LPS). First, LPS increased UCP2 expression in cardiomyocytes in a time-dependent manner. LPS increased the production of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and malondialdehyde (MDA) and decreased the level of superoxide dismutase (SOD). However, UCP2 knockdown increased the LPS-induced cardiac injury and oxidative stress. In addition, LPS damaged the mitochondrial ultrastructure and led to the disruption of mitochondrial membrane potential (MMP), as well as the release of mitochondrial cytochrome c. UCP2 knockdown aggravated mitochondrial injury and the release of mitochondrial cytochrome c. LPS increased the protein levels of Bax and cleaved-caspase-3, decreased the protein level of Bcl-2, and upregulated the protein level of mitogen-activated protein kinase. However, upon UCP2 knockdown, the protein levels of Bax and cleaved-caspase-3 increased even further, and the protein level of Bcl-2 was further decreased. The protein level of phosphorylated p38 was also further enhanced. Thus, UCP2 protects against LPS-induced oxidative stress and apoptosis in cardiomyocytes.
    DOI:  https://doi.org/10.1155/2019/2758262
  3. Metab Brain Dis. 2019 Jun 13.
    Mitochondrial oxidative stress-induced brain and hippocampus apoptosis decrease through modulation of caspase activity, Ca2+ influx and inflammatory cytokine molecular pathways in the docetaxel-treated mice by melatonin and selenium treatments.
    Zeki Serdar Ataizi, Kemal Ertilav, Mustafa Nazıroğlu.
      Docetaxel (DOCE) is widely used to treat several types of glioblastoma. Adverse effects DOCE seriously limit its clinical use in several tissues. Its side effects on brain cortex and hippocampus have not been clarified yet. Limited data indicated a protective effect of melatonin (MLT) and selenium (SELEN) on DOCE-induced apoptosis, Ca2+ influx and mitochondrial reactive oxygen species (ROS) in several tissues except brain and hippocampus. The purpose of this study is to discover the protective effect of MLT and SELEN on DOCE-induced brain and hippocampus oxidative toxicity in mice. MLT and SELEN pretreatments significantly ameliorated acute DOCE-induced mitochondrial ROS production in the hippocampus and brain tissues by reducing levels of lipid peroxidation, intracellular ROS production and mitochondrial membrane depolarization, while increasing levels of total antioxidant status, glutathione, glutathione peroxidase, MLT, α-tocopherol, γ-tocopherol, vitamin A, vitamin C and β-carotene in the tissues. Furthermore, MLT and SELEN pretreatments increased cell viability and TRPM2 channel activation in the hippocampus and brain followed by decreased activations of TNF-α, IL-1β, IL-6, and caspase -3 and - 9, suggesting a suppression of calcium ion influx, apoptosis and inflammation responses. However, modulator role of SELEN on the values in the tissues is more significant than in the MLT treatment. MLT and SELEN prevent DOCE-induced hippocampus and brain injury by inhibiting mitochondrial ROS and cellular apoptosis through regulating caspase -3 and - 9 activation signaling pathways. MLT and SELEN may serve as potential therapeutic targets against DOCE-induced toxicity in the hippocampus and brain.
    Keywords:  Apoptosis; Docetaxel; Hippocampus; Inflammation; Melatonin; Mitochondrial oxidative cytotoxicity
    DOI:  https://doi.org/10.1007/s11011-019-00428-x
  4. Drug Des Devel Ther. 2019 ;13 1659-1666
    Andrographolide attenuates bupivacaine-induced cytotoxicity in SH-SY5Y cells through preserving Akt/mTOR activity.
    Huiyuan Zhang, Weiwei Wang, Qian Du.
      Background: Bupivacaine (Bup) is the most commonly used local anesthetic. However, Bup induces cytotoxicity, especially in older patients. Recent reports have indicated that andrographolide (Andro) exhibits protective effects on human neurons. Nevertheless, whether Andro can inhibit Bup-induced cytotoxicity remains unclear. As such, we investigated the effect of Andro on Bup-induced cytotoxicity of SH-SY5Y cells in the present study. Methods: Western blotting was used to examine expression of Bax, Bcl2, active caspase 3, p-Akt, and p-mTOR in SH-SY5Y cells. In addition, ELISA was used to detect levels of total glutathione and reactive oxygen species in cells. Results: We found that Andro attenuated Bup-induced cytotoxicity of SH-SY5Y cells. In addition, Andro inhibited Bup-induced apoptosis via downregulating the expression of Bax and active caspase 3 and upregulating the proteins Bcl2, p-Akt, and p-mTOR in SH-SY5Y cells. Moreover, Andro alleviated Bup-induced oxidative damage in SH-SY5Y cells via downregulating the level of reactive oxygen species and upregulating of the level of total glutathione. More significantly, inhibition of Akt abolished the protective effect of Andro in Bup-treated SH-SY5Y cells. Conclusion: Our findings indicated that Andro played a neuroprotective role via preserving Akt/mTOR activity and increasing antioxidative status in Bup-treated SH-SY5Y cells. Therefore, Andro may be a potential agent for the treatment of human cytotoxicity induced by Bup.
    Keywords:  Akt; andrographolide; apoptosis; bupivacaine; cytotoxicity
    DOI:  https://doi.org/10.2147/DDDT.S201122
  5. J Diabetes Investig. 2019 Jun 14.
    The protective effects of glucagon-like peptide-1 on cardiac remodeling by inhibiting oxidative stress through mammalian target of rapamycin complex 1 /p70 ribosomal protein S6 kinase pathway in diabetes mellitus.
    Dongjuan Wang, Longfu Jiang, Beili Feng, Nana He, Yue Zhang, Honghua Ye.
      AIMS/INTRODUCTION: Although increased reactive oxygen species (ROS) generation is a major mechanism leading to cardiac remodeling in diabetes mellitus (DM), research into the effects of antioxidation on diabetic cardiac remodeling remains scarce and controversial. Glucagon-like peptide-1 (GLP-1) displays potential anti-oxidative effects besides lowering blood glucose. The objective of this research was to investigate the effects of GLP-1 on cardiac remodeling and the molecular mechanism involved in DM.MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic rats received exenatide treatment for 3 months. Cardiac function, cardiac weight index and myocardial interstitial fibrosis were measured. Cardiomyocytes were cultured in high glucose medium with GLP-1 treatment. The ROS production, apoptosis and the levels of mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal protein S6 kinase (p70S6k) protein expression in cardiomyocytes were analyzed.
    RESULTS: Experimental DM exhibited impaired cardiac diastolic function, increased brain natriuretic peptide expression, and increased interstitial collagen deposition in the myocardium, which were ameliorated by exenatide treatment. Exenatide reduced myocardial ROS production and apoptosis in DM. Also, high glucose-induced ROS generation and apoptosis in cardiomyocyte were inhibited by GLP-1, as well as the levels of mTORC1/p70S6k phosphorylation. Furthermore, GLP-1 treatment upregulated adenosine monophosphate activated protein kinase (AMPK) activity in high glucose-induced cardiomyocyte.
    CONCLUSIONS: GLP-1 protects the cardiomyocyte from oxidative stress and apoptosis in DM, which may contribute to the improvement of cardiac remodeling. The cardiac protection of GLP-1 may be dependent on inhibition of mTORC1/p70S6K, via an AMPK-mediated pathway. This article is protected by copyright. All rights reserved.
    Keywords:  cardiac remodeling; diabetes mellitus; glucagon-like peptide-1
    DOI:  https://doi.org/10.1111/jdi.13098
  6. J Surg Res. 2019 Jun 06. pii: S0022-4804(19)30336-1. [Epub ahead of print]243 165-172
    Potential Effect of 1,25 Dihydroxyvitamin D3 on Thioacetamide-Induced Hepatotoxicity in Rats.
    Zarife N Özdemir-Kumral, Burak E Erkek, Buse Karakuş, Meslina Almacı, Reza Fathi, Meral Yüksel, Alev Cumbul, İnci Alican.
      BACKGROUND: 1,25 Dihydroxyvitamin D3 (1,25(OH)2D3) modulates inflammation and immune responses. Deficiency of 1,25(OH)2D3 was found to be associated with the risk of cancer, cardiovascular disease, osteoarthritis, infections, and autoimmune diseases. This study evaluated the effect of 1,25 dihydroxyvitamin D3 1,25(OH)2D3 on thioacetamide (TAA)-induced acute liver injury in rats.MATERIALS AND METHODS: Rats were treated with either saline or 1,25(OH)2D3 (0.30 μg/kg; orogastrically) for 15 d. Starting from day 13, TAA (200 mg/kg; intraperitoneally) was given for 3 d. On day 15, all rats were euthanized. Liver and blood samples were collected.
    RESULTS: TAA caused severe damage, increased lipid peroxidation with reductions in endogenous antioxidants, increased apoptosis, increased production of reactive oxygen species, and elevated inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) expression in liver. Extent of damage was decreased by 1,25(OH)2D3 (P < 0.01). 1,25(OH)2D3 attenuated the increase in malondialdehyde (P < 0.01), increase in myeloperoxidase (P < 0.01), increase in chemiluminescence levels (P < 0.05) and apoptotic activity (P < 0.001). Elevated liver iNOS and NF-κB expression in TAA group was also reduced by 1,25(OH)2D3 (P < 0.001, for iNOS; P < 0.001, for NF-κB). TAA group revealed high serum aspartate transaminase and alanine transaminase (ALT) activities (P < 0.01, for aspartate transaminase; P = 0.08, for ALT) and reduced albumin levels (P < 0.01) compared with control. 1,25(OH)2D3 had no statistically significant effect on these parameters.
    CONCLUSIONS: 1,25(OH)2D3 provides protection against hepatic injury in a rat model of TAA-induced hepatotoxicity via suppression of inflammatory reaction, oxidative stress, and apoptosis.
    Keywords:  1,25(OH)(2)D(3); Apoptosis; Hepatotoxicity; Oxidative stress; Rat; Thioacetamide
    DOI:  https://doi.org/10.1016/j.jss.2019.05.020
  7. Oxid Med Cell Longev. 2019 ;2019 4273261
    Cul4a as a New Interaction Protein of PARP1 Inhibits Oxidative Stress-Induced H9c2 Cell Apoptosis.
    Ning Ye, Naijin Zhang, Ying Zhang, Hao Qian, Boquan Wu, Yingxian Sun.
      Oxidative stress plays a major part in myocardial reperfusion injury. Cul4a is the core protein of CRLs E3 ubiquitin ligase complex; while it is known that Cul4a is responsible for various cancers, its role in cardiac function remains unclear. Hence, we have shown the protective function of Cul4a and its protection mechanism in oxidative stress-induced H9c2 cardiomyocyte apoptosis. Here, oxidative stress was induced by hydrogen peroxide (H2O2), CCK-8 assay and flow cytometry were used to analyze cell viability and apoptosis rate, western blot and immunofluorescence were used to quantitatively analyze the expression of protein, ROS fluorescence kit was used to detect reactive oxygen species (ROS) formation, and coimmunoprecipitation was used to identify protein interaction. In the results, it was found that Cul4a was involved in oxidative stress-induced H9c2 cell apoptosis and could inhibit H2O2-induced ROS generation and H9c2 cell apoptosis. Furthermore, we identified that when combining with PARP1, Cul4a could reduce its expression, and the interaction was enhanced under oxidative stress. In conclusion, our results indicate that Cul4a is a new protective factor involved in oxidative stress-induced cardiomyocyte injury and functions by tying and decreasing overactivated PARP1.
    DOI:  https://doi.org/10.1155/2019/4273261
  8. Biosci Biotechnol Biochem. 2019 Jun 12. 1-12
    Cantharidin decreased viable cell number in human osteosarcoma U-2 OS cells through G2/M phase arrest and induction of cell apoptosis.
    Chia-Ching Chen, Fu-Shin Chueh, Shu-Fen Peng, Wen-Wen Huang, Chang-Hai Tsai, Fuu-Jen Tsai, Chih-Yang Huang, Chih-Hsin Tang, Jai-Sing Yang, Yuan-Man Hsu, Mei-Chin Yin, Yi-Ping Huang, Jing-Gung Chung.
      Cantharidin (CTD), a sesquiterpenoid bioactive substance, has been reported to exhibit anticancer activity against various types of cancer cells. The aim of the present study was to investigate the apoptosis effects and the underlying mechanisms of CTD on osteosarcoma U-2 OS cells. Results showed that CTD induced cell morphologic changes, reduced total viable cells, induced DNA damage, and G2/M phase arrest. CTD increased the production of reactive oxygen species and Ca2+, and elevated the activities of caspase-3 and -9, but decreased the level of mitochondrial membrane potential. Furthermore, CTD increased the ROS- and ER stress-associated protein expressions and increased the levels of pro-apoptosis-associated proteins, but decreased that of anti-apoptosis-associated proteins. Based on these observations, we suggested that CTD decreased cell number through G2/M phase arrest and the induction of cell apoptosis in U-2 OS cells and CTD could be a potential candidate for osteosarcoma treatments.
    Keywords:  Cantharidin; G/M phase arrest; apoptosis; cell cycle; osteosarcoma U-2 OS cells
    DOI:  https://doi.org/10.1080/09168451.2019.1627182
  9. Exp Clin Endocrinol Diabetes. 2019 Jun 11.
    Dimethyloxalylglycine (DMOG) and the Caspase Inhibitor "Ac-LETD-CHO" Protect Neuronal ND7/23 Cells of Gluocotoxicity.
    Debasmita Mukhopadhyay, Mohammad Hammami, Amani Khalouf, Yazan Al Shaikh, Abdul Khader Mohammed, Mawieh Hamad, Albert Salehi, Jalal Taneera.
      It well known that long-lasting hyperglycaemia disrupts neuronal function and leads to neuropathy and other neurodegenerative diseases. The α-ketoglutarate analogue (DMOG) and the caspase-inhibitor "Ac-LETD-CHO are potential neuroprotective molecules. Whether their protections may also extend glucotoxicity-induced neuropathy is not known. Herein, we evaluated the possible cell-protective effects of DMOG and Ac-LETD-CHO against hyperglycaemia-induced reactive oxygen species and apoptosis in ND7/23 neuronal cells. The impact of glucotoxicity on the expression of HIF-1α and a panel of micro-RNAs of significance in hyperglycaemia and apoptosis was also investigated.ND7/23 cells cultured under hyperglycaemic conditions showed decreased cell viability and elevated levels of ROS production in a dose- and time-dependent manner. However, presence DMOG (500 µM) and/or Ac-LETD-CHO (50 µM) counteracted this effect and increase cell viability concomitant with reduction in ROS production, DNA damage and apoptosis. AcLETD-CHO suppressed hyperglycaemia-induced caspase 3 activation in ND7/23 cells. Both DMOG and Ac-LETD-CHO increased HIF-1α expression paralleled with the suppression of miR-126-5p, miR-128-3p and miR-181 expression and upregulation of miR-26b, 106a-5p, 106b-5p, 135a-5p, 135b-5p, 138-5p, 199a-5p, 200a-3p and 200c-3p expression.We demonstrate a mechanistic link for the DMOG and Ac-LETD-CHO protection against hyperglycaemia-induced neuronal dysfunction, DNA damage and apoptosis and thereby propose that pharmacological agents mimicking these effects may represent a promising novel therapy for the hyperglycaemia-induced neuropathy.
    DOI:  https://doi.org/10.1055/a-0919-4489
  10. Curr Eye Res. 2019 Jun 12.
    DL-3-n-butylphthalide protected retinal Müller cells dysfunction from oxidative stress.
    Xiaoli Xing, Liangyu Huang, Yingjuan Lv, Xun Liu, Ruihong Su, Xiaorong Li, Lijie Dong.
      Purpose: To observe the protective effects and underlying mechanisms of dl-3-n-butylphthalide (NBP) against H2O2-induced oxidative damage in retinal Müller cells. Methods: Cultured human Müller cell line (MIO-M1line) were exposed to H2O2 for 2 hours. Cell survival was evaluated by Calcein AM cell viability assay. Dichlorofluorescein diacetate (DCFDA) + endoplasmic reticulum (ER) red fluorescent probe (ER-Tracker Red) staining was used to observe the expression level of reactive oxygen species (ROS) in ER of cells. Mitochondrial membrane potential detection (JC-1) was used to observe cell membrane potential change and early apoptosis. Cell apoptosis was detected by Hoechst33258 staining. The expressions of Nrf2, HO-1 were documented by Western blot analysis. Results: NBP effectively improved the survival ability of Müller cells shown by MTT assay. NBP effectively alleviated the morphological and apoptotic changes induced by H2O2 stimulation by Calcein AM assay, HE staining, Hoechst 33258, JC-1 staining. H2O2 induction increased the expression level of ROS, whereas, the treatment with NBP could remarkably lower the expression level of ROS. Cell immunofluorescence staining indicated that the fluorescence staining intensity of HO-1 in the NBP group was significantly higher than that in the control group. While the western blotting results showed that the expression level of HO-1 could be increased by NBP in a time-dependent manner. The translocation of Nrf2 in nuclei was observed within 2 h and Nrf2 was identified in nuclei for up to 48h. Conclusions: Our study demonstrated that NBP had a protective effect on H2O2-induced cytotoxicity in retinal Müller cells in vitro and that it was a potent activator of Nrf2 and HO-1signaling.
    Keywords:  HO-1; Nrf2; Oxidative stress; Retinal Müller cell; dl-3-n-butylphthalide
    DOI:  https://doi.org/10.1080/02713683.2019.1624777
  11. Chem Biol Interact. 2019 Jun 10. pii: S0009-2797(19)30270-4. [Epub ahead of print]
    Downregulation of Bach1 protects osteoblasts against hydrogen peroxide-induced oxidative damage in vitro by enhancing the activation of Nrf2/ARE signaling.
    Xiaoning Tian, Fei Cong, Hua Guo, Jinzhu Fan, Gao Chao, Tao Song.
      Oxidative-stress-induced osteoblast dysfunction plays an important role in the development and progression of osteoporosis. BTB and CNC homology 1 (Bach1) has been suggested as a critical regulator of oxidative stress; however, whether Bach1 plays a role in regulating oxidative-stress-induced osteoblast dysfunction remains unknown. Thus, we investigated the potential role and mechanism of Bach1 in regulating oxidative-stress-induced osteoblast dysfunction. Osteoblasts were treated with hydrogen peroxide (H2O2) to mimic a pathological environment for osteoporosis in vitro. H2O2 exposure induced Bach1 expression in osteoblasts. Functional experiments demonstrated that Bach1 silencing improved cell viability and reduced cell apoptosis and reactive oxygen species (ROS) production in H2O2-treated cells, while Bach1 overexpression produced the opposite effects. Notably, Bach1 inhibition upregulated alkaline phosphatase activity and osteoblast mineralization. Mechanism research revealed that Bach1 inhibition increased the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling and upregulated heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 mRNA expression. The Bach1 inhibition-mediated protective effect was partially reversed by silencing Nrf2 in H2O2-exposed osteoblasts. Taken together, these results demonstrate that Bach1 inhibition alleviates oxidative-stress-induced osteoblast apoptosis and dysfunction by enhancing Nrf2/ARE signaling activation, findings that suggest a critical role for the Bach1/Nrf2/ARE regulation axis in osteoporosis progression. Our study suggests that Bach1 may serve as a potential therapeutic target for treating osteoporosis.
    Keywords:  Bach1; Nrf2; Osteoblast; Osteoporosis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cbi.2019.06.019
  12. Antioxid Redox Signal. 2019 Jun 11.
    Follistatin Protects against Glomerular Mesangial Cell Apoptosis and Oxidative Stress to Ameliorate Chronic Kidney Disease.
    Neel Mehta, Agata Lages Gava, Dan Zhang, Bo Gao, Joan Krepinsky.
      AIMS: Interventions to inhibit oxidative stress and apoptosis, important pathogenic contributors towards the progression of chronic kidney disease (CKD), are not well established. Here, we investigated the role of a TGFβ superfamily neutralizing protein, follistatin (FST), in the regulation of apoptosis and oxidative stress in glomerular mesangial cells (MC) and in the progression of CKD.RESULTS: The ER stress inducer thapsigargin (Tg), known to cause MC apoptosis, led to a post-translational increase in the expression of FST. Recombinant FST protected, while FST down-regulation augmented, Tg-induced apoptosis without affecting Ca2+ release or ER stress induction. Although activins are the primary ligands neutralized by FST, their inhibition with neutralizing antibodies did not affect Tg-induced apoptosis. Instead, FST protected against Tg-induced apoptosis through neutralization of reactive oxygen species (ROS) independently of its ability to neutralize activins. Importantly, administration of FST to mice with CKD protected against renal cell apoptosis and oxidative stress. This was associated with improved kidney function, reduced albuminuria and attenuation of fibrosis. Innovation and Conclusion: Independent of its activin neutralizing ability, FST protected against Tg-induced apoptosis through neutralization of ROS and consequent suppression of oxidative stress, seen both in vitro and in vivo. Importantly, FST also ameliorated fibrosis and improved kidney function in CKD. FST is thus a novel potential therapeutic agent for delaying the progression of CKD.
    DOI:  https://doi.org/10.1089/ars.2018.7684
  13. Oxid Med Cell Longev. 2019 ;2019 2985956
    Dehydroepiandrosterone Prevents H2O2-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways.
    Longlong Li, Yao Yao, Zhihao Jiang, Jinlong Zhao, Ji Cao, Haitian Ma.
      Dehydroepiandrosterone (DHEA) is a popular dietary supplement that has well-known benefits in animals and humans, but there is not enough information about the mechanisms underlying its effects. The present study aimed at investigating these mechanisms through in vitro experiments on the effects of DHEA on rat liver BRL-3A cells exposed to oxidative stress through H2O2. The findings showed that DHEA increased the antioxidant enzyme activity, decreased ROS generation, and inhibited apoptosis in H2O2-treated cells. These effects of DHEA were not observed when the cells were pretreated with known antagonists of sex hormones (Trilostane, Flutamide, or Fulvestrant). Furthermore, treatment with estradiol and testosterone did not have the same protective effects as DHEA. Thus, the beneficial effects of DHEA were associated with mechanisms that were independent of steroid hormone pathways. With regard to the mechanism underlying the antiapoptotic effect of DHEA, pretreatment with DHEA was found to induce a significant decrease in the protein expression of Bax and caspase-3 and a significant increase in the protein expression of PI3K and p-Akt in H2O2-treated BRL-3A cells. These effects of DHEA were abolished when the cells were pretreated with the PI3K inhibitor LY294002. No changes were observed on the p-ERK1/2, p-p38, and p-JNK protein levels in H2O2-induced BRL-3A cells pretreated with DHEA. In conclusion, our data demonstrate that DHEA protects BRL-3A cells against H2O2-induced oxidative stress and apoptosis through mechanisms that do not involve its biotransformation into steroid hormones or the activation of sex hormone receptors. Importantly, the protective effect of DHEA on BRL-3A cells was mainly associated with PI3K/Akt signaling pathways, rather than MAPK signaling pathways.
    DOI:  https://doi.org/10.1155/2019/2985956
  14. Oxid Med Cell Longev. 2019 ;2019 7940808
    Icariin Inhibits AGE-Induced Injury in PC12 Cells by Directly Targeting Apoptosis Regulator Bax.
    Shao-Yang Zhao, Li-Xi Liao, Peng-Fei Tu, Wei-Wei Li, Ke-Wu Zeng.
      Diabetic encephalopathy (DE) is a serious complication caused by long-term cognitive impairment in diabetic patients. At present, there is no effective treatment for DE. Icariin (ICA) is a bioactive ingredient isolated from Epimedium. Previous research indicated that ICA was neuroprotective against Aβ-induced PC12 cell insult; however, the effect of ICA on an advanced glycosylation end product- (AGE-) induced neural injury model has not been studied. In this study, we investigated the neuroprotective effects of ICA on AGE-induced injury in PC12 cells. Our findings revealed that ICA could effectively protect PC12 cells from AGE-induced cell apoptosis by suppressing oxidative stress. Moreover, we observed that ICA could significantly protect against mitochondrial depolarization following AGE stimulation and inactivate the mitochondria-dependent caspase-9/3 apoptosis pathway. Most notably, we identified the direct target protein of ICA as apoptosis regulator Bax by a pulldown assay. We found that ICA could specifically target Bax protein and inhibit Bax dimer formation and migration to mitochondria. Furthermore, a siRNA knockdown experiment revealed that ICA could inhibit PC12 cell apoptosis and oxidative stress through targeting Bax. Taken together, our findings demonstrated that ICA could attenuate AGE-induced oxidative stress and mitochondrial apoptosis by specifically targeting Bax and further regulating the biological function of Bax on mitochondria.
    DOI:  https://doi.org/10.1155/2019/7940808
  15. Oxid Med Cell Longev. 2019 ;2019 7897584
    Antiepileptic Effects of Protein-Rich Extract from Bombyx batryticatus on Mice and Its Protective Effects against H2O2-Induced Oxidative Damage in PC12 Cells via Regulating PI3K/Akt Signaling Pathways.
    Meibian Hu, Yujie Liu, Liying He, Xing Yuan, Wei Peng, Chunjie Wu.
      Bombyx batryticatus is a known traditional Chinese medicine (TCM) utilized to treat convulsions, epilepsy, cough, asthma, headaches, and purpura in China for thousands of years. This study is aimed at investigating the antiepileptic effects of protein-rich extracts from Bombyx batryticatus (BBPs) on seizure in mice and exploring the protective effects of BBPs against H2O2-induced oxidative stress in PC12 cells and their underlying mechanisms. Maximal electroshock-induced seizure (MES) and pentylenetetrazole- (PTZ-) induced seizure in mice and the histological analysis were carried out to evaluate the antiepileptic effects of BBPs. The cell viability of PC12 cells stimulated by H2O2 was determined by MTT assay. The apoptosis and ROS levels of H2O2-stimulated PC12 cells were determined by flow cytometry analysis. Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione (GSH) in PC12 cells were assayed by ELISA and expressions of caspase-3, caspase-9, Bax, Bcl-2, PI3K, Akt, and p-Akt were evaluated by Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR) assays. The results revealed that BBPs exerted significant antiepileptic effects on mice. In addition, BBPs increased the cell viability of H2O2-stimulated PC12 cells and reduced apoptotic cells and ROS levels in H2O2-stimulated PC12 cells. By BBPs treatments, the levels of MDA and LDH were reduced and the levels of SOD and GSH-Px were increased in H2O2-stimulated PC12 cells. Moreover, BBPs upregulated the expressions of PI3K, Akt, p-Akt, and Bcl-2, whereas they downregulated the expressions of caspase-9, caspase-3, and Bax in H2O2-stimulated PC12 cells. These findings suggested that BBPs possessed potential antiepileptic effects on MES and PTZ-induced seizure in mice and protective effects on H2O2-induced oxidative stress in PC12 cells by exerting antioxidative and antiapoptotic effects via PI3K/Akt signaling pathways.
    DOI:  https://doi.org/10.1155/2019/7897584
  16. Chem Biol Interact. 2019 Jun 04. pii: S0009-2797(19)30137-1. [Epub ahead of print]
    The protective effects of liraglutide on AD-like neurodegeneration induced by oxidative stress in human neuroblastoma SH-SY5Y cells.
    Chen Zheng, Mei Zhou, Jie Sun, Hui Xiong, Peng Peng, Zhongya Gu, Yanqiu Deng.
      Glucagon-like peptide 1 (GLP-1) has neuroprotective properties in Alzheimer's disease (AD). In this study, our aim is to explore the neuroprotective effects of liraglutide, a GLP-1 analogue, on AD-like neurodegeneration induced by H2O2 in human neuroblastoma SH-SY5Y cells. Cytotoxicity was determined by MTT assay and lactate dehydrogenase level was monitored by LDH assay. The level of lipid peroxidation and cell apoptosis rate were measured by malondialdehyde (MDA) assay Annexin V-FITC/propidium iodide (PI) staining. Western blotting was used to assess the expression of Bcl-2, Bax, caspase-3, tau and the Akt/GSK-3β. Liraglutide pre-treatment enhanced cell viability with reduced cytotoxicity, lipid peroxidationand and apoptosis. In addition, pre-treatment of liraglutide displayed that increased the expression of the pro-survival Bcl-2 and reduced pro-apoptotic Bax with ameliorated the hyperphosphorylation of tau and Akt/GSK-3β signaling pathway in H2O2 stressed SH-SY5Y cells. These finding provided evidences that liraglutide protected the H2O2 induced AD-like neurodegeneration through improving Akt/GSK-3β signaling pathway. These results suggest that liraglutide may have potential values for the treatment for AD.
    Keywords:  Alzheimer's disease; Apoptosis; Liraglutide; Neurodegeneration; Oxidative stress; Tau
    DOI:  https://doi.org/10.1016/j.cbi.2019.06.001
  17. Int J Nanomedicine. 2019 ;14 3491-3502
    In vitro and in vivo mechanism of hepatocellular carcinoma inhibition by β-TCP nanoparticles.
    Langlang Liu, Honglian Dai, Yanzeng Wu, Binbin Li, Jiling Yi, Chao Xu, Xiaopei Wu.
      Background: Studies have showed that nanoparticles have a certain anti-cancer activity and can inhibit many kinds of cancer cells. β-tricalcium phosphate nanoparticles (nano-β-TCP) displays better biodegradation, but the application and mechanism of nano-β-TCP in anti-cancer activity are still not clear. Purpose: The objective of this study was to synthesize nano-β-TCP and investigate its inhibitory properties and mechanism on hepatocellular carcinoma (HepG2) cells in vitro and in vivo. Methods: Nano-β-TCP was synthesized using ethanol-water system and characterized. The effects of nano-β-TCP on cell viability, cell uptake, intracellular oxidative stress (ROS), cell cycle and apoptosis were also investigated with HepG2 cells and human hepatocyte cells (L-02). Intratumoral injection of nano-β-TCP was performed on the xenograft liver cancer model to explore the inhibitory effect and mechanism of nano-β-TCP on liver tumors. Results: In vitro results revealed that nano-β-TCP caused reduced cell viability of HepG2 cells in a time-and dose-dependent manner. Nano-β-TCP was internalized through endocytosis and degraded in cells, resulting in obvious increase of the intracellular Ca2+ and PO4 3- ions. Nano-β-TCP induced cancer cells to produce ROS and induced apoptosis of tumor cells by an apoptotic signaling pathways both in extrinsic and intrinsic pathway. In addition, nano-β-TCP blocked cell cycle of HepG2 cells in G0/G1 phase and disturbed expression of some related cyclins. In vivo results showed that 40 mg/kg of nano-β-TCP had no significant toxic side effects, but could effectively suppress hepatocellular carcinoma growth. Conclusion: These findings revealed the anticancer effect of nano-β-TCP and also clarified the mechanism of its inhibitory effect on hepatocellular carcinoma.
    Keywords:  HepG2 cells; ROS; apoptosis; cell cycle; inhibition; nano-β-TCP
    DOI:  https://doi.org/10.2147/IJN.S193192
  18. Sci Total Environ. 2019 Jun 03. pii: S0048-9697(19)32562-8. [Epub ahead of print]686 893-902
    Diastereoisomer-specific neurotoxicity of hexabromocyclododecane in human SH-SY5Y neuroblastoma cells.
    Xiaoli Shi, Jinmiao Zha, Bei Wen, Shuzhen Zhang.
      Hexabromocyclododecane (HBCD) is a widely applied brominated flame retardant (BFR) and is regarded as a persistent organic pollutant. It has been found in human tissues and has the potential to cause neurological disorders. However, our understanding of HBCD neurotoxicity at the diastereoisomer level remains lacking. Here, we investigated the neurotoxicity of three HBCD diastereoisomers, i.e., α-, β-, and γ-HBCD, in SH-SY5Y human neuroblastoma cells. Results showed that the HBCD diastereoisomers decreased cell viability, increased lactate dehydrogenase (LDH) release, and impaired cytoskeleton development. Typical morphological features and apoptosis rates showed that the HBCD diastereoisomers induced SH-SY5Y cell apoptosis. The expression levels of several cell apoptosis-related genes and proteins, including Bax, caspase-3, caspase-9, cytochrome c, Bcl-2, and X-linked inhibitor of apoptosis (XIAP), as well as the cell cycle arrest, DNA damage, adenosine triphosphate (ATP) consumption, reactive oxygen species (ROS) levels, and intracellular calcium ion (Ca2+) levels, were examined. Results showed that the HBCD diastereoisomer neurotoxicity was ranked β-HBCD > γ-HBCD > α-HBCD. The cell apoptosis and caspase expression levels of the three HBCD diastereoisomers followed the same order, suggesting that caspase-dependent apoptosis may be one mechanism responsible for the structure-selective HBCD diastereoisomer neurotoxicity. The levels of intracellular Ca2+ and ROS increased significantly. The ROS levels were ordered β-HBCD > γ-HBCD > α-HBCD, whereas those of intracellular Ca2+ were γ-HBCD > β-HBCD > α-HBCD. Thus, ROS may be a key factor regulating the neurotoxicity of HBCD diastereoisomers. To the best of our knowledge, this is the first study to report on the diastereoisomer-specific toxicity of HBCD in human neural cells and on the possible mechanisms responsible for the selective neurotoxicity of HBCD diastereoisomers.
    Keywords:  Apoptosis; Hexabromocyclododecane diastereoisomers; Neurotoxicity; Oxidative stress; SH-SY5Y cells
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.06.008
  19. Oxid Med Cell Longev. 2019 ;2019 2717986
    Cyclophilin A Protects Cardiomyocytes against Hypoxia/Reoxygenation-Induced Apoptosis via the AKT/Nox2 Pathway.
    Fuyu Cheng, Wei Yuan, Mengfei Cao, Rui Chen, Xiuli Wu, Jinchuan Yan.
      Hypoxia/reoxygenation (H/R) accelerates the process of cardiomyocyte apoptosis during ischemia-reperfusion. Excessive reactive oxygen species (ROS) are a critical driver of oxidative stress injury. Cyclophilin A (CyPA) is a major ROS-induced factor in atherosclerosis. There is a positive feedback mechanism between CyPA and ROS, which enables the oxidative stress response to continue and expand. However, it is unclear whether this positive feedback mechanism exists in cardiomyocytes. Through western blotting and flow cytometric assays and TUNEL assay, we found that CyPA inhibited the apoptosis of H9c2 cardiomyocytes under H/R conditions. By dihydroethidium (DHE) staining and electron spin resonance (ESR) assays, we demonstrated that CyPA reduced ROS production and suppressed O2 - production dependent on reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. By western blotting, we showed that CyPA inhibited the expression of NADPH oxidase 2 (Nox2) protein by the AKT pathway. Through confocal microscopy assay, we found that CyPA reduced the expression of Nox2 membrane-bound subunits. The current study shows that a positive feedback mechanism does not exist in H9c2 cardiomyoblasts. CyPA protects H9c2 cardiomyoblasts against H/R-induced apoptosis via the AKT/Nox2 pathway. This could be a potential target for ischemia-reperfusion injury therapy.
    DOI:  https://doi.org/10.1155/2019/2717986
  20. Front Neurosci. 2019 ;13 512
    Redox-Related Neuronal Death and Crosstalk as Drug Targets: Focus on Epilepsy.
    Xiao-Yuan Mao, Hong-Hao Zhou, Wei-Lin Jin.
      Cell death has a vital role in embryonic development and organismal homeostasis. Biochemical, pharmacological, behavioral, and electrophysiological evidences support the idea that dysregulation of cell death programs are involved in neuropathological conditions like epilepsy. The brain is particularly vulnerable to oxidative damage due to higher oxygen consumption and lower endogenous antioxidant defense than other bodily organ. Thus, in this review, we focused on the comprehensive summarization of evidence for redox-associated cell death pathways including apoptosis, autophagy, necroptosis, and pyroptosis in epilepsy and the oxidative stress-related signaling in this process. We specially proposed that the molecular crosstalk of various redox-linked neuronal cell death modalities might occur in seizure onset and/or epileptic conditions according to the published data. Additionally, abundance of polyunsaturated fatty acids in neuronal membrane makes the brain susceptible to lipid peroxidation. This presumption was then formalized in the proposal that ferroptosis, a novel type of lipid reactive oxygen species (ROS)-dependent regulatory cell death, is likely to be a critical mechanism for the emergence of epileptic phenotype. Targeting ferroptosis process or combination treatment with multiple cell death pathway inhibitors may shed new light on the therapy of epilepsy.
    Keywords:  apoptosis; autophagy; epilepsy; ferroptosis; necroptosis; pyroptosis
    DOI:  https://doi.org/10.3389/fnins.2019.00512
  21. Oncol Lett. 2019 Jun;17(6): 4795-4802
    Alantolactone induces gastric cancer BGC-823 cell apoptosis by regulating reactive oxygen species generation and the AKT signaling pathway.
    Xin Zhang, Hong-Ming Zhang.
      Alantolactone (ALT), a natural sesquiterpene lactone, has been suggested to exert anti-cancer activities in various cancer cell lines. However, the effects and mechanisms of action of ALT in human gastric cancer remains to be elucidated. In the present study, the effects of ALT on BGC-823 cells were examined and the underlying molecular mechanisms associated with these effects were investigated. Cell viability was detected by using an MTT assay. Cell cycle, cell apoptosis and the level of reactive oxygen species (ROS) were assessed by flow cytometry, and the expression levels of proteins of interest were analyzed by western blot assay. The results demonstrated that ALT triggered apoptosis and induced G0/G1 phase arrest in a dose-dependent manner. Furthermore, the expression level of the anti-apoptosis protein Bcl-2 was downregulated, and expression of the pro-apoptosis proteins Bax and cleaved PARP were significantly upregulated. The cell cycle-associated proteins cyclin-dependent kinase inhibitor 1 and cyclin-dependent kinase inhibitor 1B were also increased, while cyclin D1 was deceased. In addition, ALT induced apoptosis via the inhibition of RAC-alpha serine/threonine-protein kinase (AKT) signaling and ROS generation, which was effectively inhibited by the ROS scavenger, N-acetyl cysteine. Therefore, the results from the present study indicated that the ROS-mediated inhibition of the AKT signaling pathway serves an important role in ALT-induced apoptosis in BGC-823 cells. In conclusion, the results demonstrated that ALT exerted significant anti-cancer effects against gastric cancer cells in vitro.
    Keywords:  BGC-823 cells; alantolactone; apoptosis; protein kinase B serine/threonine kinase signaling pathway; reactive oxygen species
    DOI:  https://doi.org/10.3892/ol.2019.10172
  22. Free Radic Res. 2019 Jun 11. 1-14
    Eclalbasaponin I causes mitophagy to repress oxidative stress-induced apoptosis via activation of p38 and ERK in SH-SY5Y cells.
    Wei Wang, Guo-Dong Yao, Xin-Yue Shang, Ying-Ying Zhang, Xiao-Yu Song, Toshihiko Hayashi, Yan Zhang, Shao-Jiang Song.
      Oxidative stress accompanying excessive accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction leads to the occurrence of neurodegenerative diseases. Our previous study showed that Eclalbasaponin I (EcI), a triterpene saponin isolated from Aralia elata (Miq.) Seem. (A. elata), repressed oxidative stress in human neuroblastoma SH-SY5Y cells. However, the detailed mechanism remains unclear. In this study, pretreatment with EcI in SH-SY5Y cells significantly activated the p38-mitogenactivated protein kinase (p38), the extracellular regulated protein kinase (ERK), whereas it did not affect the c-jun NH2 terminal kinases (JNK). In accordance with the initial findings, EcI-induced neuroprotective effect was attenuated by SB203580 (SB, a p38 inhibitor) or FR180204 (FR, an ERK inhibitor), being further confirmed by specific small interfering RNA (siRNA). Inhibition of either p38 or ERK up-regulated the apoptosis induction in EcI- and H2O2-cotreated cells. Furthermore, p38 or ERK suppression enhanced intracellular and mitochondrial ROS generation, decreased the activities of endogenous antioxidant defences as well as the mitochondrial membrane potential (MMP), resulting in dysfunction of mitochondria. In addition, EcI-induced autophagy and mitophagy were obviously down-regulated when p38 or ERK activation was blocked. Cumulatively, these findings supported that EcI-caused mitophagy contributed to the neuroprotective effect through p38 or ERK activation. Mitophagy induction might be an effective therapeutic intervention in neurodegenerative diseases.
    Keywords:  ERK; Eclalbasaponin I; Oxidative stress; mitophagy; p38; triterpene saponin
    DOI:  https://doi.org/10.1080/10715762.2019.1620937
  23. Mol Med Rep. 2019 May 22.
    Callistephin enhances the protective effects of isoflurane on microglial injury through downregulation of inflammation and apoptosis.
    Lili Zhao, Shibiao Chen, Tianyin Liu, Xiuhong Wang, Haijin Huang, Weicheng Liu.
      Microglia are the major immune cells in the central nervous system. Microglial activation can be beneficial or detrimental depending on the stimuli and the physiopathological environment. Microglial activation is involved in a variety of neurodegenerative disorders. Different anesthetic agents have exhibited diverse effects on microglial activation and the engulfment process. The anthocyanin callistephin has been demonstrated to have antioxidant and anti‑inflammatory properties, and these were assessed in the present study, with a focus on its effect on microglial activation. Mouse microglial cells C8‑4B were treated with 100 ng/µl lipopolysaccharide (LPS) and 1 ng/µl interferon‑γ. Cells were subsequently treated with 2% isoflurane, 100 µM callistephin or both. LPS promoted apoptosis in C8‑B4 cells, and this was reduced following treatment with isoflurane and callistephin. LPS‑treated C8‑B4 cells also exhibited enhanced production of reactive oxygen species and nitric oxide, excessive engulfment and increased caspase 3/7 activity. These detrimental alterations were suppressed following co‑treatment with isoflurane and callistephin. LPS‑induced apoptosis was facilitated via the expression of B‑cell lymphoma‑2 like 1 and poly (ADP‑ribose) polymerase, which were subsequently restored following treatment with isoflurane and callistephin. Callistephin was demonstrated to be involved in the modulation of inducible nitric oxide synthase, cytochrome c oxidase subunit 2, tumor necrosis factor‑α and nuclear factor‑κ B. Callistephin enhanced the protective effects of isoflurane by modulating engulfment and apoptosis in C8‑B4 cells. The potential underlying mechanism was identified to be the suppression of p38 phosphorylation. The present study thus suggested that the negative effects on microglial activity induced by LPS were ameliorated following treatment with callistephin, which also enhanced the effects of isoflurane. Callistephin may therefore constitute a candidate drug agent that may target inflammatory and growth regulatory signaling pathways, thus ameliorating certain aspects of neurodegenerative diseases.
    DOI:  https://doi.org/10.3892/mmr.2019.10282
  24. Exp Eye Res. 2019 Jun 09. pii: S0014-4835(19)30181-2. [Epub ahead of print] 107692
    A novel NADPH oxidase inhibitor targeting Nox4 in TGFβ-induced lens epithelial to mesenchymal transition.
    Shannon Das, Per Wikström, Erik Walum, Frank J Lovicu.
      Many of the small molecule-based inhibitors of NADPH oxidase activity are largely inadequate to substantiate broad claims, often exhibiting a lack of Nox-isoform-specificity, and sometimes only acting as scavengers of reactive oxygen species (ROS). In the present study, we use a newly developed highly selective Nox4 inhibitor, GLX7013114, to modulate TGFβ-induced lens epithelial to mesenchymal transition (EMT). Rat lens epithelial explants were pre-treated with 0.3  μM of GLX7013114, and then treated with 200 pg/ml of TGF-β2 to induce lens EMT. ROS production was visualized microscopically using the superoxide fluorogenic probe, dihydroethidium (DHE). The EMT process was documented using phase-contrast microscopy, and molecular EMT markers were immunolabeled. qPCR was also performed to observe changes in EMT-associated genes. TGFβ-induced ROS was evident at 8 h of culture and its intensity was found to be significantly reduced when GLX7013114 was applied, comparable to ROS levels measured in untreated explants. Using phase-contrast microscopy to follow TGFβ-induced EMT over 5 days in the presence of the inhibitor, lens epithelial cells in explants became myofibroblastic by day 2 and underwent progressive apoptosis to reveal a bare lens capsule by day 5. Explants treated with TGFβ and GLX7013114 had some increased cell survival; however, these differences were not significant. For the first time, Nox4 inhibition by GLX7013114 was shown to reduce the TGFβ-induced gene expression of α-smooth muscle actin (SMA), collagen 1a and fibronectin. GLX7013114, given that it appears to block aspects of TGFβ-induced EMT, including ROS production, may be a new useful Nox4-selective inhibitor for further studies.
    DOI:  https://doi.org/10.1016/j.exer.2019.107692
  25. Adv Exp Med Biol. 2019 Jun 08.
    Cytotoxicity, Oxidative Stress, and Autophagy in Human Alveolar Epithelial Cell Line (A549 Cells) Exposed to Standardized Urban Dust.
    A Lukaszewicz, M Cwiklinska, M Zarzecki, P Szoka, J Lachowicz, A Holownia.
      Exposure to urban airborne particulate matter (PM) associates with adverse health effects, but the exact mechanisms remain unclear. In this study, we focused on cytotoxicity (MTT), oxidative stress (DCF/FC), DNA damage (PI/FC), necrosis/apoptosis (FC), and autophagy (LC3 expression; WB/FC) triggered by urban dust (UD) in naïve human alveolar epithelial A549 cells and in the cells with reduced glutathione (GSH). The A549 cells were grown in F12K/FCS media supplemented with coarse carbon black (CB; Huber990; 260 nm diameter; 200 μg·ml-1) or urban dust (UD; Standard Reference Materials; 200 μg·ml-1) for 24 h. To deplete intracellular glutathione (GSH), l-buthionine-(S,R)-sulfoximine (BSO; 100 mM; 24 h) was used. Pre-treatment with BSO depleted the cellular GSH by about 30%. A similar effect was noticed after UD. The CB was without any effects on the parameters tested, except for LC3 expression (autophagy) which increased by about twofold. However, UD decreased cell viability by about 27%, decreased cell proliferation in BSO pre-treated cells, increased ROS production, and increased both Hsp70 and LC3 proteins by about twofold, but most changes were unrelated to ROS-mediated GSH depletion. We conclude that urban dust-induced oxidative stress is important in PM toxicity, but other as yet unrecognized mechanisms are also involved.
    Keywords:  A549 cells; Alveolar cells; Apoptosis; Autophagy; Cytotoxicity; Oxidative stress; Particulate matter; Urban dust
    DOI:  https://doi.org/10.1007/5584_2019_387
  26. Oxid Med Cell Longev. 2019 ;2019 8465030
    Protective Effect of Ginsenoside Rg1 on Oxidative Damage Induced by Hydrogen Peroxide in Chicken Splenic Lymphocytes.
    Shicheng Bi, Xiaodan Ma, Yuemin Wang, Xiaoqing Chi, Yong Zhang, Wei Xu, Songhua Hu.
      Previous investigation showed that ginsenoside Rg1 (Rg1) extracted from Panax ginseng C.A. Mey has antioxidative effect on oxidative stress in chickens. The present study was designed to investigate the protective effects of Rg1 on chicken lymphocytes against hydrogen peroxide-induced oxidative stress and the potential mechanisms. Cell viability, apoptotic cells, malondialdehyde, activity of superoxide dismutase, mitochondrial membrane potential, and [Ca2+]i concentration were measured, and transcriptome analysis and quantitative real-time polymerase chain reaction were used to investigate the effect of Rg1 on gene expression of the cells. The results showed that treatment of lymphocytes with H2O2 induced oxidative stress and apoptosis. However, pretreatment of the cells with Rg1 dramatically enhanced cell viability, reduced apoptotic cells, and decreased oxidative stress induced by H2O2. In addition, Rg1 reduced these H2O2-dependent decreases in mitochondrial membrane potential and reversed [Ca2+]i overload. Transcriptome analysis showed that 323 genes were downregulated and 105 genes were upregulated in Rg1-treated cells. The differentially expressed genes were involved in Toll-like receptors, peroxisome proliferator-activated receptor signaling pathway, and cytokine-cytokine receptor interaction. The present study indicated that Rg1 may act as an antioxidative agent to protect cell damage caused by oxidative stress via regulating expression of genes such as RELT, EDA2R, and TLR4.
    DOI:  https://doi.org/10.1155/2019/8465030
  27. J Cell Mol Med. 2019 Jun 14.
    Pro-apoptotic effect of haem oxygenase-1 in human colorectal carcinoma cells via endoplasmic reticular stress.
    Ming-Shun Wu, Chih-Chiang Chien, Jungshan Chang, Yen-Chou Chen.
      Several biological effects of haem oxygenase (HO)-1, including anti-inflammatory, antiapoptotic and antioxidative properties were reported; however, the role of HO-1 in apoptosis is still unclear. In the presence of stimulation by cobalt protoporphyrin (CoPP), an HO-1 inducer, apoptotic characteristics were observed, including DNA laddering, hypodiploid cells, and cleavages of caspase (Casp)-3 and poly(ADP) ribose polymerase (PARP) proteins in human colon carcinoma COLO205, HCT-15, LOVO and HT-29 cells in serum-free (SF) conditions with increased HO-1, but not heat shock protein 70 (HSP70) or HSP90. The addition of 10% foetal bovine serum (FBS) or 1% bovine serum albumin accordingly inhibited CoPP-induced apoptosis and HO-1 protein expression in human colon cancer cells. CoPP-induced apoptosis of colon cancer cells was prevented by the addition of the pan-caspase inhibitor, Z-VAD-FMK (VAD), and the Casp-3 inhibitor, Z-DEVD-FMK (DEVD). N-Acetyl cysteine inhibited reactive oxygen species-generated H2 O2 -induced cell death with reduced intracellular peroxide production, but did not affect CoPP-induced apoptosis in human colorectal carcinoma (CRC) cells. Two CoPP analogs, ferric protoporphyrin and tin protoporphyrin, did not affect the viability of human CRC cells or HO-1 expression by those cells, and knockdown of HO-1 protein expression by HO-1 small interfering (si)RNA reversed the cytotoxic effect elicited by CoPP. Furthermore, the carbon monoxide (CO) donor, CORM, but not FeSO4 or biliverdin, induced DNA ladders, and cleavage of Casp-3 and PARP proteins in human CRC cells. Increased phosphorylated levels of the endoplasmic reticular (ER) stress proteins, protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2α (eIF2α) by CORM and CoPP were identified, and the addition of the PERK inhibitor, GSK2606414, inhibited CORM- and CoPP-induced apoptosis. Increased GRP78 level and formation of the HO-1/GRP78 complex were detected in CORM- and CoPP-treated human CRC cells. A pro-apoptotic role of HO-1 against the viability of human CRC cells via induction of CO and ER stress was firstly demonstrated herein.
    Keywords:  CoPP; ER stress; apoptosis; haem oxygenase-1; human colorectal carcinoma cells
    DOI:  https://doi.org/10.1111/jcmm.14482
  28. Life Sci. 2019 Jun 08. pii: S0024-3205(19)30479-5. [Epub ahead of print] 116553
    Protective effect of dexmedetomidine against diabetic hyperglycemia-exacerbated cerebral ischemia/reperfusion injury: An in vivo and in vitro study.
    Lingyang Chen, Jianbin Cao, Donghang Cao, Mingcang Wang, Haifei Xiang, Yanqing Yang, Tingting Ying, Haitao Cong.
      AIMS: Dexmedetomidine (Dex) has been noted to have neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury. However, the effect of Dex in diabetic hyperglycemia-exacerbated cerebral I/R injury and its underlying mechanism remain unclear.MAIN METHODS: The infarct volume and brain edema were evaluated by 2,3,5-triphenyltetrazolium chloride staining and standard wet-dry method. Modified neurological severity score was utilized to assess the neurological deficits. The oxidative stress and inflammation were evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and cell count kit-8 were applied to measure cell apoptosis and viability.
    KEY FINDINGS: Dex treatment reduced infarct volume, decreased brain water content and improved neurological deficit in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Dex treatment reduced the levels of ROS, MDA, TNF-α and IL-1β in the entire middle cerebral artery territory of diabetic mice subjected to MCAO/R, as well as in primary culture of mouse hippocampal neurons stimulated with 50 mM glucose and oxygen glucose deprivation/reperfusion. Dex treatment inhibited neuronal apoptosis induced by diabetic hyperglycemia-exacerbated cerebral I/R injury. Dex upregulated nuclear factor of activated T-cells 5 (NFAT5) and Sirtuin 1 (SIRT1) expression, induced NF-E2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and inhibited the acetylation of Nrf2. However, these changes triggered by Dex treatment were abrogated by NFAT5 knockdown.
    SIGNIFICANCE: Dex protects against diabetic hyperglycemia-exacerbated cerebral I/R injury through attenuation of oxidative stress, inflammation and apoptosis. The underlying mechanism is at least the NFAT5/SIRT1/Nrf2 signaling pathway dependent.
    Keywords:  Dexmedetomidine; Diabetic hyperglycemia-exacerbated cerebral ischemia/reperfusion injury; NF-E2-related factor 2; Nuclear factor of activated T-cells 5; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.lfs.2019.116553
  29. Chem Biol Interact. 2019 Jun 11. pii: S0009-2797(19)30619-2. [Epub ahead of print]
    Downregulation of microRNA-302b-3p relieves oxygen-glucose deprivation/re-oxygenation induced injury in murine hippocampal neurons through up-regulating Nrf2 signaling by targeting fibroblast growth factor 15/19.
    Zhenni Zhang, Ning Wang, Yong Zhang, Jing Zhao, Jianrui Lv.
      MicroRNAs have emerged as critical mediators of cerebral ischaemia/reperfusion injury. Recent studies have demonstrated that microRNA-302b-3p (miR-302b-3p) plays an important role in regulating apoptosis and oxidative stress in various cells. However, whether miR-302b-3p is involved in regulating cerebral ischaemia/reperfusion injury-induced neuronal apoptosis and oxidative stress remains unknown. In the present study, we explored the potential function and molecular mechanism of miR-302b-3p in oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal injury, using an in vitro model of cerebral ischaemia/reperfusion injury. We found that miR-302b-3p expression was up-regulated by OGD/R treatment in neurons. The inhibition of miR-302b-3p improved cell viability, and reduced apoptosis and the production of reactive oxygen species, showing a protective effect against OGD/R-induced injury. Interestingly, miR-302b-3p was shown to target and modulate murine fibroblast growth factor 15 (FGF15). Moreover, our results showed that miR-302b-3p down-regulation contributed to the promotion of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE)-mediated antioxidant signaling associated with the inactivation of glycogen synthase kinase-3β. However, the knockdown of FGF15 significantly reversed the miR-302b-3p inhibition-mediated protective effect in OGD/R-treated neurons. Overall, these results demonstrated that miR-302b-3p inhibition confers a neuroprotective effect in OGD/R-treated neurons by up-regulating Nrf2/ARE antioxidant signaling via targeting FGF15, providing a novel target for neuroprotection in cerebral ischaemia/reperfusion injury.
    Keywords:  Cerebral ischaemia/reperfusion injury; FGF15; GSK-3β; Nrf2
    DOI:  https://doi.org/10.1016/j.cbi.2019.06.018
  30. Mol Med Rep. 2019 May 27.
    Baicalin inhibits C2C12 myoblast apoptosis and prevents against skeletal muscle injury.
    Yutao Pan, Dongli Song, Weiyan Zhou, Xiuhong Lu, Haiyan Wang, Zengchun Li.
      Anti‑apoptotic and anti‑inflammatory treatments are imperative for skeletal muscle regeneration following injury. Baicalin is well known and has previously been investigated for its role in the treatment of injury and inflammatory diseases. Therefore, the present study aimed to investigate the effects of baicalin in inhibiting apoptosis of C2C12 myoblasts and preventing skeletal muscle injury. A cell counting kit‑8 (CCK‑8) assay and Annexin V/PI staining were initially performed to measure cell viability and apoptosis under conditions of H2O2 exposure with or without baicalin. Subsequently, oxidative activity, mitochondrial function, mitochondrial apoptogenic factors and caspase proteins were analyzed to examine the mechanism underlying the effect of baicalin on inhibiting apoptosis in C2C12 myoblasts. Furthermore, BALB/C mice with skeletal muscle injuries were established, and the potential application of baicalin for anti‑apoptotic and anti‑inflammatory effects was examined via small animal β‑2‑[18F]‑fluoro‑2‑deoxy‑D‑glucose (18F‑FDG) positron emission tomography (PET) imaging and pathological examination. The CCK‑8 assay and Annexin V/PI staining revealed cell death in the C2C12 myoblasts induced by H2O2, which was apoptotic, and this was effectively reversed by treatment with baicalin. H2O2 increased the reactive oxygen species and malondialdehyde levels in C2C12 myoblasts, which was caused by mitochondrial dysfunction, decreased expression of cytochrome c and apoptosis‑inducing factor from cytosolic and mitochondrial fractions, and activated expression of caspase‑3 and caspase‑9; however, treatment with baicalin reversed these effects. In addition, small animal PET imaging revealed that treatment with baicalin decreased the accumulation of FDG by ~65.9% in the injured skeletal muscle induced by H2O2. These pathological results also confirmed the protective effect of baicalin on injured skeletal muscle. Taken together, the results of the present study indicated that baicalin effectively inhibited the apoptosis of C2C12 myoblasts and protected skeletal muscle from injury, which may have potential therapeutic benefits for patients in a clinical setting.
    DOI:  https://doi.org/10.3892/mmr.2019.10298
  31. Antioxidants (Basel). 2019 Jun 10. pii: E169. [Epub ahead of print]8(6):
    Role of Cytosolic 2-Cys Prx1 and Prx2 in Redox Signaling.
    Yosup Kim, Ho Hee Jang.
      Peroxiredoxins (Prxs), a family of peroxidases, are reactive oxygen species scavengers that hydrolyze H2O2 through catalytic cysteine. Mammalian Prxs comprise six isoforms (typical 2-Cys Prxs; Prx1-4, atypical 2-Cys Prx; Prx5, and 1-Cys Prx; Prx6) that are distributed over various cellular compartments as they are classified according to the position and number of conserved cysteine. 2-Cys Prx1 and Prx2 are abundant proteins that are ubiquitously expressed mainly in the cytosol, and over 90% of their amino acid sequences are homologous. Prx1 and Prx2 protect cells from ROS-mediated oxidative stress through the elimination of H2O2 and regulate cellular signaling through redox-dependent mechanism. In addition, Prx1 and Prx2 are able to bind to a diversity of interaction partners to regulate other various cellular processes in cancer (i.e., regulation of the protein redox status, cell growth, apoptosis, and tumorigenesis). Thus, Prx1 and Prx2 can be potential therapeutic targets and it is particularly important to control their level or activity. This review focuses on cytosolic 2-Cys Prx1 and Prx2 and their role in the regulation of redox signaling based on protein-protein interaction.
    Keywords:  antioxidant enzymes; chaperone activity; hyperoxidation; peroxidase activity; peroxiredoxin; protein-protein interaction; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox8060169
  32. Curr Pharm Biotechnol. 2019 Jun 11.
    The protective effect of Korean Red Ginseng against rotenone-induced Parkinson's disease in rat model: modulation of nuclear factor-κβ and caspase-3.
    Mai A Zaafan, Amr M Abdelhamid, Sherine M Ibrahim.
      OBJECTIVE: Korean red ginseng was reported to have many biological effects like the antioxidant and the anti-inflammatory activities. Oxidative stress and neuro-inflammation play major roles in the pathogenesis of Parkinson's disease (PD). The current study aimed to investigate the protective effects of ginseng on rotenone-induced PD in rats.METHODS: Rats were randomly allocated into 4 groups: normal rats, rotenone control, ginseng+rotenone and ginseng only treated rats. The severity of PD was evaluated through locomotor activity perceiving in the open field test, histological examination and immunohistochemical detection of amyloid-β in brain tissues, in addition to the biochemical assessment of tyrosine hydroxylase activity in brain tissues. Moreover, the following parameters were investigated for studying the possible mechanisms of ginseng neuroprotective effect: nuclear factor-κβ (NF-κβ), tumor necrosis factor-alpha (TNF-α), caspase-3, lipid peroxides and reduced glutathione (GSH).
    RESULTS: Ginseng exhibited potent neuroprotective effect that was reflected upon the histopathological examination, the marked improvement in the locomotor activity and through its ability to suppress the amyloid-β deposition in the cortex and striatum along with the significant increase in the tyrosine hydroxylase activity. Ginseng successfully inhibited the NF-κβ inflammatory pathway in brain tissues beside the inhibition of other oxidative stress and inflammatory mediators. Furthermore, it exhibited anti-apoptotic effect via the inhibition of caspase-3 expression.
    CONCLUSION: Ginseng could be a promising treatment in PD. It can suppress the dopaminergic neuron degeneration through variable mechanisms mainly via inhibition of NF-κβ pathway in addition to inhibition oxidative stress and apoptosis.
    Keywords:  Ginseng; Parkinson’s disease; anti-oxidant; caspase-3; nuclear factor-κβ
    DOI:  https://doi.org/10.2174/1389201020666190611122747
  33. Naunyn Schmiedebergs Arch Pharmacol. 2019 Jun 14.
    Piceatannol protects against cisplatin nephrotoxicity via activation of Nrf2/HO-1 pathway and hindering NF-κB inflammatory cascade.
    Sara A Wahdan, Samar S Azab, Doaa A Elsherbiny, Ebtehal El-Demerdash.
      This study investigates the molecular mechanisms of the nephroprotective effect of piceatannol (PIC) against cisplatin-induced nephrotoxicity in rats. PIC (10 mg/kg i.p.) was given for 7 days, starting 2 days before cisplatin single injection (7 mg/kg i.p.). Serum creatinine, blood urea nitrogen (BUN), kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin were used as nephrotoxicity markers. Oxidative stress, inflammatory, and apoptotic markers were determined. In addition, the role of PIC in Nrf2 activation and its subsequent induction of antioxidant enzymes, as well as its potential cross talk with nuclear factor kappa-B, were addressed. PIC reversed cisplatin-induced elevation of nephrotoxicity markers and restored the normal kidney ultrastructure. PIC attenuated cisplatin-induced reduction in Nrf2 expression and the relative mRNA level of antioxidant enzymes: hemeoxygenase-1, cysteine ligase catalytic, and modifier subunits, as well as superoxide dismutase and glutathione-S-transferase activities. Cisplatin pro-inflammatory response was reduced by PIC treatment as evidenced by the suppression of nuclear factor kappa-B activation and the subsequent decreased tissue levels of interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and inducible nitric oxide synthase. PIC suppressed cisplatin-induced apoptosis by decreasing p53 and cytochrome C expression and caspase-3 activity. Therefore, PIC may protect against cisplatin-induced nephrotoxicity by modulating Nrf2/HO-1 signaling and hindering the inflammatory and apoptotic pathways.
    Keywords:  Cisplatin; Inflammation; Nephrotoxicity; Oxidative stress; Piceatannol
    DOI:  https://doi.org/10.1007/s00210-019-01673-8
  34. Biomed Pharmacother. 2019 Jun 06. pii: S0753-3322(19)31002-9. [Epub ahead of print]117 109062
    Vagus nerve stimulation protects against acute liver injury induced by renal ischemia reperfusion via antioxidant stress and anti-inflammation.
    Yanqiu Lai, Jielin Deng, Menglong Wang, Meng Wang, Liping Zhou, Guannan Meng, Zhen Zhou, Yuhong Wang, Fuding Guo, Ming Yin, Xiaoya Zhou, Hong Jiang.
      OBJECTIVE: Renal ischemia reperfusion (I/R) is not an isolated event; however, it results in remote organ dysfunction. Vagus nerve stimulation (VNS) has shown protective effects against renal I/R injury via an anti-inflammatory mechanism. This study aimed to investigate whether VNS could attenuate liver injury induced by renal I/R and identify the underlying mechanisms.METHODS: Eighteen healthy male Sprague-Dawley rats (200-250 g) were equally divided into three groups: sham group (sham surgery without I/R or VNS), I/R group (renal I/R) and VNS group (renal I/R plus VNS). The I/R model was established by excising the right kidney and then clamping the left renal pedicle with an occlusive nontraumatic microaneurysm clamp for 45 min followed by a 6-h reperfusion. The rats in the VNS group received spontaneous left cervical VNS with renal ischemia and reperfusion. At the end of the experiment, blood and liver tissues were collected to detect liver function, oxidative stress and inflammatory parameters. Additionally, TUNEL staining, real-time PCR, western blotting and hematoxylin and eosin staining of liver tissues were performed to assess liver injury and the underlying mechanisms.
    RESULTS: Kidney and liver function was severely damaged in the I/R group compared to the sham group. However, VNS significantly protected kidney and liver function. Rats treated with VNS revealed decreases in oxidative enzymes, apoptosis and levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in serum and liver compared with rats in the I/R group. Rats in the VNS group also showed increased antioxidant stress responses compared to rats in the I/R group.
    CONCLUSION: VNS exerts protective effects against liver injury from renal I/R via inhibiting oxidative stress and apoptosis, downregulating inflammatory cytokines and enhancing antioxidative capability in the liver, and may become a promising adjuvant therapeutic strategy for treating liver injury induced by acute renal injury.
    Keywords:  Inflammation; Liver injury; Organ crosstalk; Renal ischemia reperfusion injury; vagus nerve stimulation
    DOI:  https://doi.org/10.1016/j.biopha.2019.109062
  35. Mol Med Rep. 2019 May 22.
    Resveratrol alleviates inflammatory injury and enhances the apoptosis of fibroblast‑like synoviocytes via mitochondrial dysfunction and ER stress in rats with adjuvant arthritis.
    Jinsen Lu, Yongshun Zheng, Jiazhao Yang, Junqiang Zhang, Wei Cao, Xiaoyu Chen, Shiyuan Fang.
      Resveratrol, a bioactive compound predominantly found in grapes and red wine, provides a wide range of properties that are beneficial for health, including anticancer and anti‑inflammatory activities. Previously published studies have addressed the potential therapeutic effects of resveratrol on rheumatoid arthritis (RA); however, the subcellular mechanism remains to be fully elucidated. In the present study, the therapeutic effects of resveratrol on adjuvant arthritis (AA) in Sprague‑Dawley rats were investigated, and the mechanisms of resveratrol‑induced apoptosis in fibroblast‑like synoviocytes (FLSs) were further examined. Based on the findings, resveratrol treatment over a 12‑day period led to a reduction in paw swelling and arthritis scores at the macroscopic level, and an attenuation of inflammatory cell infiltration and synovial hyperplasia, upon a histopathological examination of the AA rats. Furthermore, the administration of resveratrol triggered decreases in the expression of interleukin (IL)‑1, IL‑6, IL‑8 and tumor necrosis factor‑α (TNF‑α) and an increase in the expression of IL‑10, alleviating inflammatory injury in AA rats in a dose‑dependent manner. In addition, resveratrol was revealed to induce the apoptosis of FLSs when administered with 5 µM H2O2 as determined by elevated levels of Bax, caspase‑3, caspase‑12 and C/EBP‑homologous protein, and the downregulation of B‑cell lymphoma 2 (Bcl‑2), suggesting that resveratrol is able to induce apoptosis in FLSs via the mitochondrial pathway and endoplasmic reticulum (ER) stress in a milieu containing 5 µM H2O2. Furthermore, JC‑1 was used as a fluorescent probe to detect the mitochondrial membrane potential (Δψm), and resveratrol was shown to reduce the Δψm in FLSs in the presence of 5 µM H2O2. However, resveratrol was not able to trigger intracellular calcium overload, although it did suppress ATP‑ and thapsigargin‑induced calcium release from the ER. In conclusion, the present study revealed that resveratrol was able to alleviate inflammatory injury in AA rats, triggering the apoptosis of FLSs via the mitochondrial pathway and ER stress. These results provide a theoretical basis for future treatments using resveratrol for RA.
    DOI:  https://doi.org/10.3892/mmr.2019.10273
  36. J Diabetes Res. 2019 ;2019 2981705
    Effect of Baoshenfang Formula on Podocyte Injury via Inhibiting the NOX-4/ROS/p38 Pathway in Diabetic Nephropathy.
    Fang-Qiang Cui, Long Tang, Yan-Bin Gao, Yue-Fen Wang, Yuan Meng, Cun Shen, Zi-Long Shen, Zhi-Qiang Liu, Wen-Jing Zhao, Wei Jing Liu.
      Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 and type 2 diabetes. The Chinese herbal formula Baoshenfang (BSF) shows therapeutic potential in attenuating oxidative stress and apoptosis in podocytes in DN. This study evaluated the effects of BSF on podocyte injury in vivo and in vitro and explored the possible involvement of the nicotinamide adenine dinucleotide phosphate-oxidase-4/reactive oxygen species- (NOX-4/ROS-) activated p38 pathway. In the identified compounds by mass spectrometry, some active constituents of BSF were reported to show antioxidative activity. In addition, we found that BSF significantly decreased 24-hour urinary protein, serum creatinine, and blood urea nitrogen in DN patients. BSF treatment increased the nephrin expression, alleviated oxidative cellular damage, and inhibited Bcl-2 family-associated podocyte apoptosis in high-glucose cultured podocytes and/or in diabetic rats. More importantly, BSF also decreased phospho-p38, while high glucose-mediated apoptosis was blocked by p38 mitogen-activated protein kinase inhibitor in cultured podocytes, indicating that the antiapoptotic effect of BSF is p38 pathway-dependent. High glucose-induced upexpression of NOX-4 was normalized by BSF, and NOX-4 siRNAs inhibited the phosphorylation of p38, suggesting that the activated p38 pathway is at least partially mediated by NOX-4. In conclusion, BSF can decrease proteinuria and protect podocytes from injury in DN, in part through inhibiting the NOX-4/ROS/p38 pathway.
    DOI:  https://doi.org/10.1155/2019/2981705
  37. J Inorg Biochem. 2019 Jun 01. pii: S0162-0134(19)30090-X. [Epub ahead of print]198 110727
    Exploring the cytotoxic activity of new phenanthroline salicylaldimine Zn(II) complexes.
    Cristina P Matos, Yemataw Addis, Patrique Nunes, Sónia Barroso, Irina Alho, Marta Martins, António P A Matos, Fernanda Marques, Isabel Cavaco, João Costa Pessoa, Isabel Correia.
      Zinc(II) complexes bearing N-salicylideneglycinate (Sal-Gly) and 1,10-phenanthroline (phen) or phenanthroline derivatives [NN = 5-chloro-1,10-phenanthroline, 5-amine-1,10-phenanthroline (amphen), 4,7-diphenyl-1,10-phenanthroline (Bphen) and 5,6-epoxy-5,6-dihydro-1,10-phenanthroline] are synthesized. Complexes formulated as [Zn(NN)2(H2O)2]2+(NN = phen and amphen), are also prepared. The cytotoxicity of the compounds is evaluated towards a panel of human cancer cells: ovarian (A2780), breast (MCF7) and cervical (HeLa), as well as non-tumoral V79 fibroblasts. All compounds display higher cytotoxicity than cisplatin (IC50 = 22.5 ± 5.0 μM) towards ovarian cells, showing IC50values in the low micromolar range. Overall, all compounds show higher selectivity for the A2780 cells than for the non-tumoral cells and higher selectivity indexes (IC50(V79)/IC50(A2780) than cisplatin. [Zn(Sal-Gly)(NN)(H2O)] complexes induce caspase-dependent apoptosis in A2780 cells, except [Zn(Sal-Gly)(Bphen)(H2O)], one of the most cytotoxic of the series. The cellular uptake in the ovarian cells analyzed by Inductively Coupled Plasma mass spectrometry indicates different Zn distribution profiles. Transmission electronic microscopy shows mitochondria alterations and apoptotic features consistent with caspase activation; cells incubated with [Zn(Sal-Gly)(amphen)(H2O)] present additional nuclear membrane alterations in agreement with significant association with the nucleus. The increase of reactive oxygen species and lipid peroxidation forms could be related to apoptosis induction. [Zn(NN)2(H2O)2]2+complexes have high ability to bind DNA through intercalation/groove binding, and circular dichroism data suggests that the main type of species that interact with DNA is [Zn(NN)]2+. Studies varying the % of fetal bovine serum (1-15%) in cell media show that albumin binding decreases the complex activity, indicating that distinct speciation of Zn- and phen-containing species in cell media may affect the cytotoxicity.
    Keywords:  Anticancer activity; Lipid peroxides; Polypyridyl ligands; ROS; Salicylaldimines; Zinc(II) complexes
    DOI:  https://doi.org/10.1016/j.jinorgbio.2019.110727
  38. Oxid Med Cell Longev. 2019 ;2019 2761041
    Morinda citrifolia and Its Active Principle Scopoletin Mitigate Protein Aggregation and Neuronal Apoptosis through Augmenting the DJ-1/Nrf2/ARE Signaling Pathway.
    Kishore Kumar S Narasimhan, Deepthy Jayakumar, Prema Velusamy, Ashokkumar Srinivasan, Thangarajeswari Mohan, Divya Bhavani Ravi, Saraswathi Uthamaraman, Yogesh Kanna Sathyamoorthy, Namakkal Soorappan Rajasekaran, Kalaiselvi Periandavan.
      Given the role of oxidative stress in PD pathogenesis and off-target side effects of currently available drugs, several natural phytochemicals seem to be promising in the management of PD. Here, we tested the hypothesis that scopoletin, an active principle obtained from Morinda citrifolia (MC), efficiently quenches oxidative stress through DJ-1/Nrf2 signaling and ameliorates rotenone-induced PD. Despite reducing oxidative stress, the administration of MC extract (MCE) has lessened protein aggregation as evident from decreased levels of nitrotyrosine and α-synuclein. In vitro studies revealed that scopoletin lessened rotenone-induced apoptosis in SH-SY5Y cells through preventing oxidative injury. Particularly, scopoletin markedly upregulated DJ-1, which then promoted the nuclear translocation of Nrf2 and transactivation of antioxidant genes. Furthermore, we found that scopoletin prevents the nuclear exportation of Nrf2 by reducing the levels of Keap1 and thereby enhancing the neuronal defense system. Overall, our findings suggest that scopoletin acts through DJ-1-mediated Nrf2 signaling to protect the brain from rotenone-induced oxidative stress and PD. Thus, we postulate that scopoletin could be a potential drug to treat PD.
    DOI:  https://doi.org/10.1155/2019/2761041
  39. Ecotoxicol Environ Saf. 2019 Jun 05. pii: S0147-6513(19)30627-X. [Epub ahead of print]181 89-95
    Small interfering RNA targeting of peroxiredoxinⅡ gene enhances formaldehyde-induced toxicity in bone marrow cells isolated from BALB/c mice.
    Guangyan Yu, Yixin Zhang, Shimeng Liu, Lida Fan, Yixue Yang, Yulu Huang, Jiayi Song.
      BACKGROUDS: Formaldehyde (FA) is an important chemicals that can induce sick house syndrome and may be an incentive of childhood leukemia, however the exact mechanism is unclear. Oxidative stress may be an underlying reason of cancer occurring, while diverse antioxidants can protect the bone marrow cells (BMCs) from damaged. PeroxiredoxinⅡ (PrxⅡ) is an important member of the peroxiredoxin family, can remove reactive oxygen species (ROS), and is closely related with the occurrence of tumor. The present study aimed to detect a possible relationship between PrxⅡ gene and FA-induced bone marrow toxicity.METHODS: The BMCs were taken out from BALB/c mice, then exposed to control and different doses of FA (50, 100, 200 μmol/L). The cell viability, ROS level and expressions of PrxⅡ gene were examined. Afterwards, we used a small interfering RNA (siRNA) to inhibit the expression of PrxⅡ gene, and chose 100 μmol/L FA for exposure dose, to examine the cell viability, ROS level, cell cycle, apoptotic rate, expressions of PrxⅡ gene in BMCs.
    RESULTS: After a 24 h exposure to different doses of FA, the cell viability, expressions of PrxⅡ gene were decreased with the increasing of FA concentration, while the ROS level was increased. Inhibiting PrxⅡ gene's expression could enhance above FA-induced events. Additionally, siRNA targeting of PrxⅡcould aggravate cell cycle arrest to inhibit cell's growth and development, as well as increase apoptotic rates induced by FA.
    CONCLUSION: These results demonstrated that PrxⅡ gene was involved in FA-induced bone marrow toxicity, and siRNA targeting of PrxⅡcould enhance this toxic process.
    Keywords:  Apoptosis; Cell cycle; Formaldehyde; PrxⅡ; ROS; siRNA
    DOI:  https://doi.org/10.1016/j.ecoenv.2019.05.086
  40. Bone Rep. 2019 Jun;10 100206
    Increased FoxO3a expression prevents osteoblast differentiation and matrix calcification.
    Kathy C Tang, Wanling Pan, Michael R Doschak, R Todd Alexander.
      Forkhead Box O transcription factors play important roles in bone metabolism by defending against oxidative stress and apoptosis. FoxO3a is of special interest as it is the predominant isoform expressed in bone. In osteoblasts, the administration of 1,25 dihydroxyvitamin D3 (1,25D3) increases FoxO3a expression, and alters calcium handling. We therefore queried whether FoxO3a participates in vitamin D-mediated regulation of calcium transport pathways or matrix calcification, independent of reactive oxygen species (ROS) formation. To examine this possibility, we differentiated MC3T3-E1 cells into mature osteoblast-like cells over 7 days. This coincided with an increased ability to mineralize extracellular matrix. FoxO3a expression increased throughout differentiation. 1,25D3 enhanced both FoxO3a mRNA and protein expression. Immunofluorescence microscopy found increased FoxO3a nuclear localization with differentiation and after treatment with 1,25D3. Live cell ratiometric imaging with Fura-2AM identified significant L-type calcium channel mediated calcium uptake that was enhanced by 1,25D3. We observed expression of both Cav1.2 and Cav1.3, although expression decreased throughout differentiation and was not altered by 1,25D3 treatment. FoxO3a overexpression reduced calcium uptake and calcium deposition. FoxO3a overexpression also prevented alterations in calcium channel expression and the cell differentiation associated decrease in expression of Runx2 and increased expression of osteocalcin, findings consistent with a failure for the cells to differentiate. Based on both our expression and functional data, we suggest that high levels of FoxO3a prevent osteoblast differentiation and matrix calcification.
    Keywords:  Calcium deposition; Forkhead Box O3; MC3T3-E1 cells; Matrix calcification; Osteoblast differentiation; Osteoblast mineralization
    DOI:  https://doi.org/10.1016/j.bonr.2019.100206
  41. Eur J Med Chem. 2019 Jun 04. pii: S0223-5234(19)30523-9. [Epub ahead of print]178 365-379
    Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells.
    Dongdong Luo, Yujiao Yi, Kai Peng, Tangrong Liu, Jiayu Yang, Shan Liu, Wanzhou Zhao, Xianjun Qu, Wengong Yu, Yuchao Gu, Shengbiao Wan.
      The biological function of the natural ent-kaurene diterpenoid isolated from genus Isodon, oridonin, has been intensively studied. However, its mechanism studies and clinical applications were hampered by its moderate biological activities. In order to enlarge the applied range of oridonin and explore its mechanism of action, a series of derivatives were designed and synthesized based on the structure of oridonin. Some of the derivatives were significantly more potent than oridonin against four cancer cell lines. Especially, the most potent compound 20 markedly inhibited the proliferation of well differentiated HepG2 and poorly differentiated PLC/PRF/5 cells, with IC50 values as low as 1.36 μM and 0.78 μM respectively, while the IC50 values of oridonin are 8.12 μM and 7.41 μM. We found that compound 20 inhibited liver cancer cell proliferation via arresting cell cycle at G1 phase. Moreover, it induced liver cancer cell apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular reactive oxygen species level and inducing the expression of apoptosis-related proteins. Furthermore, compound 20 significantly inhibited growth of PLC/PRF/5 xenograft tumors in nude mice and had no observable toxic effect. Altogether, these results indicated that compound 20 is a promising lead for liver cancer therapeutics.
    Keywords:  Anticancer activity; Apoptosis; Liver cancer; Mouse xenograft model; Oridonin derivatives
    DOI:  https://doi.org/10.1016/j.ejmech.2019.06.006
  42. Int J Biol Sci. 2019 ;15(5): 1052-1071
    Construing the Biochemical and Molecular Mechanism Underlying the In Vivo and In Vitro Chemotherapeutic Efficacy of Ruthenium-Baicalein Complex in Colon Cancer.
    Yixuan Wang, Li Bian, Tania Chakraborty, Torsha Ghosh, Pallakhi Chanda, Souvik Roy.
      In pursuit of a novel approach in colon cancer therapy, we explored the ability of ruthenium baicalein complex to eradicate colon cancer by efficiently targeting various apoptotic pathways on human colon cancer cell line and on a DMH and DSS induced murine model of colorectal cancer. In this study, we provide direct proof of the chemotherapeutic potential of the ruthenium baicalein complex by activating p-53 dependent intrinsic apoptosis and modulating the AKT/mTOR and WNT/β- catenin pathways. The ruthenium baicalein complex was synthesized and its characterizations were accomplished through various spectroscopic techniques followed by assessment of antioxidant potential by DPPH, FRAP, and ABTS methods. In vitro study established that the complex increased p53 and caspase-3 expressions while down regulating VEGF and mTOR expression, induced apoptosis, and DNA fragmentation in the HT-29 cells. Acute and sub-acute toxicity study was also considered and results from in vivo study revealed that complex was effective in suppressing ACF multiplicity and hyperplastic lesions and also raised the CAT, SOD, and glutathione levels. Furthermore, the complex decreased cell proliferation and increased apoptotic events in tumor cells correlated with the upregulation of Bax and downregulation of Bcl2, WNT and β- catenin expressions. Our findings from the in vitro and in vivo study provide robust confirmation that ruthenium baicalein complex possesses a potential chemotherapeutic activity against colon cancer and is competent in reducing ACF multiplicity, hyperplastic lesions in the colon tissues of rats by inducing apoptosis.
    Keywords:  colon carcinogenesis; in vitro study; ruthenium baicalein complex; structural characterization; toxicity study
    DOI:  https://doi.org/10.7150/ijbs.31143
  43. Appl Microbiol Biotechnol. 2019 Jun 07.
    The inhibitor of apoptosis protein MoBir1 is involved in the suppression of hydrogen peroxide-induced fungal cell death, reactive oxygen species generation, and pathogenicity of rice blast fungus.
    Lisha Zhang, Kaili Zhong, Ruili Lv, Xiaobo Zheng, Zhengguang Zhang, Haifeng Zhang.
      The inhibitor of apoptosis protein (IAP) family has been identified in a variety of organisms. All IAPs contain one to three baculoviral IAP repeat (BIR) domains, which are required for anti-apoptotic activity. Here, we identified a type II BIR domain-containing protein, MoBir1, in the rice blast fungus Magnaporthe oryzae. Expression of the MoBIR1 gene in Saccharomyces cerevisiae suppressed hydrogen peroxide-induced cell death and delayed yeast cell chronological aging. Delayed aging was found to require the carboxyl terminus of MoBir1. M. oryzae transformants overexpressing the MoBIR1 gene demonstrated increased growth rate and biomass, delayed mycelial aging, and enhanced resistance to hydrogen peroxide but reduced reactive oxygen species generation and virulence. Moreover, MoBIR1-overexpressing transformants exhibited anti-apoptotic activity. However, MoBIR1 silencing resulted in no obvious phenotypic changes, compared with the wild-type M. oryzae strain Guy11. Our findings broaden the knowledge on fungal type II BIR domain-containing proteins.
    Keywords:  Cell death; Inhibitor of apoptosis; Magnaporthe oryzae; Pathogenicity; ROS
    DOI:  https://doi.org/10.1007/s00253-019-09931-8
  44. Front Neurosci. 2019 ;13 537
    The Neuroprotective Effect of Hemin and the Related Mechanism in Sevoflurane Exposed Neonatal Rats.
    Fan Yang, Yangyang Shan, Zhiyin Tang, Xiuying Wu, Congjie Bi, Yongfang Zhang, Yan Gao, Hongtao Liu.
      Background: Many studies have reported that sevoflurane can increase neuronal apoptosis and result in cognitive deficits in rodents. Although neurotoxicity may be associated with mitochondrial dysfunction and oxidative stress, the exact mechanism remains unclear. In order to evaluate potential treatment therapies, we studied the effects of hemin on neurotoxicity of neonatal rat sevoflurane exposure.Methods: Postnatal day (P) seven rats were assigned randomly to four groups; (1) group C: non-anesthesia, (2) group H: intraperitoneal hemin (50 mg kg-1) treatment on days 5 and 6, (3) group S: 3% sevoflurane exposure for 4 h, and (4) group SH: hemin treatment + sevoflurane exposure. The expression of neuroglobin in neonatal hippocampus was determined by western blot and immunohistochemistry. Neuroglobin was localized by immunofluorescence. Western blot for the expression of cleaved caspase-3 and TUNEL were used to detect neonatal hippocampal apoptosis, and cytochrome c was used to evaluate mitochondrial function. Drp-1 and Mfn-2 immunoblotting were used to assess mitochondrial dynamics. The Morris water maze test was performed to detect cognitive function in the rats on P30.
    Results: Exposure to sevoflurane increased the expression of cleaved caspase-3, cytochrome c, and Drp1 in the neonatal hippocampus and resulted in cognitive deficiency but decreased expression of Mfn2. Hemin reduced apoptosis, improved mitochondrial dynamics and ameliorated the cognitive impairment caused by sevoflurane exposure.
    Conclusion: Hemin reduced neuronal apoptosis, improved mitochondrial dynamics and protected against cognitive deficits induced by sevoflurane in neonatal rats. This neuroprotective effect may be achieved by increasing the expression of neuroglobin.
    Keywords:  hemin; mitochondria; neuroglobin; neurotoxicity; sevoflurane
    DOI:  https://doi.org/10.3389/fnins.2019.00537
  45. Biochem Biophys Res Commun. 2019 Jun 06. pii: S0006-291X(19)31075-7. [Epub ahead of print]
    Targeting cullin 3 by miR-601 activates Nrf2 signaling to protect retinal pigment epithelium cells from hydrogen peroxide.
    Zhi-Jun Chen, Ling Rong, Dan Huang, Qin Jiang.
      Activation of Nrf2 cascade can protect retinal pigment epithelium (RPE) cells from hydrogen peroxide (H2O2) and other oxidative injury. The current study identified microRNA-601 (miR-601) as a novel cullin 3 (Cul3)-targeting miRNA that activates Nrf2 cascade. In ARPE-19 cells and primary human RPE cells, forced overexpression of miR-601 significantly inhibited Cul3 3'-UTR activity and downregulated Cul3 mRNA/protein expression, leading to Nrf2 protein stabilization and its nuclear translocation as well as expression of anti-oxidant response elements (ARE)-dependent genes (HO1, NQO1 and GCLC). H2O2 treatment increased miR-601 levels in RPE cells. Significantly, ectopic miR-601 overexpression attenuated H2O2-induced oxidative injury and apoptosis in RPE cells. In contrast, miR-601 inhibition promoted Cul3 expression, lowered basal Nrf2 activation, and enhanced H2O2-induced oxidative stress and apoptosis in RPE cells. In ARPE-19 cells, CRISPC/Cas9-mediated knockout (KO) of Cul3 or Keap1 not only mimicked, but also nullified, miR-601-inudced anti-H2O2 actions. Furthermore, Nrf2 silencing by targeted shRNAs abolished miR-601-inudced cytoprotection in H2O2-treated ARPE-19 cells. Taken together, we show that miR-601 activates Nrf2 signaling to protect RPE cells from H2O2 by targeting Cul3.
    Keywords:  Nrf2; Oxidative injury; Retinal pigment epithelium cells; cullin 3; miR-601
    DOI:  https://doi.org/10.1016/j.bbrc.2019.05.171
  46. Oxid Med Cell Longev. 2019 ;2019 7857082
    Irisin Contributes to the Hepatoprotection of Dexmedetomidine during Intestinal Ischemia/Reperfusion.
    Xin Fan, Juan Du, Mao-Hua Wang, Jia-Man Li, Bo Yang, Ye Chen, Jun-Chao Dai, Chunxiang Zhang, Jun Zhou.
      Intestinal ischemia/reperfusion (I/R), which is associated with high morbidity and mortality, is also accompanied with abnormal energy metabolism and liver injury. Irisin, a novel exercise-induced hormone, can regulate adipose browning and thermogenesis. The following study investigated the potential role of dexmedetomidine in liver injury during intestinal I/R in rats. Adult male Sprague-Dawley rats underwent occlusion of the superior mesenteric artery for 90 min followed by 2 h of reperfusion. Dexmedetomidine or irisin-neutralizing antibody was intravenously administered for 1 h before surgery. The results demonstrated that severe intestine and liver injuries occurred during intestinal I/R as evidenced by pathological scores and an apparent increase in serum diamine oxidase (DAO), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels. In addition, the hepatic irisin, cleaved caspase-3, Bax, and NLRP3 inflammasome components (including NLRP3, ASC, and caspase-1), protein expressions, apoptotic index, reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 6 levels increased; however, the serum irisin level and hepatic Bcl-2 protein expression and superoxide dismutase (SOD) activity decreased after intestinal I/R. Interestingly, dexmedetomidine could reduce the above listed changes and increase the irisin levels in plasma and the liver in I/R rats. Dexmedetomidine-mediated protective effects on liver injury and NLRP3 inflammasome activation during intestinal I/R were partially abrogated via irisin-neutralizing antibody treatment. The results suggest that irisin might contribute to the hepatoprotection of dexmedetomidine during intestinal ischemia/reperfusion.
    DOI:  https://doi.org/10.1155/2019/7857082
  47. Front Pharmacol. 2019 ;10 567
    Total Extracts of Abelmoschus manihot L. Attenuates Adriamycin-Induced Renal Tubule Injury via Suppression of ROS-ERK1/2-Mediated NLRP3 Inflammasome Activation.
    Wei Li, Weiming He, Ping Xia, Wei Sun, Ming Shi, Yao Zhou, Weiwei Zhu, Lu Zhang, Buhui Liu, Jingjing Zhu, Yiye Zhu, Enchao Zhou, Minjie Sun, Kun Gao.
      Abelmoschus manihot (L.) Medik. (Malvaceae) is a herb used in traditional Chinese medicine to treat some kidney diseases. To date, the detailed mechanisms by which A. manihot improves some kinds of renal disease are not fully understood. In this study, we established Adriamycin-induced NRK-52E cells, the normal rat kidney epithelial cell line, injury, and Sprague-Dawley rats with Adriamycin-induced nephropathy to evaluate the role and mechanisms of total extracts of A. manihot flower (TEA) both in vitro and in vivo. We found that TEA ameliorated Adriamycin-induced cellular morphological changes, cell viability, and apoptosis through the suppression of protein oxidation and ERK1/2 signaling. However, this anti-oxidative stress role of TEA was independent of ROS inhibition. Adriamycin activated ERK1/2 signaling followed by activation of NLRP3 inflammasomes. TEA suppressed NLRP3 inflammasomes via inhibition of ERK1/2 signal transduction; decreased proteinuria and attenuated renal tubule lesions; and inhibited the expression of NLRP3 in tubules in rats with Adriamycin nephropathy. Collectively, TEA protects renal tubular cells against Adriamycin-induced tubule injury via inhibition of ROS-ERK1/2-NLRP3 inflammasomes.
    Keywords:  Abelmoschus manihot L.; Adriamycin nephropathy; ERK1/2; NLRP3 inflammasome; oxidative stress; renal tubular cell; total extract
    DOI:  https://doi.org/10.3389/fphar.2019.00567
  48. J Neurochem. 2019 Jun 12.
    Sex differences in neonatal mouse brain injury after hypoxia ischemia and adaptaquin treatment.
    Kenan Li, Tao Li, Yafeng Wang, Yiran Xu, Shan Zhang, Carsten Culmsee, Xiaoyang Wang, Changlian Zhu.
      Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-PHDs) are important targets against oxidative stress. We hypothesized that inhibition HIF-PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. The pups were treated intraperitoneally immediately with adaptaquin after hypoxia-ischemia (HI) and then every 24 hours for 3 days. Adaptaquin treatment reduced infarction volume by an average of 26.3% at 72 h after HI compared to vehicle alone, and this reduction was more pronounced in males (34.8%) than in females (11.7%). The protection was also more pronounced in the cortex. The subcortical white matter injury as measured by tissue loss volume was reduced by 24.4% in the adaptaquin treatment group, and this reduction was also more pronounced in males (28.4%) than in females (18.9%). Cell death was decreased in the cortex as indicated by Fluoro-Jade labeling, but not in other brain regions with adaptaquin treatment. Furthermore, in the brain injury area, adaptaquin did not alter the number of cells positive for caspase-3 activation or translocation of apoptosis-inducing factor to the nuclei. Adaptaquin treatment increased glutathione peroxidase 4 mRNA expression in the cortex but had no impact on 3-nitrotyrossine, 8-hydroxy-2 deoxyguanosine, or malondialdehyde production. Hif1α mRNA expression increased after HI, and adaptaquin treatment also stimulated Hif1α mRNA expression, which was also more pronounced in males than in females. However, nuclear translocation of HIF1α protein was decreased after HI, and adaptaquin treatment had no influence on HIF1α expression in the nucleus. These findings demonstrate that adaptaquin treatment is neuroprotective, but the potential mechanisms need further investigation. This article is protected by copyright. All rights reserved.
    Keywords:  cell death; hypoxia inducible factor; neonates; oxidative stress; reactive oxygen species; sex difference
    DOI:  https://doi.org/10.1111/jnc.14790
  49. Oxid Med Cell Longev. 2019 ;2019 6791457
    Ligustrazine Attenuates Myocardial Injury Induced by Coronary Microembolization in Rats by Activating the PI3K/Akt Pathway.
    Qiang Su, Xiangwei Lv, Ziliang Ye.
      Background/Aims: Coronary microembolization- (CME-) induced myocardial injury and progressive cardiac dysfunction are mainly caused due to CME-induced myocardial local inflammatory response and myocardial apoptosis. Ligustrazine plays an important protective role in multiple cardiovascular diseases, but its role and the protection mechanism in CME is unclear. This study hypothesized that ligustrazine attenuates CME-induced myocardial injury in rats. This study also explored the mechanism underlying this attenuation.Methods: Forty SD rats were randomly divided into CME group, ligustrazine group, ligustrazine+LY294002 (ligustrazine+LY) group, and sham group (ten rats in each). In each group, the cardiac function, apoptotic index, serum c-troponin I (cTnI) level, inflammation [interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α)], and oxidative stress [nitric oxide (NO), superoxide dismutase (SOD), and malondialdehyde (MDA)] were determined. Western blotting was used to detect the proteins which are present in the PI3K/Akt pathway.
    Results: Ligustrazine improved cardiac dysfunction induced by CME, increased serum NO and SOD activities, and decreased the serum level in IL-1β, MDA, cTnI, and TNF-α. Moreover, ligustrazine inhibited myocardial apoptosis, which is perhaps caused by the upregulated Bcl-2, the downregulated cleaved caspase-3 and Bax, and the increased protein level in endothelial nitric oxide synthase and phosphorylated Akt. These effects, however, were reduced if ligustrazine was coadministered with LY294002.
    Conclusions: Ligustrazine attenuates CME-induced myocardial injury. The effects associated with this attenuation may be achieved by activating the myocardium PI3K/Akt signaling pathway.
    DOI:  https://doi.org/10.1155/2019/6791457
  50. Toxicol Appl Pharmacol. 2019 Jun 06. pii: S0041-008X(19)30219-4. [Epub ahead of print] 114617
    Tricetin protects against 6-OHDA-induced neurotoxicity in Parkinson's disease model by activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway.
    Jie Ren, Ling Yuan, Wenbin Wang, Meiju Zhang, Qun Wang, Simin Li, Ling Zhang, Kun Hu.
      Apoptosis of DA neurons is a contributing cause of disability and death for Parkinson's disease (PD). In this experiment, the neuroprotective effect of Tricetin was examined in PD models both in vitro and in vivo. The results suggested that 6-OHDA-induced cytotoxicity was accompanied by an increase in ROS generation, an increase in caspase-3 protein activity, an increase in Lactate dehydrogenase (LDH) release and an increase in the ratio of Bax/Bcl-2, but the pretreatment with Tricetin significantly improved cell viability and suppressed mitochondria-mediated apoptosis. Moreover, Tricetin also induced the protein expression of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its transcriptional activation, resulting in the up-regulated expression of heme oxygenase-1 (HO-1), which conferred neuroprotection against 6-OHDA-induced oxidative damage. Results from molecular docking indicated that Tricetin could be a potent competitive inhibitor of the Keap1-Nrf2 Protein Protein Interaction (PPI). Finally, in vivo findings were confirmed in the 6-OHDA-PD C. elegans model. Thus, Tricetin may be an attractive therapeutic candidate for the neuroprotection.
    Keywords:  Apoptosis; C. elegans; Nrf2; Oxidative stress; Parkinson's disease; Tricetin
    DOI:  https://doi.org/10.1016/j.taap.2019.114617
  51. Biochim Biophys Acta Mol Basis Dis. 2019 Jun 10. pii: S0925-4439(19)30201-7. [Epub ahead of print]
    Apoptosis and cell proliferation in proximal tubular cells exposed to apoptotic bodies. Novel pathophysiological implications in cisplatin-induced renal injury.
    Coral García-Pastor, Rafael Blázquez-Serra, Ricardo J Bosch, Francisco J Lucio Cazaña, Ana B Fernández-Martínez.
      The therapeutic efficacy of the antineoplastic drug cisplatin is limited by its nephrotoxicity, which affects particularly to proximal tubular cells (PTC). Cisplatin-induced cytotoxicity appears to be multifactorial and involves inflammation, oxidative stress as well as apoptosis. We have recently shown that the cyclo-oxygenase-2 (COX-2)/intracellular prostaglandin E2 (iPGE2)/EP receptor pathway mediates the apoptotic effect of cisplatin on human proximal tubular HK-2 cells. Here, we studied the effects on HK-2 cells of apoptotic bodies (ABs) generated after treatment of HK-2 cells with cisplatin. We found that ABs inhibited cell growth, induced apoptosis and increased COX-2 expression and iPGE2 in ABs-recipient HK-2 cells. Inhibition of the COX-2/iPGE2/EP receptor pathway in these cells prevented the effects of ABs without interfering with their internalization. Interestingly, 2nd generation ABs (i.e. ABs released by cells undergoing apoptosis upon treatment with ABs) did not trigger apoptosis in naïve HK-2 cells, and stimulated cell proliferation through the COX-2/iPGE2/EP receptor pathway. These results suggest that ABs, through iPGE2-dependent mechanisms, might have a relevant role in the natural history of cisplatin-induced acute kidney failure because they contribute first to the propagation of the noxious effects of cisplatin to non-injured PTC and then to the promotion of the proliferative tubular response required for proximal tubule repair. Since iPGE2 also mediates both cisplatin-induced HK-2 cell apoptosis, intervention in the COX-2/iPGE2/EP receptor pathway might provide us with new therapeutic avenues in patients with cisplatin-induced acute kidney injury.
    Keywords:  Apoptotic bodies; Cisplatin; Intracellular prostaglandin E2; Proximal tubular cells
    DOI:  https://doi.org/10.1016/j.bbadis.2019.06.008
  52. Life Sci. 2019 Jun 10. pii: S0024-3205(19)30480-1. [Epub ahead of print] 116554
    Asprosin improves the survival of mesenchymal stromal cells in myocardial infarction by inhibiting apoptosis via the activated ERK1/2-SOD2 pathway.
    Zhengbin Zhang, Yanzhen Tan, Liwen Zhu, Bing Zhang, Pan Feng, Erhe Gao, Chennian Xu, Xiaoming Wang, Wei Yi, Yang Sun.
      AIMS: Several adipokines have been proven to improve the therapeutic efficacy of mesenchymal stromal cells (MSCs) when used to treat ischemic heart disease. Asprosin (ASP) is a newly-discovered adipokine. ASP might also predict the severity of coronary pathology. We investigated the role of ASP on MSCs and the effects of ASP-pretreated MSCs on myocardial infarction (MI).MAIN METHODS: MSCs were labelled with a lentivirus carrying green fluorescent protein (GFP). For in vivo study, after pretreatment with vehicle or ASP, MSCs were injected into infarcted hearts. Cardiac function and fibrosis were then evaluated 4 weeks after the induction of MI and survival of MSCs evaluated after 1 week. MSCs proliferation and migration were investigated after ASP treatment in vitro. MSCs apoptosis induced by hydrogen peroxide (H2O2) was assessed using flow cytometry.
    KEY FINDINGS: Compared to vehicle-pretreated MSCs, ASP-pretreated MSCs significantly improved the left ventricular ejection fraction (LVEF), and inhibited myocardial fibrosis 4 weeks after MI. ASP pretreatment may have promoted homing of transplanted MSCs. In vitro results showed that ASP had no significant effect on MSC proliferation and migration, but protected these cells from H2O2-induced apoptosis. Among 21 molecules associated with antioxidation and cell death, the antioxidant enzyme SOD2 was significantly upregulated by ASP. Furthermore, ASP treatment inhibited H2O2-induced ROS generation and apoptosis via the activated ERK1/2-SOD2 pathway.
    SIGNIFICANCE: This is the first evidence that ASP can regulate MSCs function and enhance MSCs therapy for ischemic heart disease. Furthermore, we demonstrate that ASP protects MSCs from oxidative stress-induced apoptosis via the ERK1/2-SOD2 pathway.
    Keywords:  Asprosin; Cell transplantation therapy; Mesenchymal stromal cells; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.lfs.2019.116554
  53. Antioxidants (Basel). 2019 Jun 06. pii: E164. [Epub ahead of print]8(6):
    Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications.
    Ananda S Prasad, Bin Bao.
      The essentiality of zinc as a trace mineral in human health has been recognized for over five decades. Zinc deficiency, caused by diet, genetic defects, or diseases, can cause growth retardation, delayed sexual maturation, depressed immune response, and abnormal cognitive functions in humans. Zinc supplementation in zinc-deficient individuals can overcome or attenuate these abnormalities, suggesting zinc is an essential micro-nutrient in the body. A large number of in vitro and in vivo experimental studies indicate that zinc deficiency also causes apoptosis, cellular dysfunction, deoxyribonucleic acid (DNA) damage, and depressed immune response. Oxidative stress, due to the imbalance of reactive oxygen species (ROS) production and detoxification in the anti-oxidant defense system of the body, along with subsequent chronic inflammation, is believed to be associated with many chronic degenerative diseases such as diabetes, heart diseases, cancers, alcohol-related disease, macular degenerative disease, and neuro-pathogenesis. A large number of experimental studies including cell culture, animal, and human clinical studies have provided supportive evidence showing that zinc acts as an anti-oxidative stress agent by inhibition of oxidation of macro-molecules such as (DNA)/ribonucleic acid (RNA) and proteins as well as inhibition of inflammatory response, eventually resulting in the down-regulation of (ROS) production and the improvement of human health. In this article, we will discuss the molecular mechanisms of zinc as an anti-oxidative stress agent or mediator in the body. We will also discuss the applications of zinc supplementation as an anti-oxidative stress agent or mediator in human health and disease.
    Keywords:  A20; HNF-4α; MT; NF-κB; ROS; zinc
    DOI:  https://doi.org/10.3390/antiox8060164
  54. Exp Gerontol. 2019 Jun 05. pii: S0531-5565(19)30173-1. [Epub ahead of print]124 110627
    Towards a unified mechanistic theory of aging.
    Gustavo Barja.
      A large amount of the longevity-modulating genes discovered during the last two decades are highly conserved during evolution from yeast and invertebrates to mammals. Many different kinds of evidence converge in the concept that life extending manipulations like the dietary restrictions or rapamycin signal the nucleus specifically changing gene expression to increase longevity. The response of the cell aging regulation system is to change the level of activity of many different aging effectors to modulate longevity. Aging effectors include mitROS production, lipid unsaturation, autophagy, mitochondrial DNA repair and possibly others like apoptosis, proteostasis, or telomere shortening, corresponding to different classic theories of aging. The constitutive spontaneous activity of this aging regulating system, likely including epigenetics, can also explain species longevity. The aging regulating system reconciles the previously considered independent theories of aging bringing them together into a single unified theory of aging.
    Keywords:  Aging; Autophagy; Free radicals; Longevity; Reactive oxygen species production
    DOI:  https://doi.org/10.1016/j.exger.2019.05.016
  55. Microvasc Res. 2019 Jun 05. pii: S0026-2862(18)30278-4. [Epub ahead of print]125 103885
    Protective effects of hydrogen inhalation during the warm ischemia phase against lung ischemia-reperfusion injury in rat donors after cardiac death.
    Jiahang Zhang, Huacheng Zhou, Jinfeng Liu, Chao Meng, Lin Deng, Wenzhi Li.
      BACKGROUND: Successful amelioration of long-term warm ischemia lung injury in donors after cardiac death (DCDs) can remarkably improve outcomes. Hydrogen gas provides potent anti-inflammatory and antioxidant effects against ischemia-reperfusion injury (IRI). This study observed the effects of hydrogen inhalation on lung grafts during the warm ischemia phase in cardiac death donors.METHODS: After cardiac death, rat donor lungs (n = 8) underwent mechanical ventilation with 40% oxygen plus 60% nitrogen (control group) or 3% hydrogen and 40% oxygen plus 57% nitrogen (hydrogen group) for 2 h during the warm ischemia phase in situ. Then, lung transplantation was performed after 2 h of cold storage and 3 h of recipient reperfusion prior to lung graft assessment. Rats that underwent left thoracotomy without transplantation served as the sham group (n = 8). The results of static compliance and arterial blood gas analysis were assessed in the recipients. The wet-to-dry weight ratio (W/D), inflammation, oxidative stress, cell apoptosis and histologic changes were evaluated after 3 h of reperfusion. Nuclear factor kappa B (NF-κB) protein expression in the graft was analyzed by Western blotting.
    RESULTS: Compared with the sham group, lung function, W/D, inflammatory reaction, oxidative stress and histological changes were decreased in both transplant groups (control and hydrogen groups). However, compared with the control group, exposure to 3% hydrogen significantly improved lung graft static compliance and oxygenation and remarkably decreased the wet-to-dry weight ratio, inflammatory reactions, and lipid peroxidation. Furthermore, hydrogen improved the lung graft histological changes, decreased the lung injury score and apoptotic index and reduced NF-κB nuclear accumulation in the lung grafts.
    CONCLUSION: Lung inhalation with 3% hydrogen during the warm ischemia phase attenuated lung graft IRI via NF-κB-dependent anti-inflammatory and antioxidative effects in rat donors after cardiac death.
    Keywords:  Hydrogen; Ischemia-reperfusion injury; Warm ischemia phase
    DOI:  https://doi.org/10.1016/j.mvr.2019.103885
  56. Life Sci. 2019 Jun 06. pii: S0024-3205(19)30458-8. [Epub ahead of print]
    Effects of novel antidiabetes agents on apoptotic processes in diabetes and malignancy: Implications for lowering tissue damage.
    Habib Yaribeygi, Fadel Lhaf, Thozhukat Sathyapalan, Amirhossein Sahebkar.
      Apoptosis is a complicated process that involves activation of a series of intracellular signaling. Tissue injuries from diabetes mellitus mostly occur as a consequence of higher rate of apoptosis process due to activation of a series of molecular mechanisms. Several classes of anti-hyperglycaemic agents have been developed which could potentially modulate the apoptotic process resulting in fewer tissue damages. Novel types of anti-hyperglycaemic medications such as sodium glucose cotransporters-2 inhibitors, glucagon like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have shown to provide potent anti-hyperglycaemic effects, but their influences on diabetes-induced apoptotic injuries is largely unknown. Therefore, in the current study, we reviewed the published data about the possible effects of these anti-hyperglycaemic agents on apoptosis in diabetic milieu as well as in cancer cells.
    Keywords:  Apoptosis; Cancer; Caspase; DPP-4 inhibitor; Diabetes mellitus; GLP-1 receptor agonist; Oxidative stress; SGLT2 inhibitor
    DOI:  https://doi.org/10.1016/j.lfs.2019.06.013
  57. Pharmacol Rep. 2019 Feb 20. pii: S1734-1140(18)30650-9. [Epub ahead of print]71(4): 583-590
    Time course of cardiomyopathy induced by doxorubicin in rats.
    Daniel J M Medeiros-Lima, Jorge J Carvalho, Eduardo Tibirica, Juliana P Borges, Cristiane Matsuura.
      BACKGROUND: Doxorubicin (DOX)-related cardiotoxicity may expose cancer survivors to increased risk of cardiovascular morbidity and mortality. Here, we characterized the time course of DOX-induced cardiomyopathy in rats.METHODS: Sprague-Dawley male rats (12 wk old) received doxorubicin hydrochloride (1 mg/kg/d, ip) during 10 consecutive days and they were euthanized one (DOX1), two (DOX2) or four (DOX4) weeks after the last drug injection. Control group received NaCl 0.9% (ip). Hearts were mounted on a Langendorff perfusion system, left ventricle fragments were processed for microscopy and oxidative stress-related assays, and blood was collected for cardiac troponin I assay.
    RESULTS: All DOX-treated groups showed swollen and vacuolated cardiomyocytes with myofilaments disarray and mitochondrial damage. These changes were already evident after one week and became more pronounced after four weeks. Cardiac troponin I plasma levels were significantly increased in DOX1 and further increased in DOX4 compared to control group. Increased oxidative damage to lipids was observed in DOX1, and to proteins in DOX4. Glutathione peroxidase activity increased in DOX4. The morphological changes resulted in cardiac remodeling, including interstitial fibrosis, apoptosis and significant impairment of both contractile and relaxation function in DOX 4 compared to control group. Hearts from all animals displayed an early reduction in the responsiveness to norepinephrine.
    CONCLUSIONS: These findings support the view that DOX cardiotoxicity occurs in a "continuum", and as the hypothesis of an irreversible cardiac injury is being challenged, understanding the progression of morphological and functional changes caused by DOX may allow proper timing of initiation of prophylactic treatment.
    Keywords:  Cardiomyopathy; Cardiotoxic agents; Reactive oxygen species; Ventricular cardiac remodeling
    DOI:  https://doi.org/10.1016/j.pharep.2019.02.013
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