bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019–07–14
seventy papers selected by
Gavin McStay, Staffordshire University
  1. Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma.
  2. Protective effect of 3-bromo-4,5-dihydroxybenzaldehyde from Polysiphonia morrowii Harvey against hydrogen peroxide-induced oxidative stress in in vitro and in vivo model zebrafish.
  3. Increased Oxidative Stress Induced by Rubus Bioactive Compounds Induce Apoptotic Cell Death in Human Breast Cancer Cells.
  4. Protective Effects of Trimetazidine in Retarding Selenite-Induced Lens Opacification.
  5. Encircling granulosa cells protects against di-(2-ethylhexyl)phthalate-induced apoptosis in rat oocytes cultured in vitro.
  6. Sperm DNA Fragmentation: Mechanisms of Origin.
  7. Polydatin Attenuates Neuronal Loss via Reducing Neuroinflammation and Oxidative Stress in Rat MCAO Models.
  8. Biochemical regulation and structural analysis of copper-transporting ATPase in a human hepatoma cell line for Wilson disease.
  9. Ethanolic Extract of Senna velutina Roots: Chemical Composition, In Vitro and In Vivo Antitumor Effects, and B16F10-Nex2 Melanoma Cell Death Mechanisms.
  10. ROS -mediated p53 activation by juglone enhances apoptosis and autophagy in vivo and in vitro.
  11. Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling.
  12. Ameliorative Effect of Beta vulgaris Root Extract on Chlorpyrifos-Induced Oxidative Stress, Inflammation and Liver Injury in Rats.
  13. Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and suppression of NF-κB/NLRP3 inflammasome axis.
  14. Sulfiredoxin-1 alleviates high glucose-induced podocyte injury though promoting Nrf2/ARE signaling via inactivation of GSK-3β.
  15. Naringin alleviates H2O2-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus-derived mesenchymal stem cells.
  16. Oxidative Stress Induced by the Deubiquitinase Inhibitor b-AP15 Is Associated with Mitochondrial Impairment.
  17. AKT-GSK3β Signaling Pathway Regulates Mitochondrial Dysfunction-Associated OPA1 Cleavage Contributing to Osteoblast Apoptosis: Preventative Effects of Hydroxytyrosol.
  18. VDAC1 and the TSPO: Expression, Interactions, and Associated Functions in Health and Disease States.
  19. Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies.
  20. Peroxiredoxin V Inhibits Emodin-induced Gastric Cancer Cell Apoptosis via the ROS/Bcl2 Pathway.
  21. Pristimerin induces autophagy-mediated cell death in K562 cells through the ROS/JNK signaling pathway.
  22. Nuclear Nrf2 Activity in Laryngeal Carcinoma is Regulated by SENP3 After Cisplatin-Induced Reactive Oxygen Species Stress.
  23. Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats.
  24. Anti-Apoptotic Effect of G-Protein-Coupled Receptor 40 Activation on Tumor Necrosis Factor-α-Induced Injury of Rat Proximal Tubular Cells.
  25. Microarray analysis of apoptosis gene expression in liver injury induced by chronic exposure to arsenic and high-fat diet in male mice.
  26. Thymoquinone suppresses the proliferation of renal cell carcinoma cells via reactive oxygen species-induced apoptosis and reduces cell stemness.
  27. 2,4-D causes oxidative stress induction and apoptosis in human dental pulp stem cells (hDPSCs).
  28. Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms.
  29. Platelet Membrane Camouflaged Black Phosphorus Quantum Dots Enhance Anticancer Effect Mediated by Apoptosis and Autophagy.
  30. Angelica polysaccharide alleviates oxidative response damage in HaCaT cells through up-regulation of miR-126.
  31. Oleuropein suppresses oxidative, inflammatory, and apoptotic responses following glycerol-induced acute kidney injury in rats.
  32. FNDC5/Irisin counteracts lipotoxic-induced apoptosis in hypoxic H9c2 cells.
  33. Mitochondrial MsrB2 serves as a switch and transducer for mitophagy.
  34. Proteomic analysis reveals that Odoroside A triggers G2/M arrest and apoptosis in colorectal carcinoma through ROS-p53 pathway.
  35. Oxidative stress and sperm function: A systematic review on evaluation and management.
  36. Radioprotective Properties of Pterocarpus santalinus Chloroform Extract in Murine Splenic Lymphocytes and Possible Mechanism.
  37. Inhibition of miR-181b-5p protects cardiomyocytes against ischemia/reperfusion injury by targeting AKT3 and PI3KR3.
  38. Exogenous Ca2+ mitigates the toxic effects of TiO2 nanoparticles on phagocytosis, cell viability, and apoptosis in haemocytes of a marine bivalve mollusk, Tegillarca granosa.
  39. Up-regulation of HIF-1α is associated with neuroprotective effects of agmatine against rotenone-induced toxicity in differentiated SH-SY5Y cells.
  40. Depletion of NBR1 in urothelial carcinoma cells enhances rapamycin-induced apoptosis through impaired autophagy and mitochondrial dysfunction.
  41. Catalase-like metal-organic framework nanoparticles to enhance radiotherapy in hypoxic cancer and prevent cancer recurrence.
  42. Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification.
  43. Moringa seed extract alleviates titanium oxide nanoparticles (TiO2-NPs)-induced cerebral oxidative damage, and increases cerebral mitochondrial.
  44. Effects of Cigarette Smoke on TSPO-related Mitochondrial Processes.
  45. SIRT7 Regulates Lipopolysaccharide-Induced Inflammatory Injury by Suppressing the NF-κB Signaling Pathway.
  46. The protective mechanism of cannabidiol in cardiac injury: A systematic review of non-clinical studies.
  47. Alternations in oxidative stress, apoptosis, and innate-immune gene expression at mRNA levels in subadult tiger puffer (Takifugu rubripes) under two different rearing systems.
  48. N-acetylcysteine reverses the decrease of DNA methylation status caused by engineered gold, silicon, and chitosan nanoparticles.
  49. Modulation of selenium-dependent glutathione peroxidase activity enhances doxorubicin-induced apoptosis, tumor cell killing, and hydroxyl radical production in human NCI/ADR-RES cancer cells despite high-level P-glycoprotein expression.
  50. Hyodeoxycholic acid protects the neurovascular unit against oxygen-glucose deprivation and reoxygenation-induced injury in vitro.
  51. 2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: Synthesis, evaluation of in vitro leishmanicidal activity, and mechanism of action.
  52. Functional Regulation of an Oxidative Stress Mediator, Rac1, in Diabetic Retinopathy.
  53. Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy.
  54. Pd(II) complexes with N-heteroaromatic hydrazone ligands: Anticancer activity, in silico and experimental target identification.
  55. Role of ectopically expressed mtDNA encoded cytochrome c oxidase subunit I (MT-COI) in tumorigenesis.
  56. SIRT2 functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes.
  57. Triggering of eryptosis, the suicidal erythrocyte death, by phenoxodiol.
  58. Toxic effects and involved molecular pathways of nanoparticles on cells and subcellular organelles.
  59. A review on anticancer potentials of benzothiazole derivatives.
  60. Synthesis of silver nanoparticles (AgNPs) from leaf extract of Salvia miltiorrhiza and its anticancer potential in human prostate cancer LNCaP cell lines.
  61. Mitochondria-Targeted Peptide SS31 Attenuates Renal Tubulointerstitial Injury via Inhibiting Mitochondrial Fission in Diabetic Mice.
  62. Protective effect of remifentanil on myocardial ischemia-reperfusion injury through Fas apoptosis signaling pathway.
  63. 22-oxacalcitriol protects myocardial ischemia-reperfusion injury by suppressing NF-κB/TNF-α pathway.
  64. Tension induces intervertebral disc degeneration via endoplasmic reticulum stress-mediated autophagy.
  65. Cadmium induces GAPDH- and- MDH mediated delayed cell aging and dysfunction in Candida tropicalis 3Aer.
  66. Beneficial effects of δ-tocotrienol against oxidative stress in osteoblastic cells: studies on the mechanisms of action.
  67. Shape-dependent toxicity of alumina nanoparticles in rat astrocytes.
  68. Self-defense of macrophages against oxidative injury: Fighting for their own survival.
  69. Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract.
  70. Tea polyphenol protects against cisplatin-induced meiotic defects in porcine oocytes.
  1. Oxid Med Cell Longev. 2019 ;2019 5083158
    Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma.
    Min Shen, Yiqiang Hu, Yan Yang, Lanlan Wang, Xin Yang, Bo Wang, Mei Huang.
      Betulinic acid (BA), as a prospective natural compound, shows outstanding antitumor bioactivities against many solid malignancies. However, its mechanism against multiple myeloma (MM) remains elusive. Herein, for the first time, we studied the antitumor activity of BA against MM both in vivo and in vitro. We showed that BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation. Moreover, when the ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed. Our results revealed that BA-mediated ROS overproduction played a pivotal role in anticancer activity. Molecularly, we found that BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM. As demonstrated by using the NF-κB pathway-specific activator TNF-α and the inhibitor BAY 11-7082, BA-mediated inhibition of the NF-κB pathway directly promoted the overproduction of ROS and, ultimately, cell death. Furthermore, BA also exerted enormous tumor-inhibitory effects via repressing proliferation and inhibiting the NF-κB pathway in our xenograft model. Overall, by blocking the NF-κB pathway that breaks redox homeostasis, BA, as a potent NF-κB inhibitor, is a promising therapeutic alternative for MM.
    DOI:  https://doi.org/10.1155/2019/5083158
  2. J Microbiol Biotechnol. 2019 Jul 09.
    Protective effect of 3-bromo-4,5-dihydroxybenzaldehyde from Polysiphonia morrowii Harvey against hydrogen peroxide-induced oxidative stress in in vitro and in vivo model zebrafish.
    Su-Hyeon Cho, Soo-Jin Heo, Hye-Won Yang, Eun-Yi Ko, Myeong Seon Jung, Seon-Heui Cha, Ginnae Ahn, You-Jin Jeon, Kil-Nam Kim.
      We investigated the protective effects of 3-bromo-4,5-dihydroxybenzaldehyde (BDB) from Polysiphonia morrowii Harvey against hydrogen peroxide (H2O2)-induced apoptosis in Vero cells. BDB exhibited scavenging activity for DPPH, hydroxyl, and alkyl radicals. BDB also inhibited H2O2-induced lipid peroxidation, cell death, and apoptosis in Vero cells by inhibiting the production of ROS. To evaluate the molecular mechanisms of apoptosis inhibition, the expression of Bax/Bcl-xL and NF-κB was assessed by western blot assay. BDB significantly inhibited the cleavage of caspase-9 and PARP and reduced Bax levels in H2O2-induced Vero cells. In addition, BDB suppressed the phosphorylation of NF-κB and the translocation of p65 in H2O2-induced cells. Furthermore, we evaluated the effect of BDB on ROS production, cell death, and lipid peroxidation in a H2O2-stimulated zebrafish embryo model. The results indicated that ROS generation and cell death were significantly inhibited by BDB in zebrafish embryos. These results prove that BDB has excellent antioxidant activity in vitro and in vivo.
    Keywords:  3-bromo-4,5-dihydroxybenzaldehyde; Polysiphonia morrow Harvey; antioxidant; oxidative stress; reactive oxygen species; zebrafish embryos
    DOI:  https://doi.org/10.4014/jmb.1904.04062
  3. Oxid Med Cell Longev. 2019 ;2019 6797921
    Increased Oxidative Stress Induced by Rubus Bioactive Compounds Induce Apoptotic Cell Death in Human Breast Cancer Cells.
    Blassan P George, Heidi Abrahamse.
      Bioactive compounds from plants represent good candidate drugs for the prevention and treatment of various forms of cancer. Berries are rich sources of bioactive compounds, and there has been an increasing interest in the study of therapeutic action of wild berries. Oxidants are generated continuously in biological system as a result of physiological process. When there is an imbalance between oxidants and antioxidants, it leads to a condition called oxidative stress. Natural compounds as inducers of oxidative stress are able to modulate the physiological functions of cancer cells leading to cell death or survival. The aim of this study was to evaluate the induction of apoptosis by isolated bioactive compounds (1-(2-hydroxyphenyl)-4-methylpentan-1-one (C1) and 2-[(3-methylbutoxy) carbonyl] benzoic acid (C2)) from Rubus fairholmianus against MCF-7 breast cancer cells. The exposure of C1 and C2 reduced viability (IC50 of C1: 4.69; C2: 8.36 μg/mL) and proliferation. Cytochrome c release from mitochondria and changes in mitochondrial membrane potential of treated cells supported the intrinsic apoptotic cell death. Reactive oxygen species (ROS) production after treatment with C1 and C2 was found to be higher and induced nuclear damage. Expression of apoptotic proteins after the treatments was significantly upregulated as indicated using immunofluorescence (caspase 9, p53, and Bax), western blotting (p53, cleaved PARP, cytochrome c, and Bax), and ELISA (caspase 9) analysis. Overall, C1 was more cytotoxic, increased the ROS production in dichlorodihydrofluorescein diacetate assay, and induced apoptosis in breast cancer cells. These results illustrate that berry bioactive compounds have strong chemopreventive potential. In this article, we provide information on prooxidant and anticancer activities of Rubus bioactive compounds. Natural products have always demonstrated a significant contribution to the development of several cancer chemotherapeutic drugs. Most of these compounds are known to affect the redox state of the cell; and studies on these compounds have focused on their antioxidant property instead of prooxidant properties.
    DOI:  https://doi.org/10.1155/2019/6797921
  4. Curr Eye Res. 2019 Jul 08. 1-12
    Protective Effects of Trimetazidine in Retarding Selenite-Induced Lens Opacification.
    Weifang Fang, Qin Ye, Yihua Yao, Yanghui Xiu, Feng Gu, Yihua Zhu.
      Purpose: Cataracts are the leading cause of vision loss worldwide, and the over-production of reactive oxygen species (ROS) is the foremost underlying cause of cataracts. Reducing ROS levels can efficiently prevent lens opacification, as evidenced by many studies. Here, we inhibited ROS overproduction with trimetazidine (TMZ), which is an antioxidant, to explore the therapeutic effects of TMZ and the mechanism of lens opacification. Materials and methods: Sodium selenite-induced cataract formation resulted in a significant loss of lens transparency. This effect could be efficiently rescued by TMZ, which was further found to be an inhibitor of ROS production, as determined by assaying oxidative stress-related parameters (SOD activity, MDA, ·OH and H2O2 levels) during cataract formation. The experimental protocols involving animal research were approved by the Animal Care and Ethics Committee of Wenzhou Medical University and conducted according to the Association for Research in Vision and Ophthalmology under the guidelines of the Animal Welfare Act (SYXK 2015-0009). Results: Our study found that TMZ can retard the onset and progression of lens opacification in vivo in experiments using Sprague-Dawley (SD) suckling rats and can rescue the morphology of HLEB3 cells in vitro. The flow cytometry and DNA fragmentation assays showed that TMZ could prevent sodium selenite-induced apoptosis. The western blot analysing showed that the levels of apoptosis-associated Bcl-2 and Nrf2 were dramatically decreased following the sodium selenite treatment. In addition, the bisulfate DNA sequencing revealed that the demethylation of CpGs in the promoter region of Keap1 was stimulated, and that this demethylation could be inhibited by TMZ by rescuing the Nrf2 expression level. Conclusions: Our findings indicate that the antioxidant TMZ strongly reduces ROS production, which ultimately delays the progression of cataract formation, suggesting that treatment with TMZ represents a novel, promising antioxidant protection to retard cataract formation.
    Keywords:  / pathway; Cataract; Trimetazidine (TMZ); reactive oxygen species
    DOI:  https://doi.org/10.1080/02713683.2019.1633359
  5. Zygote. 2019 Jul 12. 1-11
    Encircling granulosa cells protects against di-(2-ethylhexyl)phthalate-induced apoptosis in rat oocytes cultured in vitro.
    Anima Tripathi, Vivek Pandey, A N Sahu, Alok K Singh, Pawan K Dubey.
      SummaryThe present study investigated if the presence of encircling granulosa cells protected against di(2-ethylhexyl)phthalate (DEHP)-induced oxidative stress in rat oocytes cultured in vitro. Denuded oocytes and cumulus-oocyte complexes (COCs) were treated with or without various doses of DEHP (0.0, 25.0, 50.0, 100, 200, 400 and 800 μM) in vitro. Morphological apoptotic changes, levels of oxidative stress and reactive oxygen species (ROS), mitochondrial membrane potential, and expression levels of apoptotic markers (Bcl2, Bax, cytochrome c) were analyzed. Our results showed that DEHP induced morphological apoptotic changes in a dose-dependent manner in denuded oocytes cultured in vitro. The effective dose of DEHP (400 µg) significantly (P>0.05) increased oxidative stress by elevating ROS levels and the mitochondrial membrane potential with higher mRNA expression and protein levels of apoptotic markers (Bax, cytochrome c). Encircling granulosa cells protected oocytes from DEHP-induced morphological changes, increased oxidative stress and ROS levels, as well as increased expression of apoptotic markers. Taken together our data suggested that encircling granulosa cells protected oocytes against DEHP-induced apoptosis and that the presence of granulosa cells could act positively towards the survival of oocytes under in vitro culture conditions and may be helpful during assisted reproductive technique programmes.
    Keywords:   AO acridine orange; ART assisted reproduction technique; COCs cumulus–oocyte complexes; CTCF corrected total cell fluorescence; DCFH-DA dichlorofluorescein diacetate; DEHP di(2-ethylhexyl)phthalate; EDCs endocrine-disrupting chemicals; JC-1 5; MEHP mono(2-ethylhexyl)phthalate; OS oxidative stress; PI propidium iodide; ROS reactive oxygen species; TCM-199 tissue culture medium; 1; 3; 3-tetra-ethyl-benz-imidazolo-carbocyanine iodide; 5; 6; 6-tetra-chloro-1; Apoptosis; DEHP; Gene expression; Granulosa cells; Oocyte; Oxidative stress
    DOI:  https://doi.org/10.1017/S0967199419000121
  6. Adv Exp Med Biol. 2019 ;1166 75-85
    Sperm DNA Fragmentation: Mechanisms of Origin.
    Monica Muratori, Sara Marchiani, Lara Tamburrino, Elisabetta Baldi.
      Spermatozoa have the task to deliver an intact paternal genome to the oocyte and to support a successful embryo development. The high levels of sperm DNA fragmentation (sDF) found in sub-/infertile men threat human reproduction and health of the offspring. Strategies to prevent the onset of this type of sperm damage are extensively sought.sDF can be induced by factors like lifestyle-related habits, diseases, drugs, aging, infections and exposure to pollutants. At the cell level, all these factors induce sperm DNA breaks by three main mechanisms: apoptosis, impairment of sperm chromatin maturation and oxidative stress. Apoptosis and defects in maturation of sperm chromatin appear to act in the testis and account for DNA breaks found in dead ejaculated spermatozoa, whereas oxidative stress is likely inducing sDF during the transit through the male genital tracts and accounting for DNA breaks observed in viable spermatozoa of the ejaculate. Oxidative stress appears to be also the main mechanism responsible for induction of sDF after ejaculation, during in vitro manipulation of spermatozoa. Whether or not mature spermatozoa are able to trigger a cell death program is not yet clarified. In particular, it is not clear whether apoptotic nucleases or reactive oxygen species are responsible for producing DNA breaks in ejaculated mature spermatozoa. Knowledge of the mechanisms inducing sDF is a valuable starting point to define possible therapeutic options that however are still far to be established.
    Keywords:  Abortive apoptosis; Chromatin maturation; Male infertility; Oxidative stress; Reactive oxygen species; Sperm DNA fragmentation
    DOI:  https://doi.org/10.1007/978-3-030-21664-1_5
  7. Front Pharmacol. 2019 ;10 663
    Polydatin Attenuates Neuronal Loss via Reducing Neuroinflammation and Oxidative Stress in Rat MCAO Models.
    Fawad Ali Shah, Lina Al Kury, Tao Li, Alam Zeb, Phil Ok Koh, Fang Liu, Qiang Zhou, Ishtiaq Hussain, Arif Ullah Khan, Yuhua Jiang, Shupeng Li.
      Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, starting from acute ATP loss and ionic imbalance to subsequent membrane depolarization, glutamate excitotoxicity, and calcium overload. These initial events are followed by neuroinflammation and oxidative stress, eventually causing neuronal neurosis and apoptosis. Complicated interplays exist between these steps happening across various stages, which not only represent the complicated nature of ischemic pathology but also warrant a detailed delineation of the underlying molecular mechanisms to develop better therapeutic options. In the present study, we examined the neuroprotective effects of polydatin against ischemic brain injury using a rat model of permanent middle cerebral artery occlusion (MCAO). Our results demonstrated that polydatin treatment reduced the infarction volume and mitigated the neurobehavioral deficits, sequentially rescued neuronal apoptosis. Ischemic stroke induced an elevation of neuroinflammation and reactive oxygen species, which could be attenuated by polydatin via the reduced activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In addition, polydatin upregulated the endogenous antioxidant nuclear factor erythroid 2-related factor 2, heme oxygenase-1, the thioredoxin pathway, and eventually reversed ischemic-stroke-induced elevation of ROS and inflammation in ischemic cortical tissue. The diverse and broad actions of polydatin suggested that it could be a multiple targeting neuroprotective agent in ameliorating the detrimental effects of MCAO, such as neuroinflammation, oxidative stress, and neuronal apoptosis. As repetitive clinical trials of neuroprotectants targeting a single step of stroke pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles in MCAO.
    Keywords:  ischemic stroke; neuroinflammation; neuronal death; oxidative stress; polydatin
    DOI:  https://doi.org/10.3389/fphar.2019.00663
  8. J Cell Biochem. 2019 Jul 09.
    Biochemical regulation and structural analysis of copper-transporting ATPase in a human hepatoma cell line for Wilson disease.
    Shikha Agnihotry, Kalyani Dhusia, Ajeet K Srivastav, Jaya Upadhyay, Vinod Verma, Pradeep K Shukla, Pramod W Ramteke, Budhayash Gautam.
      Hepatic copper levels differ among patients with Wilson disease (WD) and normal individuals depending on the dietary intake, copper bioavailability, and genetic factors. Copper chloride (CuCl2 ) caused dose-dependent reduction in cell viability of human teratocarcinoma (HepG2) cell line, measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Cells were exposed to different concentrations of CuCl2 in log doses and maximum cell viability reduction was recorded at 15 µg/mL. Toxic dose of CuCl2 is potent inducer of reactive oxygen species (ROS). Apoptosis as a pattern of cell death was confirmed through sub-G1 fraction and morphological changes such as mitochondrial depolarization, endoplasmic reticulum and lysosomal destabilization, phosphatidylserine translocation, and DNA damage. Our transcriptional and translational results strongly support apoptotic cell death. Using the available data present in dbSNP and bioinformatics tools, three nonsynonymous single nucleotide polymorphisms (nsSNPs) were identified as deleterious, reducing the stability of protein ATP7B. Structural analysis of native and mutant ATP7B proteins was investigated using molecular dynamics simulation (MDS) approach. Mutation in ATP7B gene might disturb the structural conformation and catalytic function of the ATP7B protein may be inducing WD. Hence, excess dietary intake of copper chloride must be avoided for safety of health to prevent from WD.
    Keywords:  ATP7B; DNA damage; Wilson disease; apoptosis; oxidative stress
    DOI:  https://doi.org/10.1002/jcb.29199
  9. Oxid Med Cell Longev. 2019 ;2019 5719483
    Ethanolic Extract of Senna velutina Roots: Chemical Composition, In Vitro and In Vivo Antitumor Effects, and B16F10-Nex2 Melanoma Cell Death Mechanisms.
    David Tsuyoshi Hiramatsu Castro, Jaqueline Ferreira Campos, Marcio José Damião, Heron Fernandes Vieira Torquato, Edgar Julian Paredes-Gamero, Carlos Alexandre Carollo, Elaine Guadelupe Rodrigues, Kely de Picoli Souza, Edson Lucas Dos Santos.
      Cutaneous melanoma is among the most aggressive types of cancer, and its rate of occurrence increases every year. Current pharmacological treatments for melanoma are not completely effective, requiring the identification of new drugs. As an alternative, plant-derived natural compounds are described as promising sources of new anticancer drugs. In this context, the objectives of this study were to identify the chemical composition of the ethanolic extract of Senna velutina roots (ESVR), to assess its in vitro and in vivo antitumor effects on melanoma cells, and to characterize its mechanisms of action. For these purposes, the chemical constituents were identified by liquid chromatography coupled to high-resolution mass spectrometry. The in vitro activity of the extract was assessed in the B16F10-Nex2 melanoma cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and based on the apoptotic cell count; DNA fragmentation; necrostatin-1 inhibition; intracellular calcium, pan-caspase, and caspase-3 activation; reactive oxygen species (ROS) levels; and cell cycle arrest. The in vivo activity of the extract was assessed in models of tumor volume progression and pulmonary nodule formation in C57Bl/6 mice. The chemical composition results showed that ESVR contains flavonoid derivatives of the catechin, anthraquinone, and piceatannol groups. The extract reduced B16F10-Nex2 cell viability and promoted apoptotic cell death as well as caspase-3 activation, with increased intracellular calcium and ROS levels as well as cell cycle arrest at the sub-G0/G1 phase. In vivo, the tumor volume progression and pulmonary metastasis of ESVR-treated mice decreased over 50%. Combined, these results show that ESVR had in vitro and in vivo antitumor effects, predominantly by apoptosis, thus demonstrating its potential as a therapeutic agent in the treatment of melanoma and other types of cancer.
    DOI:  https://doi.org/10.1155/2019/5719483
  10. Toxicol Appl Pharmacol. 2019 Jul 05. pii: S0041-008X(19)30255-8. [Epub ahead of print] 114647
    ROS -mediated p53 activation by juglone enhances apoptosis and autophagy in vivo and in vitro.
    Peng Wang, Sun-Dong Zhang, Jiao Jiao, Wei Wang, Liang Yu, Xue-Lian Zhao, Li-Tao Wang, Dong Meng, Yu-Jie Fu.
      Juglone (JG) exhibits a broad-spectrum of cytotoxicity against some cancer cells. However, its molecular mechanisms have not been investigated well. Here, the present results showed that JG significantly inhibited tumor growth in vivo. CCK-8 assays, flow cytometric analysis, western blotting and immunohistochemistry revealed that JG effectively inhibited cell proliferation and induced apoptosis through extrinsic pathways. We also observed that JG treatment induced autophagy flux via activiting the AMPK-mTOR signaling pathway. In addition, we found that JG enhanced p53 activation by increasing down-regulation of ubiquitin-mediated degradation. Inhibition of p53 by siRNA attenuated JG-induced cell death and autophagy. Moreover, JG enhanced the generation of hydrogen peroxide (H2O2) and superoxide anion radical (O2• -). Further experiments proved that H2O2 was a major factor since the H2O2 scavenger catalase (CAT) reduced both autophagy and cell death to a greater extent than the O2• - scavenger SOD. Overall, our results illustrated that JG caused apoptosis and autophagy via activating the ROS-mediated p53 pathway in human liver cancer cells in vitro and in vivo, which provided basic scientific evidence that JG serves as a potential anti-cancer agent.
    Keywords:  Apoptosis; Autophagy; HepG2 cells; Juglone; Reactive oxygen species; p53
    DOI:  https://doi.org/10.1016/j.taap.2019.114647
  11. Mitochondrion. 2019 Jul 06. pii: S1567-7249(19)30009-1. [Epub ahead of print]
    Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling.
    Yuanbo Wu, Meiqiao Chen, Jielong Jiang.
      Mitochondrial dysfunction is becoming one of the most emerging pathological process in the etiology of neurological disorders. Other common etiologies of the neurological disorders are aging and oxidative stress. Neurodegenerative disorders for instance Huntington's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Epilepsy, Schizophrenia, Multiple sclerosis, Neuropathic pain and Alzheimer's disease involves mitochondrial dysfunction and is regarded as the core of their pathological processes. Most central pathological feature of the neurodegenerative diseases is apoptosis which is regulated by mitochondria. Altered signaling of the apoptotic mechanisms are involved in neurodegeneration. Abnormal levels of these molecular apoptotic proteins promotes the pathogenesis of neurological disorders. Mitochondria are also implicated in the production of reactive oxygen species (ROS). Raised ROS levels initiates the cascade leading to the non-apoptotic death of cells. ROS produced in cells acts as signaling molecules, but when produced in abundance will result in cellular consequences to deoxyribonucleic acid, proteins and lipids, decreased effectiveness of cellular mechanisms, initiation of inflammatory pathways, excitotoxicity, protein agglomeration and apoptosis. Protecting mitochondrial function has been identified as the most effective therapeutic approach to attenuate the pathogenesis of neurodegenerative diseases. This review aims to provide an insight into the mitochondrial dysfunction in the pathogenesis of neurological disorders, alteration in signaling cascades of apoptosis in mitochondrial dysfunction and the therapeutic strategies (both natural and synthetic drugs) targeting these mitochondrial apoptotic pathways and oxidative stress that holds great promise.
    Keywords:  Mitochondrial apoptotic pathway; Mitochondrial dysfunction; Neurodegenerative disorder; Oxidative stress and neuroprotection
    DOI:  https://doi.org/10.1016/j.mito.2019.07.003
  12. Biomolecules. 2019 Jul 07. pii: E261. [Epub ahead of print]9(7):
    Ameliorative Effect of Beta vulgaris Root Extract on Chlorpyrifos-Induced Oxidative Stress, Inflammation and Liver Injury in Rats.
    Gadah Albasher, Rafa Almeer, Fatimah O Al-Otibi, Noorah Al-Kubaisi, Ayman M Mahmoud.
      Exposure to organophosphorus insecticides causes several health problems to animals and humans. Red beetroot (RBR) is rich in antioxidant ingredients and possesses a promising hepatoprotective activity. This study evaluated the potential of RBR extract to prevent chlorpyrifos (CPF)-induced liver injury, with an emphasis on oxidative stress, inflammation and apoptosis. Rats received 10 mg/kg CPF and were treated with 300 mg/kg RBR extract for 28 days. CPF caused liver injury evidenced by elevated serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and bilirubin, along with several histological alterations. Hepatic lipid peroxidation (LPO) and nitric oxide (NO) levels, as well as inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines were increased in CPF-intoxicated rats. RBR prevented CPF-induced histological alterations, and ameliorated liver function, LPO, NO, iNOS and pro-inflammatory cytokines. RBR boosted glutathione and antioxidant enzymes, and increased Nrf2 expression. In addition, RBR diminished Bax and caspase-3, and increased Bcl-2 expression. In conclusion, RBR prevented CPF-induced liver injury via attenuation of oxidative stress, inflammation and apoptosis. RBR enhanced antioxidant defenses, suggesting that it could be used as a potential therapeutic intervention to minimize CPF hepatotoxicity.
    Keywords:  Nrf2; apoptosis; chlorpyrifos; oxidative stress; red beetroot
    DOI:  https://doi.org/10.3390/biom9070261
  13. Food Funct. 2019 Jul 10.
    Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and suppression of NF-κB/NLRP3 inflammasome axis.
    Ayman M Mahmoud, Omnia E Hussein, Sanaa M Abd El-Twab, Walaa G Hozayen.
      Drug-induced nephrotoxicity contributes to acute kidney injury (AKI) and represents a major problem in the clinical setting. We investigated the possible involvement of NLRP3 inflammasome activation in methotrexate (MTX)-induced nephrotoxicity and the protective potential of ferulic acid (FA), pointing out the role of PPARγ and Nrf2/HO-1 signaling. Rats that received MTX showed a significant increase in circulating creatinine and urea, and kidney Kim-1 levels along with multiple histological alterations. Reactive oxygen species (ROS), malondialdehyde and nitric oxide levels showed a significant increase in the kidney of rats that received MTX, while antioxidant defenses were diminished. FA ameliorated kidney function markers, prevented histological alterations, suppressed ROS production and enhanced antioxidant defenses. FA inhibited MTX-induced inflammasome activation as showed by the decreased phosphorylation of NF-κB, and expression of NLRP3, caspase-1 and IL-1β. MTX caused apoptosis marked by increased expression of BAX, cytochrome c and caspase-3, and suppressed Bcl-2, effects that were significantly reversed in FA-treated groups. In addition, FA up-regulated Nrf2/ARE/HO-1 signaling and PPARγ expression in the kidney of MTX-induced rats. In conclusion, activation of NLRP3 inflammasome may represent a new mechanism for MTX nephrotoxicity. FA up-regulated PPARγ and Nrf2 signaling, prevented overproduction of ROS, and suppressed NF-κB/NLRP3 inflammasome axis and apoptosis in the kidney of MTX-induced rats.
    DOI:  https://doi.org/10.1039/c9fo00114j
  14. Biochem Biophys Res Commun. 2019 Jul 05. pii: S0006-291X(19)31317-8. [Epub ahead of print]
    Sulfiredoxin-1 alleviates high glucose-induced podocyte injury though promoting Nrf2/ARE signaling via inactivation of GSK-3β.
    Yan Shen, Shengnan Chen, Yan Zhao.
      Hyperglycemia-induced podocyte injury plays a vital role in the development of diabetic nephropathy. Sulfiredoxin-1 (Srxn1) is emerging as a cytoprotective protein that protects from various insults in a wide range of cell types. However, whether Srxn1 is involved in regulating hyperglycemia-induced podocyte injury and participates in diabetic nephropathy remains unknown. In the present study, we aimed to explore the potential role of Srxn1 in regulating high glucose (HG)-induced apoptosis and oxidative stress of podocytes in vitro. Results demonstrated that Srxn1 was induced in HG-stimulated podocytes. The depletion of Srxn1 by Srxn1 siRNA-mediated gene silencing significantly exacerbated HG-induced apoptosis and the production of reactive oxygen species (ROS), while Srxn1 overexpression attenuated HG-induced apoptosis and ROS production. In-depth molecular mechanism research revealed that Srxn1 overexpression promoted the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and reinforced antioxidant response element (ARE)-mediated transcription activity. Moreover, results confirmed that Srxn1 increased the activation of Nrf2/ARE signaling associated with inactivating glycogen synthase kinase (GSK)-3β. Notably, the inhibition of GSK-3β significantly reversed Srxn1 silencing-induced adverse effects in HG-treated cells, while the knockdown of Nrf2 abrogated the Srxn1-mediated protective effect against HG-induced podocyte injury. Taken together, our results demonstrated that Srxn1 protects podocytes from HG-induced injury by promoting the activation of Nrf2/ARE signaling associated with inactivating GSK-3β, indicating a potential role of Srxn1 in diabetic nephropathy. Our study suggests that Srxn1 may serve as a potential target for kidney protection.
    Keywords:  Diabetic nephropathy; GSK-3β; High glucose; Nrf2; Srxn1
    DOI:  https://doi.org/10.1016/j.bbrc.2019.06.157
  15. Connect Tissue Res. 2019 Jul 11. 1-14
    Naringin alleviates H2O2-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus-derived mesenchymal stem cells.
    Li-Ping Nan, Feng Wang, Di Ran, Shi-Feng Zhou, Yang Liu, Zhen Zhang, Ze-Nan Huang, Ze-Yu Wang, Jing-Cheng Wang, Xin-Min Feng, Liang Zhang.
      Purpose: To investigate the protective effect of naringin (Nar) on H2O2-induced apoptosis of nucleus pulposus-derived mesenchymal stem cells (NPMSC) and the potential mechanism in this process. Methods: Rat NPMSC were cultured in MSC culture medium or culture medium with different concentrations of H2O2. Nar or the combination of Nar and LY294002 was added into the culture medium to investigate the effects of Nar. Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The apoptosis rate was determined using Annexin V/PI dual staining and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays. Additionally, the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. ATP level in NPMSC was analyzed via ATP detection kit. Mitochondrial ultrastructure change was observed through transmission electron microscope (TEM). Levels of apoptosis-associated molecules (cleaved caspase-3, Bax and Bcl-2) were evaluated via RT-PCR and western blot, respectively. Results: The cells isolated from NP met the criteria for MSC. H2O2 significantly promoted NPMSC apoptosis in a dose and time-dependent manner. Nar showed no cytotoxicity effect on NPMSC up to a concentration of 100 μM for 24 h. Nar exhibited protective effects against H2O2-induced NPMSC apoptosis including apoptosis rate, expressions of proapoptosis and antiapoptosis related genes and protein. Nar could also alleviate H2O2-induced mitochondrial dysfunction of increased mitochondrial ROS production, reduced MMP, decreased intracellular ATP and mitochondrial ultrastructure change. However, these protected effects were inhibited after LY294002 treatment. Conclusions: Our results demonstrated that Nar efficiently attenuated H2O2-induced NPMSC apoptosis and mitochondrial dysfunction. The activation of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.
    Keywords:  Naringin; PI3K/Akt pathway; intervertebral disc degeneration; nucleus pulposus-derived mesenchymal stem cells; oxidative stress
    DOI:  https://doi.org/10.1080/03008207.2019.1631299
  16. Oxid Med Cell Longev. 2019 ;2019 1659468
    Oxidative Stress Induced by the Deubiquitinase Inhibitor b-AP15 Is Associated with Mitochondrial Impairment.
    Xiaonan Zhang, Belén Espinosa, Amir Ata Saei, Padraig D'Arcy, Roman A Zubarev, Stig Linder.
      Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies. The small molecule b-AP15 is an inhibitor of proteasome-associated DUB activity that induces both proteotoxic stress and increases in the levels of reactive oxygen species (ROS) in tumor cells. Antioxidants have been shown to decrease apoptosis induction by b-AP15 and we here addressed the question of the mechanism of redox perturbation by this compound. We show that oxidative stress induction by b-AP15 is abrogated in cells deprived of mitochondrial DNA (ρ 0 cells). We also show associations between the level of proteotoxic stress, the degree of mitochondrial dysfunction, and the extent of induction of hemeoxygenase-1 (HO-1), a target of the redox-regulated Nrf-2 transcription factor. Decreased expression of COX5b (cytochrome c oxidase subunit 5b) and TOMM34 (translocase of outer mitochondrial membrane 34) was observed in b-AP15-treated cells. These findings suggest a mitochondrial origin of the increased levels of ROS observed in cells exposed to the DUB inhibitor b-AP15.
    DOI:  https://doi.org/10.1155/2019/1659468
  17. Oxid Med Cell Longev. 2019 ;2019 4101738
    AKT-GSK3β Signaling Pathway Regulates Mitochondrial Dysfunction-Associated OPA1 Cleavage Contributing to Osteoblast Apoptosis: Preventative Effects of Hydroxytyrosol.
    W J Cai, Y Chen, L X Shi, H R Cheng, I Banda, Y H Ji, Y T Wang, X M Li, Y X Mao, D F Zhang, P P Dai, X Y Sun, X H Ning, S B Huang, J F Ma, S F Zhao.
      Oxidative stress (OS) induces osteoblast apoptosis, which plays a crucial role in the initiation and progression of osteoporosis. Although OS is closely associated with mitochondrial dysfunction, detailed mitochondrial mechanisms underlying OS-induced osteoblast apoptosis have not been thoroughly elucidated to date. In the present study, we found that mitochondrial abnormalities largely contributed to OS-induced osteoblast apoptosis, as evidenced by enhanced production of mitochondrial reactive oxygen species; considerable reduction in mitochondrial respiratory chain complex activity, mitochondrial membrane potential, and adenosine triphosphate production; abnormality in mitochondrial morphology; and alteration of mitochondrial dynamics. These mitochondrial abnormalities were primarily mediated by an imbalance in mitochondrial fusion and fission through a protein kinase B- (AKT-) glycogen synthase kinase 3β- (GSK3β-) optic atrophy 1- (OPA1-) dependent mechanism. Hydroxytyrosol (3,4-dihydroxyphenylethanol (HT)), an important compound in virgin olive oil, significantly prevented OS-induced osteoblast apoptosis. Specifically, HT inhibited OS-induced mitochondrial dysfunction by decreasing OPA1 cleavage and by increasing AKT and GSK3β phosphorylation. Together, our results indicate that the AKT-GSK3β signaling pathway regulates mitochondrial dysfunction-associated OPA1 cleavage, which may contribute to OS-induced osteoblast apoptosis. Moreover, our results suggest that HT could be an effective nutrient for preventing osteoporosis development.
    DOI:  https://doi.org/10.1155/2019/4101738
  18. Int J Mol Sci. 2019 Jul 08. pii: E3348. [Epub ahead of print]20(13):
    VDAC1 and the TSPO: Expression, Interactions, and Associated Functions in Health and Disease States.
    Varda Shoshan-Barmatz, Srinivas Pittala, Dario Mizrachi.
      The translocator protein (TSPO), located at the outer mitochondrial membrane (OMM), serves multiple functions and contributes to numerous processes, including cholesterol import, mitochondrial metabolism, apoptosis, cell proliferation, Ca2+ signaling, oxidative stress, and inflammation. TSPO forms a complex with the voltage-dependent anion channel (VDAC), a protein that mediates the flux of ions, including Ca2+, nucleotides, and metabolites across the OMM, controls metabolism and apoptosis and interacts with many proteins. This review focuses on the two OMM proteins TSPO and VDAC1, addressing their structural interaction and associated functions. TSPO appears to be involved in the generation of reactive oxygen species, proposed to represent the link between TSPO activation and VDAC, thus playing a role in apoptotic cell death. In addition, expression of the two proteins in healthy brains and diseased states is considered, as is the relationship between TSPO and VDAC1 expression. Both proteins are over-expressed in in brains from Alzheimer's disease patients. Finally, TSPO expression levels were proposed as a biomarker of some neuropathological settings, while TSPO-interacting ligands have been considered as a potential basis for drug development.
    Keywords:  TSPO; VDAC1; mitochondria
    DOI:  https://doi.org/10.3390/ijms20133348
  19. Saudi Pharm J. 2019 Jul;27(5): 682-693
    Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies.
    Hamad M Alkahtani, Mohammed M Alanazi, Fadilah Sfouq Aleanizy, Fulwah Yahya Alqahtani, Ali Alhoshani, Fawaz E Alanazi, Abdulrahman A Almehizia, Ashraf N Abdalla, Mashael G Alanazi, Adel S El-Azab, Alaa A-M Abdel-Aziz.
      A new series of 5,5-diphenylhydantoin derivatives containing benzylidene or isatin (4-19) was synthesized. Their anticancer activity against HeLa, a cervical cancer cell line, A549, a lung cancer cell line, and MDA-MB-231, a breast cancer cell line, was evaluated. Compounds 13, 16, 17 and 18 exhibited potent anticancer activity with average IC50 values against the tested cell lines of 109, 59, 81 and 113 μM, respectively. Compound 16 showed potent EGFR and VEGFR2 inhibitory activity with IC50 values of 6.17 and 0.09 μM, respectively. In addition, compound 16 induced caspase-dependent apoptosis and reactive oxygen species (ROS) production at 5 and 10 μM. Moreover, a molecular docking simulation was performed for compound 16 and sunitinib to predict the protein-ligand interactions with the active site of VEGFR2.
    Keywords:  5,5-Diphenylhydantoin; Apoptosis; EGFR; Isatin; Molecular docking; VEGFR2
    DOI:  https://doi.org/10.1016/j.jsps.2019.04.003
  20. In Vivo. 2019 Jul-Aug;33(4):33(4): 1183-1192
    Peroxiredoxin V Inhibits Emodin-induced Gastric Cancer Cell Apoptosis via the ROS/Bcl2 Pathway.
    Yong-Zhe Jin, Hu-Nan Sun, Yue Liu, Dong-Ho Lee, Ji-Su Kim, Sun-Uk Kim, Bing-Yang Jiao, Ying-Hao Han, Mei-Hua Jin, Gui-Nan Shen, Dong-Seok Lee, Taeho Kwon, Dong-Yuan Xu, Y U Jin.
       BACKGROUND/AIM: Peroxiredoxin (Prx) protein family is aberrantly expressed in various cancers including gastric cancer. Among the six family members, Prx V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS) and modulates cellular apoptosis. This study aimed at investigating the role of Prx V in apoptosis of gastric cancer cells.
    MATERIALS AND METHODS: Stably constructed Prx V knockdown, over-expression and mock AGS cells (a human gastric adenocarcinoma cell line) were used to study the effect of Prx V on emodin-induced apoptosis by western blotting, cell viability, apoptosis and ROS detection assays.
    RESULTS: Overexpression of Prx V significantly decreased emodin-induced cellular apoptosis and ROS levels compared to Mock and Prx V knockdown AGS cells. Also, overexpression of Prx V down-regulated the expression of pro-apoptotic proteins, Bad and cleaved PARP, and increased the expression of anti-apoptotic protein, Bcl2.
    CONCLUSION: Prx V suppresses AGS cell apoptosis via scavenging intracellular ROS and modulating apoptosis-related markers.
    Keywords:  Peroxiredoxin V; ROS; apoptosis; emodin; gastric cancer
    DOI:  https://doi.org/10.21873/invivo.11589
  21. Chem Biodivers. 2019 Jul 09.
    Pristimerin induces autophagy-mediated cell death in K562 cells through the ROS/JNK signaling pathway.
    Xianjun Yu, Yingxiang Liu, Ziting Ren, Xiang Li, Jing Zhong, Yun Bi, Rui Li, Qun Zhao.
      Chronic myeloid leukemia (CML) is a lethal malignancy, and the progress toward long-term survival has stagnated in recent decades. Pristimerin, a quinone methide triterpenoid isolated from the Celastraceae and Hippocrateaceae families, is well known to exert potential anticancer activities. In this study, we investigated the effects and the mechanisms of action on CML. We found that pristimerin inhibited cell proliferation of K562 CML cells by causing G1 phase arrest. Furthermore, we demonstrated that pristimerin triggered autophagy and apoptosis. Intriguingly, pristimerin-induced cell death was restored by an autophagy inhibitor, suggesting that autophagy is crosslinked with pristimerin-induced apoptosis. Further studies revealed that pristimerin could produce excessive reactive oxygen species (ROS), which then induce JNK activation. These findings provide clear evidence that pristimerin might be clinical benefit to patients with CML.
    Keywords:  Apoptosis; Autophagy; K562; Pristimerin; ROS/JNK
    DOI:  https://doi.org/10.1002/cbdv.201900325
  22. J Cancer. 2019 ;10(15): 3427-3434
    Nuclear Nrf2 Activity in Laryngeal Carcinoma is Regulated by SENP3 After Cisplatin-Induced Reactive Oxygen Species Stress.
    Zheng Zhou, Ji Xu, Ximing Bao, Jiali Shi, Bin Liu, Yanqing Chen, Jiping Li.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor that is activated by reactive oxygen species (ROS). Recent studies reported that hyperactivation of the Nrf2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy. SUMO1/sentrin/SMT3 specific peptidase 3 (SENP3) reverses sumoylation of small ubiquitin-like modifier (SUMO)-conjugates. We demonstrated that Nrf2 was detected in the nuclei of laryngeal carcinoma cells, but not in cells of tissues surrounding the cancer, which correlated with the appearance of SENP3 in the nuclei. Silencing of Nrf2 in laryngeal carcinoma cell line Hep-2 significantly reduced cell viability and enhanced apoptosis rates under cisplatin, 5-fluorouracil (5-FU) and phenethyl isothiocyanate (PEITC) exposure. Cisplatin exposure induced ROS stress in Hep-2 cells in a time-dependent manner and was accompanied by increased Nrf2 and SENP3 protein accumulations, an effect reversed by the addition of the antioxidant N-acetyl-cysteine (NAC). Silencing of SENP3 led to reduced Nrf2 protein levels, whereas overexpression of SENP3 led to concomitant enhanced transcription of the Nrf2 target genes HO-1, NQO1, GCLC and GSTM1. Immunoprecipitation showed that overexpressed Nrf2 and SENP3 could be precipitated together, indicating that they were intracellular bound to each other. Our data identified intranuclear activation of Nrf2 is triggered by cisplatin-induced ROS development through the activity of SENP3. These findings provide novel insights into the Nrf2 reduced cancer cell response to the chemotherapy of laryngeal carcinoma.
    Keywords:  Hep-2 cells; Nrf2; ROS; SENP3; cisplatin
    DOI:  https://doi.org/10.7150/jca.30318
  23. Life Sci. 2019 Jul 04. pii: S0024-3205(19)30549-1. [Epub ahead of print] 116623
    Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats.
    Masoud Fallah Rajabpour Zare, Kamran Rakhshan, Nahid Aboutaleb, Farnaz Nikbakht, Nasim Naderi, Morteza Bakhshesh, Yaser Azizi.
       AIMS: Doxorubicin, an antibiotic belonging to anthracycline family, has been used for treatment of malignancies. Cardiotoxicity is the main adverse effect of doxorubicin. Apigenin, as a flavonoid, has antioxidant, anti-inflammatory and anti-tumoral properties. The aim of this study was the assessment of any protective effect of apigenin on cardiotoxicity induced by doxorubicin.
    MAIN METHODS: 40 male Wistar rats were randomly divided into 4 groups: control, cardiotoxicity (DOX), apigenin treated group (DOX + Api 25) and apigenin group (Api 25). At the end of the experiment, the markers of cardiac function (%EF, %FS, LVIDs, LVIDd), cardiac and liver injury (LDH, CK-MB, cTn-I, ALT, and AST), cardiac apoptosis (Bax, Bcl-2 and Caspase3), cardiac oxidative stress (SOD, GSH, MDA) and cardiac fibrosis were measured.
    KEY FINDINGS: Apigenin improved cardiac functional parameters. The levels of cardiac and liver injury markers were significantly decreased in DOX + Api 25 compared to DOX. Treatment with apigenin caused significant decrease in percentage of cardiac fibrosis in comparison with DOX. Apigenin in DOX + Api 25 group led to significant decrease in apoptotic proteins (Casp3, Bax) and a significant increase in anti-apoptotic proteins (Bcl2). In apigenin treatment groups, SOD levels significantly increased while a significant decrease was observed in MDA. The amount of GSH in DOX + Api 25 had no significant change in comparison to control and Api 25 groups.
    SIGNIFICANCE: Apigenin reduced cardiac injuries induced by DOX through anti-fibrotic, antioxidant and anti-apoptotic properties. It seems that apigenin prevents cardiac injuries and improves cardiac function.
    Keywords:  Apigenin; Apoptosis; Cardiac injury; Cardiotoxicity; Doxorubicin; Fibrosis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.lfs.2019.116623
  24. Int J Mol Sci. 2019 Jul 10. pii: E3386. [Epub ahead of print]20(14):
    Anti-Apoptotic Effect of G-Protein-Coupled Receptor 40 Activation on Tumor Necrosis Factor-α-Induced Injury of Rat Proximal Tubular Cells.
    Chang Seong Kim, Soo Yeon Joo, In Jin Kim, Hoon-In Choi, Eun Hui Bae, Soo Wan Kim, Seong Kwon Ma.
      G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic β-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway.
    Keywords:  G-protein-coupled receptor 40; angiotensin II type 1 receptor; apoptosis; proximal kidney tubule; tumor necrosis factor-alpha; ureteral obstruction
    DOI:  https://doi.org/10.3390/ijms20143386
  25. Environ Sci Pollut Res Int. 2019 Jul 09.
    Microarray analysis of apoptosis gene expression in liver injury induced by chronic exposure to arsenic and high-fat diet in male mice.
    Heibatullah Kalantari, Mohammad Javad Khodayar, Najmaldin Saki, Layasadat Khorsandi, Ali Teymoori, Hadis Alidadi, Azin Samimi.
      Rapid growth in the incidence of liver disease is largely attributable to lifestyle and environmental contaminants, which are often overlooked as the leading causes of this problem. Thus, the possible contribution of arsenic (As) to high-fat diet (HFD)-induced liver damage was examined via microarray analysis. To perform this experiment, a total number of 40 healthy adult male NMRI mice (22-30 g) were used. To this end, these animals were randomly assigned to four groups of 10. Oxidative stress and histopathological parameters were also evaluated in the liver of the mice exposed to a minimally cytotoxic concentration of As (50 ppm) in drinking water while being fed with a HFD for 20 weeks. Subsequently, apoptosis gene expression profiling was utilized via real-time (RT) PCR array analysis. The results showed that As had increased the amount of HFD-induced liver damage and consequently amplified changes in oxidative stress factors, histopathological parameters, as well as apoptosis pathway genes. Investigating the expression profile of apoptosis pathway genes similarly revealed that caspase-8, as a main upstream contributor to the apoptosis pathway, might play an important role in the induction of apoptosis generated by As and HFD. Ultimately, this study highlighted that As in drinking water could increase sensitivity in mice to HFD-induced liver disease through strengthening apoptosis pathway.
    Keywords:  Apoptosis; Arsenic; High-fat diet; Microarray analysis; Oxidative stress
    DOI:  https://doi.org/10.1007/s11356-019-05907-3
  26. Environ Toxicol. 2019 Jul 12.
    Thymoquinone suppresses the proliferation of renal cell carcinoma cells via reactive oxygen species-induced apoptosis and reduces cell stemness.
    Yih-Farng Liou, Pei-Ni Chen, Shu-Chen Chu, Shao-Hsuan Kao, Yan-Zin Chang, Yih-Shou Hsieh, Horng-Rong Chang.
      Thymoquinone is a phytochemical compound isolated from Nigella sativa and has various biological effects, including anti-inflammation, antioxidation, and anticancer. Here, we further investigated the anticancer effects and associated molecular mechanism of 2-methyl-5-isopropyl-1,4-benzoquinone (thymoquinone) on human renal carcinoma cell lines 786-O and 786-O-SI3 and transitional carcinoma cell line BFTC-909. Results showed that thymoquinone significantly reduced cell viability, inhibited the colony formation of renal cancer cells, and induced cell apoptosis and mitochondrial membrane potential change in both cancer cells. In addition, thymoquinone also triggered the production of reactive oxygen species (ROS) and superoxide and the activation of apoptotic and autophagic cascade. ROS inhibition suppressed the caspase-3 activation and restored the decreased cell viability of 786-O-SI3 in response to thymoquinone. Autophagy inhibition did not restore the cell viability of 786-O-SI3 suppressed by thymoquinone. Moreover, thymoquinone suppressed the cell sphere formation and the expression of aldehyde dehydrogenase, Nanog, Nestin, CD44, and Oct-4 in 786-O-SI3 cells. The tumor-bearing model showed that thymoquinone in vivo inhibited the growth of implanted 786-O-SI3 cell. All these findings indicate that thymoquinone inhibits the proliferation of 786-O-SI3 and BFTC-909 cell possibly due to the induction of ROS/superoxide and the consequent apoptosis, suggesting that thymoquinone may be a potential anticancer supplement for genitourinary cancer.
    Keywords:  apoptosis; kidney carcinoma cells; reactive oxygen species; stemness; thymoquinone
    DOI:  https://doi.org/10.1002/tox.22822
  27. Environ Sci Pollut Res Int. 2019 Jul 06.
    2,4-D causes oxidative stress induction and apoptosis in human dental pulp stem cells (hDPSCs).
    Samira Mahmoudinia, Ali Niapour, Hatef Ghasemi Hamidabadi, Mohammad Mazani.
      2,4-Dicholorophenoxy acetic acid (2,4-D) is a worldwide used hormone herbicide. Human dental pulp stem cells (hDPSCs) as a potential source of mesenchymal stem cells provide a confident model system for the assessments of chemicals in vitro. The main objective of this study was to examine the biological effects and damages attributed to 2,4-D on hDPSCs. hDPSCs were isolated from third molar pulp tissues and their mesenchymal identity were evaluated. Then, hDPSCs were treated with increasing concentrations of 2,4-D (0.1 μM-10 mM). Cell viability assay and cumulative cell counting were carried out to address 2,4-D effects on biological parameters of hDPSCs. Cell cycle distribution, ROS level and ALP activity were measured before and after treatment. AO/EB staining and caspase 3/7 activity were investigated to detect the possible mechanisms of cell death. Flow-cytometric immunophenotyping and differentiation data confirmed the mesenchymal identity of cultivated hDPSCs. 2,4-D treatment caused a hormetic response in the viability and growth rate of hDPSCs. G0/G1 cell cycle arrest, enhanced ROS level, and reduced ALP activity were detected in hDPSCs treated with EC50 dose of 2,4-D. AO/EB staining showed a higher percentage of alive cells in lower concentrations of the herbicide. The increment in 2,4-D dose and the number of early and late apoptotic cells were increased. DAPI staining and caspase 3/7 assay validated the induction of apoptosis. 2,4-D concentrations up to 100 μM did not affect hDPSCs viability and proliferation. The intense cellular oxidative stress and apoptosis were observed at higher concentration.
    Keywords:  2,4-D; Apoptosis; Hormesis; Mesenchymal stromal cells; Viability; hDPSCs
    DOI:  https://doi.org/10.1007/s11356-019-05837-0
  28. Life Sci. 2019 Jul 03. pii: S0024-3205(19)30554-5. [Epub ahead of print] 116628
    Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms.
    Maamoun Fatfat, Isabelle Fakhoury, Zeina Habli, Rasha Mismar, Hala Gali-Muhtasib.
       AIMS: Adult T-cell leukemia (ATL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus (HTLV-1) infection. Major limitations in Doxorubicin (Dox) chemotherapy are tumor resistance and severe drug complications. Here, we combined Thymoquinone (TQ) with low concentrations of Dox and determined anticancer effects against ATL in cell culture and animal model.
    MAIN METHODS: HTLV-1 positive (HuT-102) and HTLV-1 negative (Jurkat) CD4+ malignant T-cell lines were treated with TQ, Dox and combinations. Viability and cell cycle effects were determined by MTT assay and flow cytometry analysis, respectively. Combination effects on mitochondrial membrane potential and generation of reactive oxygen species (ROS) were assessed. Expression levels of key cell death proteins were investigated by western blotting. A mouse xenograft model of ATL in NOD/SCID was used for testing drug effects and tumor tissues were stained for Ki67 and TUNEL.
    KEY FINDINGS: TQ and Dox caused greater inhibition of cell viability and increased sub-G1 cells in both cell lines compared to Dox or TQ alone. The combination induced apoptosis by increasing ROS and causing disruption of mitochondrial membrane potential. Pretreatment with N-acetyl cysteine (NAC) or pan caspase inhibitor significantly inhibited the apoptotic response suggesting that cell death is ROS- and caspase-dependent. TQ and Dox combination reduced tumor volume in NOD/SCID mice more significantly than single treatments through enhanced apoptosis without affecting the survival of mice.
    SIGNIFICANCE: Our combination model offers the possibility to use up to twofold lower doses of Dox against ATL while exhibiting the same cancer inhibitory effects.
    Keywords:  Apoptosis; Combination therapy; Doxorubicin; Leukemia/lymphoma; Thymoquinone
    DOI:  https://doi.org/10.1016/j.lfs.2019.116628
  29. ACS Appl Mater Interfaces. 2019 Jul 10.
    Platelet Membrane Camouflaged Black Phosphorus Quantum Dots Enhance Anticancer Effect Mediated by Apoptosis and Autophagy.
    Yinghui Shang, Qinghai Wang, Bin Wu, Qiangqiang Zhao, Jian Li, Xueyuan Huang, Wansong Chen, Rong Gui.
      Hederagenin (HED) has poor anticancer activity, whose mechanism remains unclear and unsystematic. Free drugs for cancer treatment exhibit disadvantages such as poor targeting and efficacy. To address this problem, we constructed a nanoplatform of black phosphorus quantum dots (BPQDs) camouflaged with a platelet membrane (PLTm) carrying HED, termed PLT@BPQDs-HED. PLTm vesicles serve as a shell to encapsulate multiple high-efficiency drug-loaded nanocores, which can target tumor sites and significantly improve antitumor activity. Compared with free HED, this platform significantly reduced tumor cell viability and the mitochondrial membrane potential (MMP), while increasing the production of intracellular reactive oxygen species (ROS). The platform also significantly increased the amounts of terminal deoxyribonucleotide transferase-mediated dUTP nick-end-labeling (TUNEL)-positive cells and decreased the number of Ki-67-positive cells. In addition, the platform upregulated proapoptotic factor Bax, downregulated the anti-apoptotic molecule Bcl-2, activated Caspase-9 and Caspase-3, and stimulated Cytochrome C release. Moreover, the platform promoted the formation of autophagosomes, upregulated Beclin-1, and promoted LC3-I conversion into LC3-II. This study demonstrated that the above platform significantly enhances tumor targeting and promotes mitochondria-mediated cell apoptosis and autophagy in tumor cells.
    DOI:  https://doi.org/10.1021/acsami.9b04735
  30. Exp Mol Pathol. 2019 Jul 06. pii: S0014-4800(19)30355-7. [Epub ahead of print] 104281
    Angelica polysaccharide alleviates oxidative response damage in HaCaT cells through up-regulation of miR-126.
    Xijun Zhang, Hong Xue, Ping Zhou, Li Liu, Jing Yu, Pengfei Dai, Manqing Qu.
       BACKGROUND: Pressure ulcers (PUs) prevalence has been considered as an index for patient safety and cure quality of hospital and community. Skin cellular oxidative response damage is existed in the development of PUs. Angelica polysaccharide (AP) has the anti-oxidation function. Therefore, our goal was to investigate the mechanism of AP in relieving cellular oxidative damage.
    METHODS: Transfected HaCaT cells with miR-126 inhibitor, pre-treated by AP, and then treated by H2O2. CCK-8 assay and flow cytometry detection were set to test viability and apoptosis of cells respectively. qRT-PCR and western blot tested levels of miR-126 and oxidative damage relative factors. ROS assay tested the production of ROS in cells.
    RESULTS: Cellular oxidative response damage was induced by H2O2 at concentration of 300 μM. We found that AP could attenuate cellular oxidative response damage caused by H2O2 that it elevated cell viability, attenuated cell apoptosis and production of ROS and promoted activation of PI3K/AKT and mTOR signal pathways. Further, miR-126 was up-regulated by AP. The up-regulation of miR-126 could activate the PI3K/AKT and mTOR signal pathways.
    CONCLUSION: Our study demonstrated that AP attenuated cellular oxidative response damage in HaCaT cells by positively regulated miR-126.
    Keywords:  Angelica polysaccharide (AP); Oxidative damage; Pressure ulcers (PUs); miR-126
    DOI:  https://doi.org/10.1016/j.yexmp.2019.104281
  31. Life Sci. 2019 Jul 04. pii: S0024-3205(19)30560-0. [Epub ahead of print] 116634
    Oleuropein suppresses oxidative, inflammatory, and apoptotic responses following glycerol-induced acute kidney injury in rats.
    Min Yin, Nan Jiang, Lihua Guo, Ziyuan Ni, Ashraf Y Al-Brakati, Mohamed S Othman, Ahmed E Abdel Moneim, Rami B Kassab.
       AIM: Here, we evaluated the possible protective effects of oleuropein, the major phenolic constituent in virgin olive oil against glycerol-induced acute kidney injury (AKI) in rats.
    MAIN METHODS: Twenty-eight Sprague Dawley rats were allocated equally into four groups as follows: control group, oleuropein group (50 mg/kg body weight), AKI group and the oleuropein + AKI group. AKI was induced by injecting 50% glycerol (10 ml/kg body weight) intramuscularly.
    KEY FINDINGS: Glycerol injection increased the kidney relative weight as well as rhabdomyolysis (RM)- and AKI-related index levels, including the levels of creatine kinase, lactate dehydrogenase, creatinine, urea, and Kim-1 expression. Additionally, alteration in oxidative conditions in renal tissue was recorded, as confirmed by the elevated malondialdehyde and nitric oxide levels and the decreased glutathione content. Concomitantly, the protein and mRNA expression levels of antioxidant enzymes were suppressed. Moreover, Nfe2l2 and Hmox1 mRNA expression was also downregulated. Glycerol triggered inflammatory reactions in renal tissue, as evidenced by the increased pro-inflammatory cytokines and Ccl2 protein and mRNA expression, whereas myeloperoxidase activity was increased. Furthermore, glycerol injection enhanced apoptotic events in renal tissue by increasing the expression of the pro-apoptotic proteins and decreasing that of anti-apoptotic. However, oleuropein administration reversed the molecular, biochemical, and histological alterations resulting from glycerol injection.
    SIGNIFICANCE: Our data suggest that oleuropein has potential as an alternative therapy to prevent or minimize RM incidence and subsequent development of AKI, possibly due to its potent anti-stress, anti-inflammatory, and anti-apoptotic effects.
    Keywords:  Acute kidney injury; Apoptosis; Inflammation; Oleuropein; Oxidative stress; Rhabdomyolysis
    DOI:  https://doi.org/10.1016/j.lfs.2019.116634
  32. J Mol Endocrinol. 2019 Jul 01. pii: JME-19-0123. [Epub ahead of print]
    FNDC5/Irisin counteracts lipotoxic-induced apoptosis in hypoxic H9c2 cells.
    Isabel Moscoso, Maria Cebro Márquez, Moisés Rodríaguez Mañero, José Ramón González-Juanatey, Ricardo Lage Fernandez.
      Irisin is a newly identified adipokine critical to modulate body metabolism, fatty acid metabolism and oxidative stress; recent evidence suggests a cardioprotective role in ischemic injury. Loss of cardiomyocytes during acute myocardial infarction is strongly associated with energetic changes and lipotoxic-induced apoptosis. Our aim was to study FNDC5/irisin potential protective role against hypoxia and lipotoxicity, both related with myocardial infarction environment. H9c2 cells were treated with palmitate and/or irisin in normoxic/hypoxic conditions. Cell viability and apoptosis were assessed by MTT assay and annexin V/PI staining. Immunoblotting was used to confirm apoptotic cascade regulation. Irisin counteracts lipotoxic-induced apoptosis in hypoxic cardiomyoblasts by activating Akt signalling pathway suggesting the potential therapeutic role of irisin in ischemic heart disease.
    DOI:  https://doi.org/10.1530/JME-19-0123
  33. EMBO Mol Med. 2019 Jul 08. e10409
    Mitochondrial MsrB2 serves as a switch and transducer for mitophagy.
    Seung Hee Lee, Suho Lee, Jing Du, Kanika Jain, Min Ding, Anis J Kadado, Gourg Atteya, Zainab Jaji, Tarun Tyagi, Won-Ho Kim, Raimund I Herzog, Amar Patel, Costin N Ionescu, Kathleen A Martin, John Hwa.
      Mitophagy can selectively remove damaged toxic mitochondria, protecting a cell from apoptosis. The molecular spatial-temporal mechanisms governing autophagosomal selection of reactive oxygen species (ROS)-damaged mitochondria, particularly in a platelet (no genomic DNA for transcriptional regulation), remain unclear. We now report that the mitochondrial matrix protein MsrB2 plays an important role in switching on mitophagy by reducing Parkin methionine oxidation (MetO), and transducing mitophagy through ubiquitination by Parkin and interacting with LC3. This biochemical signaling only occurs at damaged mitochondria where MsrB2 is released from the mitochondrial matrix. MsrB2 platelet-specific knockout and in vivo peptide inhibition of the MsrB2/LC3 interaction lead to reduced mitophagy and increased platelet apoptosis. Pathophysiological importance is highlighted in human subjects, where increased MsrB2 expression in diabetes mellitus leads to increased platelet mitophagy, and in platelets from Parkinson's disease patients, where reduced MsrB2 expression is associated with reduced mitophagy. Moreover, Parkin mutations at Met192 are associated with Parkinson's disease, highlighting the structural sensitivity at the Met192 position. Release of the enzyme MsrB2 from damaged mitochondria, initiating autophagosome formation, represents a novel regulatory mechanism for oxidative stress-induced mitophagy.
    Keywords:  apoptosis; diabetes mellitus; methionine sulfoxide reductase; mitophagy; platelets
    DOI:  https://doi.org/10.15252/emmm.201910409
  34. Proteomics. 2019 Jul 11. e1900092
    Proteomic analysis reveals that Odoroside A triggers G2/M arrest and apoptosis in colorectal carcinoma through ROS-p53 pathway.
    Yan-Yan Chen, Shi-Yuan Wen, Chun-Miao Deng, Xing-Feng Yin, Zheng-Hua Sun, Miao-Miao Jiang, Qing-Yu He.
      Odoroside A (OA) is an active ingredient extracted from the leaves of Nerium oleander Linn. (Apocynaceae). This study aims to examine the anticancer bioactivity of OA against CRC cells and to investigate the action mechanisms involved. As a result, OA can significantly inhibit cellular ability and induce apoptosis of CRC cells in a concentration-dependent manner without any obvious cytotoxicity in normal colorectal epithelial cells. Then, quantitative proteomics combined with bioinformatics was adopted to investigate the alterations of proteins and signaling pathways in response to OA treatment. As suggested by the proteomic analysis, flow cytometry and Western blotting analyses validated that exposure of CRC cells to OA caused cell cycle arrest and apoptosis, accompanied with the activation of the ROS/p53 signaling pathway. This observation demonstrated that OA, as a natural product, can induce oxidative stress to suppress tumor cell growth, implicating a novel therapeutic agent against CRC without obvious side effects. This article is protected by copyright. All rights reserved.
    Keywords:  ROS/p53 pathways; apoptosis; cell cycle; colorectal cancer; natural product; odoroside A
    DOI:  https://doi.org/10.1002/pmic.201900092
  35. Arab J Urol. 2019 ;17(2): 87-97
    Oxidative stress and sperm function: A systematic review on evaluation and management.
    Sulagna Dutta, Ahmad Majzoub, Ashok Agarwal.
      Objective: To review and present the most distinct concepts on the association of reactive oxygen species (ROS) with male reproduction. Methods: The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines were used to search PubMed, Medline, EMBASE, and the Cochrane electronic databases for studies investigating the role of oxidative stress (OS) on sperm function. Results: The literature search yielded 1857 studies, of which 1791 articles were excluded because of irrelevance of data, non-English language, non-human nature or because they were case reports or commentaries. All included studies were reviews (46), meta-analyses (one), original research studies (18) and guideline articles (one). The studies were published between 1984 and 2018. Under normal physiological conditions, ROS are vital for sperm maturation, hyperactivation, capacitation, acrosome reaction, as well as fertilisation. However, a number of endogenous and exogenous causes may induce supra-physiological levels of ROS resulting in lipid peroxidation, sperm DNA fragmentation and apoptosis, and consequently infertility. Several laboratory testing methods can be used in infertile men to diagnose OS. Treatment usually involves antioxidant supplementation and, when possible, elimination of the causative factor. Conclusion: OS is an important cause of male factor infertility. Its assessment provides essential information that can guide treatment strategies aimed at improving the male's reproductive potential. Abbreviations: bp: base-pair; CAT: catalase; LPO: lipid peroxidation; MDA: malondialdehyde; MiOXSYS: Male Infertility Oxidative System; mtDNA: mitochondrial DNA; NAD(PH): nicotinamide adenine dinucleotide (phosphate); NO: nitric oxide; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; ORP: oxidation-reduction potential; OS: oxidative stress; PKA: protein kinase A; PLA2: phospholipase A2; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PUFA: poly-unsaturated fatty acid; ROS: reactive oxygen species; SOD: superoxide dismutase; TAC: total antioxidant capacity; TBA: thiobarbituric acid.
    Keywords:  Male infertility; oxidative stress; reactive oxygen species; sperm function
    DOI:  https://doi.org/10.1080/2090598X.2019.1599624
  36. Cancer Biother Radiopharm. 2018 Dec;33(10): 427-437
    Radioprotective Properties of Pterocarpus santalinus Chloroform Extract in Murine Splenic Lymphocytes and Possible Mechanism.
    E N Hanuma Kumar Ghali, Dharmendra Kumar Maurya, Balaji Meriga.
      Background:Pterocarpus santalinus popularly known as Red Sanders is an endemic species confined to Southern part of Eastern Ghats of India especially in Andhra Pradesh and has high demand for its economical importance for its use in treatment of human ailments. Materials and Methods: In the present study, the authors have examined the presence of various phytochemicals in the chloroform extract of P. santalinus heartwood (PSCE, Pterocarpus santalinus chloroform extract) by qualitative and quantitative assays. PSCE was further used to evaluate its antioxidant and metal reducing capacity. Radioprotective property was also evaluated in various subcellular and cellular model systems. Results: The phytochemical screening study showed that the extract was positive for carbohydrates, cardiac glycosides, flavonoids, phenols, tannins, saponins, and terpenoids and was negative for alkaloids, steroids, and phlobatannins. Contents of total phenol, total flavonoids, total anthocyanin, and total tannin in the PSCE are 404 μg/mg in terms of gallic acid equivalents, 22.6 μg/mg in terms of quercetin equivalents, 0.066 mg in terms of cyanidin-3-glucoside (cyn-3-glu) equivalents, and 12.477 g/L, respectively. This extract exhibited significant radical scavenging activity against model free radical 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS•+), 1,1-diphenyl picrylhydrazyl, and biologically important nitric oxide. It has significant metal reducing capacity as monitored by ferric and molybdenum reduction assay. PSCE showed a concentration dependent radioprotection to plasmid pBR322 DNA and lipids of the mitochondrial membranes. Their study also showed that PSCE protected splenic lymphocytes against radiation induced cell death, DNA double strand breaks, and lipid peroxidation as monitored by propidium iodide staining, γ-H2AX assay, neutral comet assay, and TBARS assay, respectively. Addition of PSCE to lymphocytes scavenged radiation derived reactive oxygen species, restored loss of thiol content, and inhibited cellular apoptosis. Conclusions: PSCE possesses high antioxidant activity and exhibited very good radioprotective property in cell free and cellular model systems.
    Keywords:  antioxidant; flavonoid; free radical; gallic acid; polyphenols; radical scavenging
    DOI:  https://doi.org/10.1089/cbr.2018.2532
  37. J Cell Biochem. 2019 Jul 11.
    Inhibition of miR-181b-5p protects cardiomyocytes against ischemia/reperfusion injury by targeting AKT3 and PI3KR3.
    Limei Yuan, Lihua Fan, Qinghai Li, Wei Cui, Xuechen Wang, Zhiguo Zhang.
      Ischemic heart disease (IHD) is the most occurring cardiovascular-associated disease, which is a primary leading cause of cardiac disability and death worldwide. Myocardial ischemia/reperfusion injury (MI/RI) has been linked to IHD-induced cardiomyocytes apoptosis and tissue damage. The clinical studies have indicated that pathophysiologic mechanisms of MI/RI are associated with reactive oxygen species generation, calcium overload, energy metabolism disorder, neutrophil infiltration, and others. However, the genetic mechanism of MI/RI remains unclear. In this study, we successfully established the reproducing abnormal heart observed in rat, of IHD-induced MI/RI post operation. By using these rats, we illustrated that expression of miR-181b-5p was increased not only in both hypoxia/reoxygenation-cultured H9C2 but also heart of myocardial ischemia/reperfusion (MI/R) rat. Suppression of the miR-181b-5p cardiomyocytes apoptosis and rescued myocardial infarction. Additionally, our data indicated that miR-181b-5p negatively regulates the expression of AKT3 and PIK3R3 through directly binding with its 3'-untranslated region. More importantly, suppression of miR-181b-5p protects the cardiomyocytes apoptosis and tissue damage from MI/R via regulation of PIK3R3 and AKT3. Hence, our study indicates that miR-181b-5p is essential for MI/RI via regulation of PI3K/Akt signaling pathway and could be a potential therapeutic target in IHD.
    Keywords:  PI3K/Akt signaling; apoptosis; ischemic heart disease; miR-181; myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.1002/jcb.29271
  38. Environ Pollut. 2019 Jun 14. pii: S0269-7491(19)30137-X. [Epub ahead of print]252(Pt B): 1764-1771
    Exogenous Ca2+ mitigates the toxic effects of TiO2 nanoparticles on phagocytosis, cell viability, and apoptosis in haemocytes of a marine bivalve mollusk, Tegillarca granosa.
    Xiaofan Guan, Yu Tang, Shanjie Zha, Yu Han, Wei Shi, Peng Ren, Maocang Yan, Qicun Pan, Yuan Hu, Jun Fang, Jiongming Zhang, Guangxu Liu.
      Phagocytosis suppression induced by nanoparticles (NPs) exposure is increasingly reported in marine species. However, the mechanisms underlying this impact remain poorly understood. In order to improve our present understanding of the immunotoxicity of NPs, acute (96 h) TiO2 NP exposure and rescue trials via exogenous supply of Ca2+ were performed in the blood clam, Tegillarca granosa. The results show that the phagocytosis rate, cell viability, and intracellular Ca2+ concentration of haemocytes were significantly suppressed, whereas the intracellular ROS concentration of haemocytes significantly increased upon nTiO2 exposure. Exposure to nTiO2 also led to the significant downregulation of Caspase-3, Caspase-6, apoptosis regulator Bcl-2, Bcl-2-associated X, calmodulin kinase II, and calmodulin kinase kinase II. Furthermore, the toxic impacts of nTiO2 were partially mitigated by the addition of exogenous Ca2+, as indicated by the recovery tendency in almost all the measured parameters. The present study indicates that Ca2+ signaling could be one of the key pathways through which nTiO2 attacks phagocytosis.
    Keywords:  Blood clam; Calcium; Nanoparticle; Phagocytosis; Titanium dioxide
    DOI:  https://doi.org/10.1016/j.envpol.2019.06.053
  39. Amino Acids. 2019 Jul 10.
    Up-regulation of HIF-1α is associated with neuroprotective effects of agmatine against rotenone-induced toxicity in differentiated SH-SY5Y cells.
    Nadia Ferlazzo, Monica Currò, Maria Laura Giunta, Domenico Longo, Valentina Rizzo, Daniela Caccamo, Riccardo Ientile.
      Agmatine, a metabolite generated by arginine decarboxylation, has been reported as neuromodulator and neuroactive substance. Several findings suggest that agmatine displays neuroprotective effects in several models of neurodegenerative disorders, such as Parkinson's disease (PD). It has been hypothesized that biogenic amines may be involved in neuroprotection by scavenging oxygen radicals, thus preventing the generation of oxidative stress. Mitochondrial dysfunction, that leads to a reduction of oxygen consumption, followed by activation of prolyl hydroxylase and decrease of hypoxia-inducible factor 1 alpha (HIF-1α) levels, has been demonstrated to play a role in PD pathogenesis. Using rotenone-treated differentiated SH-SY5Y cells as the in vitro PD model, we here investigated the molecular mechanisms underlying agmatine neuroprotective effects. Our results showed that the preliminary addition of agmatine induces HIF-1α activation, and prevents the rotenone-induced production of free radical species, and the activation of apoptotic pathways by inhibiting mitochondrial membrane potential decrease and caspase 3 as well as cytochrome c increase. Notably, these effects are mediated by HIF-1α, as indicated by experiments using a HIF-1α inhibitor. The present findings suggest that the treatment with agmatine is able to counteract the neuronal cell injury evoked by mitochondrial toxins.
    Keywords:  Agmatine; Apoptosis; Hypoxia-inducible factor-1; Neuroprotective activity; Oxidative stress
    DOI:  https://doi.org/10.1007/s00726-019-02759-6
  40. J Cell Biochem. 2019 Jul 11.
    Depletion of NBR1 in urothelial carcinoma cells enhances rapamycin-induced apoptosis through impaired autophagy and mitochondrial dysfunction.
    Myeong Joo Kim, Gwang Yong Hwang, Min Ji Cho, Byung Hoon Chi, Serk In Park, In Ho Chang, Young Mi Whang.
      Rapamycin is well-recognized in the clinical therapeutic intervention for patients with cancer by specifically targeting mammalian target of rapamycin (mTOR) kinase. Rapamycin regulates general autophagy to clear damaged cells. Previously, we identified increased expression of messenger RNA levels of NBR1 (the neighbor of BRCA1 gene; autophagy cargo receptor) in human urothelial cancer (URCa) cells, which were not exhibited in response to rapamycin treatment for cell growth inhibition. Autophagy plays an important role in cellular physiology and offers protection against chemotherapeutic agents as an adaptive response required for maintaining cellular energy. Here, we hypothesized that loss of NBR1 sensitizes human URCa cells to growth inhibition induced by rapamycin treatment, leading to interruption of protective autophagic activation. Also, the potential role of mitochondria in regulating autophagy was tested to clarify the mechanism by which rapamycin induces apoptosis in NBR1-knockdown URCa cells. NBR1-knockdown URCa cells exhibited enhanced sensitivity to rapamycin associated with the suppression of autophagosomal elongation and mitochondrial defects. Loss of NBR1 expression altered the cellular responses to rapamycin treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species (ROS). Although rapamycin treatment-induced autophagy by adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in NBR1-knockdown cells, it did not process the conjugated form of LC3B-II after activation by unc-51 like autophagy-activating kinase 1 (ULK1). NBR1-knockdown URCa cells exhibited rather profound mitochondrial dysfunctions in response to rapamycin treatment as evidenced by Δψm collapse, ATP depletion, ROS accumulation, and apoptosis activation. Therefore, our findings provide a rationale for rapamycin treatment of NBR1-knockdown human urothelial cancer through the regulation of autophagy and mitochondrial dysfunction by regulating the AMPK/mTOR signaling pathway, indicating that NBR1 can be a potential therapeutic target of human urothelial cancer.
    Keywords:  AMPK; NBR1; autophagy; bladder cancer; mitochondrial biogenesis; rapamycin
    DOI:  https://doi.org/10.1002/jcb.29248
  41. Chem Sci. 2019 Jun 14. 10(22): 5773-5778
    Catalase-like metal-organic framework nanoparticles to enhance radiotherapy in hypoxic cancer and prevent cancer recurrence.
    Yuanyuan Chen, Hui Zhong, Jianbo Wang, Xiuyan Wan, Yanhua Li, Wei Pan, Na Li, Bo Tang.
      Tumor hypoxia typically occurs inside a solid tumor with an inadequate oxygen supply, sharply reducing the therapeutic efficiency of radiotherapy and significantly increasing the risk of local tumor recurrence. Herein, we designed folic acid modified enzyme-like hafnium-based manganoporphyrin metal-organic framework nanoparticles (MnTCPP-Hf-FA MOF NPs) to overcome hypoxia-induced radioresistance and prevent postoperative recurrence. Hf, a high-Z element, can effectively absorb X-ray energy and convert O2 and H2O into reactive oxygen species to induce cell apoptosis. The MnTCPP ligand has an enzyme-like ability to catalytically decompose endogenous H2O2 into O2 for enhancing RT in hypoxic tumors. In vivo experiments revealed that the MOF NPs could effectively inhibit melanoma growth and prevent tumor postoperative recurrence with only one X-ray irradiation after intravenous injection. We expect that the current study provides a versatile approach for solving the critical radioresistance issue of hypoxic tumors.
    DOI:  https://doi.org/10.1039/c9sc00747d
  42. Theranostics. 2019 ;9(13): 3768-3779
    Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification.
    Tian Tian, Jiajun Li, Yizhuo Li, Yun-Xin Lu, Yan-Lai Tang, Hua Wang, Fufu Zheng, Dingbo Shi, Qian Long, Miao Chen, Guillermo Garcia-Manero, Yumin Hu, Lijun Qin, Wuguo Deng.
      Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies. Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation. Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis in FLT3/ITD-positive leukemia cells. Mechanistically, melatonin preferentially causes overproduction of reactive oxygen species (ROS) and ultimately massive cell death in FLT3-ITD AML cells. Moreover, melatonin significantly enhances the cytotoxicity induced by the FLT3 tyrosine kinase inhibitor sorafenib in AML cells with FLT3/ITD through redox modification. Importantly, combination of melatonin and sorafenib exhibited highly synergistic therapeutic activity in MV4-11 xenografts and a murine model bearing FLT3/ITD leukemia. Conclusion: This study indicates that melatonin, alone or in combination with sorafenib, has potential to improve the therapeutic outcome of AML patients with FLT3-ITD mutation that merits further investigation.
    Keywords:  FLT3-ITD; Leukemia; Melatonin; Redox modification; Sorafenib
    DOI:  https://doi.org/10.7150/thno.34327
  43. Environ Sci Pollut Res Int. 2019 Jul 08.
    Moringa seed extract alleviates titanium oxide nanoparticles (TiO2-NPs)-induced cerebral oxidative damage, and increases cerebral mitochondrial.
    Mohamed A Kandeil, Eman T Mohammed, Khalid S Hashem, Lotfi Aleya, Mohamed M Abdel-Daim.
      To investigate the influence of Moringa seed extract (MSE) on the cerebral Nrf2/NQO1 signaling in TiO2-NPs-induced brain damage, 80 male albino rats were divided into four groups (n = 20); group I was used as a control, group II received TiO2-NPs (500 mg/kg b.w/day orally) for 14 days, group III received MSE (100 mg/kg b.w/day orally) for 30 days, and group IV received MSE an hour before TiO2-NPs administration with the same doses as before. Administration of TiO2-NPs was started on the 17th day for both groups (II) and (IV). Administration of MSE significantly increased the cerebral mitochondrial viability and Nrf2 level with a simultaneous increase of NQO1 mRNA expression. This designates a powerful antioxidant effect of MSE which is indicated by a significant reduction of INOS expression, MDA, TOS, OSI levels, and DNA fragmentation % with a significant increase of GSH concentration, SOD activities, and TAC. MSE possesses an anti-inflammatory effect by a significant reduction of IL-1β and TNF-α levels, and anti-apoptotic effect manifested by a significant reduction of caspase-3 and Fas levels. In harmonization, dopamine, serotonin concentrations, and acetylcholinesterase activities return back to normal as compared to control group. These results were confirmed by the histopathological features which were alleviated with MSE administration. In conclusion, Nrf2 plays a pivotal role in the mechanism of TiO2-NPs cerebral toxicity and MSE as a Nrf2 activator can provide a powerful cerebroprotective effect, whereas MSE increased the Nrf2 expression and consequently restore the antioxidant activity of brain cells by increasing NQO1 gene expression and cerebral mitochondrial viability as well as inhibition of pro-inflammatory and apoptotic mediators.
    Keywords:  Antioxidant; Apoptosis; Brain; Moringa; NQO1; Nrf2; TiO2 nanoparticles
    DOI:  https://doi.org/10.1007/s11356-019-05514-2
  44. Cells. 2019 Jul 10. pii: E694. [Epub ahead of print]8(7):
    Effects of Cigarette Smoke on TSPO-related Mitochondrial Processes.
    Nidal Zeineh, Rafael Nagler, Martin Gabay, Abraham Weizman, Moshe Gavish.
      The 18 kDa translocator protein (TSPO) is an initiator of the mitochondrial apoptosis cascade. Cigarette smoke (CS) exposure provokes alterations in TSPO expression as well as upregulation of its related functions such as mitochondrial membrane potential (ΔψM) and reactive oxygen species generation, which are associated with cell death. In the current study, H1299 lung cancer cell line exposed to CS for various time periods (30 mins, 60 mins and 120 mins) and TSPO expression and cell death processes were studied. CS exposure for 30 mins resulted in a non-significant increase in TSPO expression by 24% (p > 0.05 vs. control). CS exposure for 60 mins and 120 mins resulted in a significant increase by 43% (p < 0.05 vs. control) and by 47% (p < 0.01 vs. control), respectively. Furthermore, TSPO-related mitochondrial functions were upregulated at the 120 mins time point following CS exposure. TSPO expression is upregulated by CS, suggesting that TSPO plays a role in cell death processes induced by CS exposure. Alterations in TSPO-related cell death processes suggest that TSPO may be involved in the tissue damage caused by CS.
    Keywords:  ROS; TSPO; apoptosis; cAMP; cell death; cigarette smoke; mitochondrial membrane potential; necrosis
    DOI:  https://doi.org/10.3390/cells8070694
  45. Oxid Med Cell Longev. 2019 ;2019 3187972
    SIRT7 Regulates Lipopolysaccharide-Induced Inflammatory Injury by Suppressing the NF-κB Signaling Pathway.
    Kun-Lin Chen, Lian Li, Cheng-Min Li, Yi-Ru Wang, Fang-Xiao Yang, Mei-Qian Kuang, Gen-Lin Wang.
      Mastitis has severely affected the cattle industry worldwide and has resulted in decreased dairy production and cattle reproduction. Although prevention and treatment methods have been implemented for decades, cattle mastitis is still an intractable disease. Sirtuin 7 (SIRT7) is an NAD+-dependent deacetylase that is involved in various biological processes, including ribosomal RNA synthesis and protein synthesis, DNA damage response, metabolism, and tumorigenesis. However, whether SIRT7 participates in inflammation remains unknown. Our results revealed that SIRT7 is downregulated in tissue samples from mastitic cattle. Therefore, we isolated dairy cow mammary epithelial cells (DCMECs) from breast tissues and developed an in vitro model of lipopolysaccharide- (LPS-) induced inflammation to examine SIRT7 function and its potential role in inflammation. We showed that SIRT7 was significantly downregulated in LPS-treated DCMECs. SIRT7 knockdown significantly increased the LPS-stimulated production of inflammatory mediators, like reactive oxygen and nitric oxide, and upregulated TAB1 and TLR4. In addition, SIRT7 knockdown significantly increased the phosphorylation of TAK1 and NF-κBp65 in LPS-treated DCMECs. Moreover, SIRT7 knockdown promoted the translocation of NF-κBp-p65 to the cell nucleus and then increased the secretion of inflammatory cytokines (IL-1β and IL-6). In contrast, SIRT7 overexpression had the opposite effects when compared to SIRT7 knockdown in LPS-treated DCMECs. In addition, SIRT7 overexpression attenuated LPS-induced DCMEC apoptosis. Taken together, our results indicate that SIRT7 can suppress LPS-induced inflammation and apoptosis via the NF-κB signaling pathway. Therefore, SIRT7 may be considered as a potential pharmacological target for clinical mastitis therapy.
    DOI:  https://doi.org/10.1155/2019/3187972
  46. Curr Pharm Des. 2019 Jul 09.
    The protective mechanism of cannabidiol in cardiac injury: A systematic review of non-clinical studies.
    Mohammad Reza Hooshangi Shayesteh, Hamed Haghi-Aminjan, Mohammad Javad Mousavi, Saeideh Momtaz, Mohammad Abdollahi.
       BACKGROUND: Cardiac disease is accounted as the leading cause of worldwide morbidity and mortality, mainly in association with induction of inflammation and oxidative stress. The disease is characterized by the overproduction of reactive oxygen and/or nitrogen species (ROS/RNS), and reduced antioxidant capacity. Cannabidiol (CBD) is a non-psychoactive ingredient of marijuana that reported to be safe and well tolerated in patients. Due to its pleiotropic effect, CBD has been shown to exert cytoprotective effects. This study intended to clarify the mechanisms and the potential role of CBD regarding cardiac injuries treatment.
    METHODS: A systematic literature search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, in the electronic databases including PubMed, Web of Science, Scopus, and Embase up to July 2018 using predefined search terms in the titles and abstracts by two independent investigators. Accordingly, a set of pre-specified inclusion and exclusion criteria were considered and 8 articles were ultimately included in this study.
    RESULTS: Our findings obviously demonstrate that CBD has multi-functional protective assets to improve cardiac injuries; preliminary through scavenging of free radicals, and reduction of oxidative stress, apoptosis, and inflammation.
    CONCLUSION: CBD can protect against cardiac injuries, mainly through its anti-oxidant, anti-inflammatory, and anti-apoptotic effects on the basis of non-clinical studies.
    Keywords:  Cannabinoids; Cardiac injury; Oxidative stress; Systematic review
    DOI:  https://doi.org/10.2174/2210327909666190710103103
  47. Fish Shellfish Immunol. 2019 Jul 06. pii: S1050-4648(19)30725-9. [Epub ahead of print]92 756-764
    Alternations in oxidative stress, apoptosis, and innate-immune gene expression at mRNA levels in subadult tiger puffer (Takifugu rubripes) under two different rearing systems.
    Yudong Jia, Qiqi Jing, Jieming Zhai, Changtao Guan, Bin Huang.
      Tiger puffer (Takifugu rubripes) is one of the major aquaculture fish species in China due to its high economic value. In this study, the transcriptions of hepatic antioxidant enzyme, stress, apoptosis, and immune-related genes of sub-adult tiger puffers (Takifugu rubripes) were evaluated under two different rearing systems [offshore sea cage aquaculture system (OSCS) and recirculating aquaculture system (RAS)]. Results showed that the mRNA expression levels of the antioxidant enzyme (mn-sod, cu/zn-sod, gpx, and gr) and stress-related (hsp70 and hsp90) genes of male tiger puffers reared in the OSCS were significantly higher than female fish reared in the OSCS and fish reared in the RAS. The anti-apoptotic gene bcl2 exhibited the similar results. By contrast, the mRNAs of the pro-apoptotic genes (p53, caspase8, caspase9, and caspase3) of male tiger puffers reared in the OSCS were significantly lower than female fish reared in the OSCS and fish reared in the RAS. Male tiger puffers reared in the OSCS displayed significantly higher complement components (c3) and inflammatory cytokine (il-6) mRNAs, whereas B-cell activating factor (baf) and tumor necrosis factor α (tnf-α) mRNAs remained unchanged. Meanwhile, the mRNA levels of pro-apoptotic (bax, caspase8) and immunity-related (c3, il-6 and il-7) genes of female tiger puffers reared in the OSCS were significantly lower and higher than female fish reared in the RAS, respectively. In conclusion, the hepatic antioxidant, anti-apoptosis, and innate immunity of tiger puffers reared in the OSCS were better than fish in the RAS, male tiger puffer obtained the best values. These results expand the knowledge on the combined RAS and OSCS alternative aquaculture model for tiger puffers and aid in their management in captive.
    Keywords:  Antioxidative stress; Apoptosis; Innate immunity; Offshore sea cage aquaculture system; Recirculating aquaculture system; Tiger puffer
    DOI:  https://doi.org/10.1016/j.fsi.2019.07.016
  48. Int J Nanomedicine. 2019 ;14 4573-4587
    N-acetylcysteine reverses the decrease of DNA methylation status caused by engineered gold, silicon, and chitosan nanoparticles.
    Kanidta Sooklert, Siwaporn Nilyai, Rojrit Rojanathanes, Depicha Jindatip, Nutchanart Sae-Liang, Nakarin Kitkumthorn, Apiwat Mutirangura, Amornpun Sereemaspun.
      Introduction: Engineered nanoparticles (ENPs) are one of the most widely used types of nanomaterials. Recently, ENPs have been shown to cause cellular damage by inducing ROS (reactive oxygen species) both directly and indirectly, leading to the changes in DNA methylation levels, which is an important epigenetic mechanism. In this study, we investigated the effect of ENP-induced ROS on DNA methylation. Materials and methods: Human embryonic kidney and human keratinocyte (HaCaT) cells were exposed to three different types of ENPs: gold nanoparticles, silicon nanoparticles (SiNPs), and chitosan nanoparticles (CSNPs). We then evaluated the cytotoxicity of the ENPs by measuring cell viability, morphology, cell apoptosis, cell proliferation, cell cycle distribution and ROS levels. Global DNA methylation levels was measured using 5-methylcytosine immunocytochemical staining and HPLC analysis. DNA methylation levels of the transposable elements, long interspersed element-1 (LINE-1) and Alu, were also measured using combined bisulfite restriction analysis technique. DNA methylation levels of the TEs LINE-1 and Alu were also measured using combined bisulfite restriction analysis technique. Results: We found that HaCaT cells that were exposed to SiNPs exhibited increased ROS levels, whereas HaCaT cells that were exposed to SiNPs and CSNPs experienced global and Alu hypomethylation, with no change in LINE-1 being observed in either cell line. The demethylation of Alu in HaCaT cells following exposure to SiNPs and CSNPs was prevented when the cells were pretreated with an antioxidant. Conclusion: The global DNA methylation that is observed in cells exposed to ENPs is associated with methylation of the Alu elements. However, the change in DNA methylation levels following ENP exposure is specific to particular ENP and cell types and independent of ROS, being induced indirectly through disruption of the oxidative defense process.
    Keywords:  Alu; DNA methylation; LINE-1; epigenetic; nanotoxicity
    DOI:  https://doi.org/10.2147/IJN.S204372
  49. Free Radic Res. 2019 Jul 10. 1-311
    Modulation of selenium-dependent glutathione peroxidase activity enhances doxorubicin-induced apoptosis, tumor cell killing, and hydroxyl radical production in human NCI/ADR-RES cancer cells despite high-level P-glycoprotein expression.
    James H Doroshow, Agnes Juhasz.
      To define the role of glutathione peroxidase (GPx) in modulating the oxygen radical-related cytotoxicity of doxorubicin and H2O2 in cells that overexpress P-glycoprotein (Pgp), the GPx activity of NCI/ADR-RES cancer cells was altered by growth in 0.5% serum with (MR-30 subline) or without (MR-0 subline) selenium supplementation. GPx activity increased from 2.2 nmol/min/mg (MR-0) to 22.5 nmol/min/mg (MR-30) when cells were grown in 30-nM selenium, p < 0.01; the activities of other antioxidant enzymes were unchanged by selenium. By reverse transcriptase polymerase chain reaction (RT-PCR), MR-30 and MR-0 cells expressed similar levels of the MDR1, GPx-1, BCL2, and TOP2A mRNA. The IC50 concentration for H2O2 in MR-0 cells was ten-fold lower than in the MR-30 subline, p < 0.01. Despite identical anthracycline accumulation and efflux in these two lines that expressed equivalent levels of Pgp, the doxorubicin IC50 decreased 5-fold in MR-0 vs. MR-30 cells, p < 0.01. Log-linear tumor cell killing by doxorubicin was observed only in selenium-deficient MR-0 cells. Doxorubicin exposure also produced substantially more apoptosis in MR-0 than MR-30 cells; this was not related to the presence of selenium per se. MR-0 cells generated ≈5-times more methane from dimethyl sulfoxide (a measure of reactive oxygen metabolism) than MR-30 cells in the presence of equimolar doxorubicin concentrations (p < 0.05). These studies suggest that GPx-mediated detoxification of peroxides can modulate the antitumor activity of doxorubicin in the presence of high levels of Pgp.
    Keywords:  Cancer; doxorubicin; glutathione peroxidase; hydrogen peroxide; reactive oxygen
    DOI:  https://doi.org/10.1080/10715762.2019.1641602
  50. Neural Regen Res. 2019 Nov;14(11): 1941-1949
    Hyodeoxycholic acid protects the neurovascular unit against oxygen-glucose deprivation and reoxygenation-induced injury in vitro.
    Chang-Xiang Li, Xue-Qian Wang, Fa-Feng Cheng, Xin Yan, Juan Luo, Qing-Guo Wang.
      Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid (HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin and jas-minoidin, HDCA prevents hypoxia-reoxygenation-induced brain injury by suppressing endoplasmic reticulum stress-mediated apoptotic signaling. However, the effects of HDCA in ischemic stroke injury have not yet been studied. Neurovascular unit (NVU) dysfunction occurs in ischemic stroke. Therefore, in this study, we investigated the effects of HDCA on the NVU under ischemic conditions in vitro. We co-cultured primary brain microvascular endothelial cells, neurons and astrocytes using a transwell chamber co-culture system. The NVU was pre-treated with 10.16 or 2.54 μg/mL HDCA for 24 hours before exposure to oxygen-glucose deprivation for 1 hour. The cell counting kit-8 assay was used to detect cell activity. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to assess apoptosis. Enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α, and neurotrophic factors, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Oxidative stress-related factors, such as superoxide dismutase, nitric oxide, malondialdehyde and γ-glutamyltransferase, were measured using kits. Pretreatment with HDCA significantly decreased blood-brain barrier permeability and neuronal apoptosis, significantly increased transendothelial electrical resistance and γ-glutamyltransferase activity, attenuated oxidative stress damage and the release of inflammatory cytokines, and increased brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression. Our findings suggest that HDCA maintains NVU morphological integrity and function by modulating inflammation, oxidation stress, apoptosis, and the expression of neurotrophic factors. Therefore, HDCA may have therapeutic potential in the clinical management of ischemic stroke. This study was approved by the Ethics Committee of Experimental Animals of Beijing University of Chinese Medicine (approval No. BUCM-3-2016040201-2003) in April 2016.
    Keywords:   anti-inflammatory; anti-apoptotic; anti-oxidative; blood-brain barrier permeability; brain-derived neurotrophic factor; glial cell line-derived neurotrophic factor; hyodeoxycholic acid; in vitro neurovascular unit; ischemic stroke; oxygen glucose deprivation and reoxygenation
    DOI:  https://doi.org/10.4103/1673-5374.259617
  51. Bioorg Med Chem. 2019 Jul 05. pii: S0968-0896(19)30370-0. [Epub ahead of print]
    2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: Synthesis, evaluation of in vitro leishmanicidal activity, and mechanism of action.
    Zahra Mojallal-Tabatabaei, Parham Foroumadi, Mahsa Toolabi, Fereshteh Goli, Setareh Moghimi, Sussan Kaboudanian-Ardestani, Alireza Foroumadi.
      The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4'-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.
    Keywords:  1,3,4-Thiadiazole; Anti-leishmanial activity; Leishmania major; Redox system
    DOI:  https://doi.org/10.1016/j.bmc.2019.07.009
  52. Mol Neurobiol. 2019 Jul 13.
    Functional Regulation of an Oxidative Stress Mediator, Rac1, in Diabetic Retinopathy.
    Ghulam Mohammad, Arul J Duraisamy, Anjan Kowluru, Renu A Kowluru.
       PURPOSE: Early activation of cytosolic NADPH oxidase-2 (Nox2) in diabetes increases retinal ROS production, damaging their mitochondria. The assembly of Nox2 holoenzyme requires activation of a small molecular weight G protein Rac1. Rac1 activation is regulated by guanine exchange factors and guanine nucleotide-dissociation inhibitors, and post-translational modifications assist in its association with exchange factors and dissociation inhibitors. The goal of this study is to investigate the mechanisms of Rac1 activation in the development of diabetic retinopathy.
    METHODS: The levels of the dissociation inhibitor, prenylating enzyme (farnesyltransferase, FNTA), and exchange factor Vav2 were quantified in human retinal endothelial cells, incubated in normal or high glucose for 96 h. The roles of prenylation and Vav2 in Rac1-Nox2-ROS mitochondrial damage were confirmed in FNTA-siRNA-transfected cells and using the Vav2 inhibitor EHop, respectively. Retinal histopathology and functional changes associated with diabetic retinopathy were analyzed in diabetic mice receiving EHop for 6 months. Key parameters of Rac1 activation were confirmed in the retinal microvasculature from human donors with diabetic retinopathy.
    RESULTS: In HRECs, glucose increased FNTA and Vav2 and decreased the dissociation inhibitor. FNTA-siRNA and EHop inhibited glucose-induced activation of Rac1-Nox2-ROS signaling. In diabetic mice, EHop ameliorated the development of retinopathy and functional/structural abnormalities and attenuated Rac1-Nox2-mitochondrial damage. Similar alterations in Rac1 regulators were observed in retinal microvasculature from human donors with diabetic retinopathy. In diabetes, Rac1 prenylation and its interactions with Vav2 contribute to Nox2-ROS-mitochondrial damage, and the pharmacological inhibitors to attenuate Rac1 interactions with its regulators could have the potential to halt/inhibit the development of diabetic retinopathy. Graphical Abstract Activation of prenylating enzyme farnesyltransferase (FNTA) in diabetes, prenylates Rac1. The binding of Rac1 with guanine nucleotide-dissociation inhibitor (GDI) is decreased, but its association with the guanine exchange factor, Vav2, is increased, resulting in Rac1 activation. Active Rac1 helps in the assembly of Nox2 holoenzyme, and Nox2 activation increases cytosolic ROS production, damaging the mitochondria. Damaged mitochondria accelerate capillary cell apoptosis, and ultimately, results in the development of diabetic retinopathy.
    Keywords:  Diabetic retinopathy; NADPH oxidase; Oxidative stress; Post-translational modifications; Ras-related C3 botulinum toxin substrate 1, Rac1
    DOI:  https://doi.org/10.1007/s12035-019-01696-5
  53. Oxid Med Cell Longev. 2019 ;2019 3150145
    Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy.
    Huanhuan Lv, Chenxiao Zhen, Junyu Liu, Pengfei Yang, Lijiang Hu, Peng Shang.
      Glutathione is the principal intracellular antioxidant buffer against oxidative stress and mainly exists in the forms of reduced glutathione (GSH) and oxidized glutathione (GSSG). The processes of glutathione synthesis, transport, utilization, and metabolism are tightly controlled to maintain intracellular glutathione homeostasis and redox balance. As for cancer cells, they exhibit a greater ROS level than normal cells in order to meet the enhanced metabolism and vicious proliferation; meanwhile, they also have to develop an increased antioxidant defense system to cope with the higher oxidant state. Growing numbers of studies have implicated that altering the glutathione antioxidant system is associated with multiple forms of programmed cell death in cancer cells. In this review, we firstly focus on glutathione homeostasis from the perspectives of glutathione synthesis, distribution, transportation, and metabolism. Then, we discuss the function of glutathione in the antioxidant process. Afterwards, we also summarize the recent advance in the understanding of the mechanism by which glutathione plays a key role in multiple forms of programmed cell death, including apoptosis, necroptosis, ferroptosis, and autophagy. Finally, we highlight the glutathione-targeting therapeutic approaches toward cancers. A comprehensive review on the glutathione homeostasis and the role of glutathione depletion in programmed cell death provide insight into the redox-based research concerning cancer therapeutics.
    DOI:  https://doi.org/10.1155/2019/3150145
  54. J Inorg Biochem. 2019 Jun 26. pii: S0162-0134(19)30030-3. [Epub ahead of print]199 110758
    Pd(II) complexes with N-heteroaromatic hydrazone ligands: Anticancer activity, in silico and experimental target identification.
    Snežana K Bjelogrlić, Tamara R Todorović, Milan Kojić, Milan Senćanski, Milan Nikolić, Aleksandar Višnjevac, Jovana Araškov, Marija Miljković, Christian D Muller, Nenad R Filipović.
      Anticancer activity of Pd complexes 1-5 with bidentate N-heteroaromatic hydrazone ligands was investigated on human acute monocytic leukemia (THP-1; cells in a suspension) and human mammary adenocarcinoma (MCF-7; two-dimensional layer and three-dimensional spheroid tumor model) cell lines. For the Pd(II) complexes with condensation products of ethyl hydrazainoacetate and quinoline-8-carboxaldehyde (complex 1) and 2-formylpyridine (complex 3), for which apoptosis was determined as a mechanism of anticancer activity, further investigation revealed that they arrest the cell cycle in G0/G1 phase, induce generation of reactive oxygen species and inhibit Topoisomerase I in vitro. In silico studies corroborate experimental findings that these complexes show topoisomerase inhibition activity in the micromolar range and indicate binding to a DNA's minor groove as another potential target. Based on the results obtained by circular dichroism and fluorescence spectroscopy measurements, the most active complexes are suitable to be delivered to a blood stream via human serum albumin.
    Keywords:  Apoptosis; DNA interactions; HSA interactions; Hydrazones; Pd(II) complexes; Topoisomerase I inhibition
    DOI:  https://doi.org/10.1016/j.jinorgbio.2019.110758
  55. Mitochondrion. 2019 Jul 09. pii: S1567-7249(18)30294-0. [Epub ahead of print]
    Role of ectopically expressed mtDNA encoded cytochrome c oxidase subunit I (MT-COI) in tumorigenesis.
    Rajnish Kumar Singh, Sunil Kumar Saini, Gopinath Prakasam, Ponnuusamy Kalairasan, Rameshwar N K Bamezai.
      Somatic mutations within mitochondrial DNA (mtDNA) encoded cytochrome c oxidase subunit I (MT-COI) are frequent in various cancer types. In addition, perturbation from orchestrated expression of mitochondrial DNA encoded genes is also associated with complex disorders, including cancer. Since codon bias and the mitochondrial translation system restricts functional characterization of over-expressed wild type or mutant mitochondrial DNA encoded genes, the codon optimization and artificial synthesis of entire MT-CO1 allowed us to over-express the wild type and one of its deleterious mutants into the mitochondria of the transfected cells. Ectopically expressed MT-CO1 was observed to efficiently expressed and localized to mitochondria but showed high level of aggregation under denaturing condition upon heating. Over-expression of wild type or mutant variant of MT-CO1 promoted anchorage dependent and independent proliferation potential in in-vitro experiments and introduced the cancer cell metabolic phenotype of high glucose uptake and lactate release. Reactive oxygen species generated in cells over-expressing MT-CO1 variants acted as key effectors mediating differential expression of apoptosis and DNA damage pathway related genes. High ROS generated also down-regulated the expression of global regulators of gene expression, DNMT3A and DNMT3B. The down-regulated expression of DNMTs co-related with differential methylation of the CpG islands in the promoter region of a select set of studied genes, in a manner to promote pro-cancerous phenotype. Apart from assigning the mechanistic role to the MT-CO1 variants and their perturbed expression in cancer development, the present study provides novel insights into the functional role of somatic mutations within MT-CO1 promoting cancer phenotype.
    DOI:  https://doi.org/10.1016/j.mito.2019.07.002
  56. Life Sci. 2019 Jul 08. pii: S0024-3205(19)30565-X. [Epub ahead of print] 116639
    SIRT2 functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes.
    Dejun Xu, Xiaohan Jiang, Huanshan He, Dingban Liu, Li Yang, Huali Chen, Lin Wu, Guoxia Geng, Qingwang Li.
       AIMS: Sirtuins have been implicated in the aging process, however, the functions of SIRT2 in post-maturation aging of oocytes are not fully understood. The purpose of the present investigation was to assess the roles of SIRT2 in aged oocytes and mechanisms involved.
    MAIN METHODS: The fresh MII oocytes were aging in vitro, and treated with SIRT2 inhibitor (SirReal2), autophagy activator (Rapamycin), and autophagy inhibitor (3-Ma) for 24 h, respectively. Oocyte activation, cytoplasmic fragmentation, and spindle defects, mitochondrial distribution, ROS levels, ATP production, mitochondrial membrane potential, and early apoptosis were investigated. Western blotting was performed to determine LC3-II accumulation, SQSTM1 degradation, and caspase-3 activity.
    KEY FINDINGS: SIRT2 expression gradually decreased in a time-dependent manner during oocyte aging. Treatment with SirReal2 significantly increased the rates of oocyte activation, cytoplasmic fragmentation, and spindle defects. In particular, the high ROS levels, abnormal mitochondrial distribution, low ATP production, and lost ΔΨm were observed in SirReal2-exposed oocytes. Further analysis revealed that LC3-II accumulation and SQSTM1 degradation were induced by SIRT2 inhibition. By performing early apoptosis analysis showed that oocyte aging was accompanied with cellular apoptosis, and SIRT2 inhibition increased apoptosis rates of aged oocytes. Importantly, upregulating autophagy with Rapamycin could mimic the effects of SIRT2 inhibition on apoptosis by increasing caspase-3 activation, whereas downregulating autophagy with 3-MA could abolish those effects by blocking caspase-3 activation.
    SIGNIFICANCE: Our results suggest that SIRT2 inactivation is a key mechanism underlying of cellular aging, and SIRT2 inhibition contributes to autophagy-dependent cellular apoptosis in post-maturation oocytes.
    Keywords:  SIRT2; aging; apoptosis; autophagy; oocyte
    DOI:  https://doi.org/10.1016/j.lfs.2019.116639
  57. Naunyn Schmiedebergs Arch Pharmacol. 2019 Jul 06.
    Triggering of eryptosis, the suicidal erythrocyte death, by phenoxodiol.
    Madeline Fink, Abdulla Al Mamun Bhuyan, Bernd Nürnberg, Caterina Faggio, Florian Lang.
      Phenoxodiol is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. At least in theory, phenoxodiol could similarly stimulate suicidal erythrocyte death or eryptosis. Eryptosis is characterized by cell shrinkage and breakdown of cell membrane asymmetry with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca2+ activity ([Ca2+]i), formation of reactive oxygen species (ROS), and increase of ceramide abundance at the cell surface. The present study explored whether phenoxodiol induces eryptosis and whether it modifies Ca2+ entry, ROS, and ceramide. Using flow cytometry, phosphatidylserine exposure at the cell surface was quantified from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3 fluorescence, ROS from DCFDA-dependent fluorescence, and ceramide abundance utilizing specific antibodies. A 48-h exposure of human erythrocytes to phenoxodiol (100 μg/ml [416 μM]) significantly increased the percentage of annexin V binding cells, significantly decreased average forward scatter, and significantly increased Fluo3 fluorescence and ceramide abundance, but did not significantly modify DCFDA fluorescence. The effect of phenoxodiol on annexin V binding tended to decrease following removal of extracellular Ca2+, an effect, however, not reaching statistical significance. In conclusion, phenoxodiol triggers eryptosis, an effect paralleled by Ca2+ entry and increase of ceramide abundance.
    Keywords:  Calcium; Ceramide; Eryptosis; Oxidative stress; Phosphatidylserine; Red blood cells; Staurosporine
    DOI:  https://doi.org/10.1007/s00210-019-01681-8
  58. J Appl Toxicol. 2019 Jul 11.
    Toxic effects and involved molecular pathways of nanoparticles on cells and subcellular organelles.
    Na Liu, Meng Tang.
      Owing to the increasing application of engineered nanoparticles (NPs), besides the workplace, human beings are also exposed to NPs from nanoproducts through the skin, respiratory tract, digestive tract and vein injection. This review states pathways of cellular uptake, subcellular distribution and excretion of NPs. The uptake pathways commonly include phagocytosis, micropinocytosis, clathrin- and caveolae-mediated endocytosis, scavenger receptor-related pathway, clathrin- or caveolae-independent pathway, and direct penetration or insertion. Then the ability of NPs to decrease cell viability and metabolic activity, change cell morphology, and destroy cell membrane, cytoskeleton and cell function was presented. In addition, the lowest dose decreasing cell metabolic viability compared with the control or IC50 of silver, titanium dioxide, zinc oxide, carbon black, carbon nanotubes, silica, silicon NPs and cadmium telluride quantum dots to some cell lines was gathered. Next, this review attempts to increase our understanding of NP-caused adverse effects on organelles, which have implications in mitochondrial dysfunction, endoplasmic reticulum stress and lysosomal rupture. In particular, the disturbance of mitochondrial biogenesis and mitochondrial dynamic fusion-fission, mitophagy and cytochrome c-dependent apoptosis are involved. In addition, prolonged endoplasmic reticulum stress will result in apoptosis. Rupture of the lysosomal membrane was associated with inflammation, and both induction of autophagy and blockade of autophagic flow can result in cytotoxicity. Finally, the network mechanism of the combined action of multiple organelle dysfunction, apoptosis, autophagy and oxidative stress was discussed.
    Keywords:  ER stress; crosstalk; cytotoxicity; lysosomal rupture; mitochondrial dysfunction; nanoparticles; uptake pathways
    DOI:  https://doi.org/10.1002/jat.3817
  59. Mini Rev Med Chem. 2019 Jun 17.
    A review on anticancer potentials of benzothiazole derivatives.
    Nandini Pathak, Ekta Rathi, Nitesh Kumar, Suvarna G Kini, C Mallikarjuna Rao.
      Benzothiazole is an organic compound bearing a heterocyclic nucleus (thiazole) that imparts a broad spectrum of biological activity to it. The significant and potent activity of benzothiazole moiety influenced distinctively by nature and position of substitutions. This review summarizes of the effect of various substituents in recent trends and approaches to design and develop novel benzothiazole derivatives for anticancer potential in different cell lines by interpreting the structure-activity relationship (SAR) and mechanism of action of a wide range of derivatives. The list of derivatives are categorized in different groups and reviewed for their anticancer activity. The structure-activity relationship for the various derivatives revealed an excellent understanding of benzothiazole moiety in the field of cancer therapy against different cancer cell line. Data obtained from the various articles showed the potential effect of benzothiazole moiety and its derivatives to produce the peculiar and significant lead compound. The important anticancer mechanisms found are tyrosine kinase inhibition, topoisomerase inhibition and induction of apoptosis by reactive oxygen species (ROS) activation. Therefore, the design and development of novel benzothiazole have broad scope in cancer chemotherapy.
    Keywords:  Anticancer; Apoptosis; Benzothiazole; Cell line Mechanism of Action; Structure-activity relationship; Topoisomerase inhibition; Tyrosine kinase inhibition
    DOI:  https://doi.org/10.2174/1389557519666190617153213
  60. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1): 2846-2854
    Synthesis of silver nanoparticles (AgNPs) from leaf extract of Salvia miltiorrhiza and its anticancer potential in human prostate cancer LNCaP cell lines.
    Ke Zhang, Xiaodong Liu, Samson Oliver Abraham Samuel Ravi, Arunkumar Ramachandran, Ibrahim Abdel Aziz Ibrahim, Anmar M Nassir, Jiapei Yao.
      Biosynthesis of silver nanoparticles (AgNPs) from the medicinal plants has been considered as a remarkable approach of several therapeutic innovations and successful drug delivery. Silver nanoparticles were biosynthesized with Salvia miltiorrhiza, Chinese medicinal herb and assessed for its anticarcinogenic property. Synthesis of AgNPs was characterized by several studies such as UV-absorbance and it shows peak values in the range of 425-445 nm. The sizes of the nanoparticles are confirmed by dynamic light scattering analysis and it shows 100 nm. Furthermore, transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDX) was to confirm the shape and Ag particles are present in the synthesized materials. FTIR analysis to find out the active biomolecules located in the surface of the synthesized particles. This AgNPs from S. miltiorrhiza inhibits the growth of Bacillus subtillis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumonia. Furthermore, the anticancer potential of AgNPs is examined in prostate adenocarcinoma (LNCaP) cell lines. In this study, we found the AgNPs effectively induces cytotoxicity, ROS and apoptosis by modulation of intrinsic apoptoic Bcl2, Bclxl, Bax and Caspase 3 protein expressions in LNCap cell lines. Based on the study, synthesis of AgNPs from S. miltiorrhiza shows eco-friendly and it exhibits antimicrobial and anticarcinogenic effects.
    Keywords:  ; prostate adenocarcinoma
    DOI:  https://doi.org/10.1080/21691401.2019.1638792
  61. Oxid Med Cell Longev. 2019 ;2019 2346580
    Mitochondria-Targeted Peptide SS31 Attenuates Renal Tubulointerstitial Injury via Inhibiting Mitochondrial Fission in Diabetic Mice.
    Shi-Kun Yang, Ai-Mei Li, Ya-Chun Han, Can-Hui Peng, Na Song, Ming Yang, Ming Zhan, Ling-Feng Zeng, Pan-Ai Song, Wei Zhang, Shi-Qi Tang, Hao Zhang.
       Objective: Renal tubular injury is an early characteristic of diabetic nephropathy (DN) that is related to mitochondrial dysfunction. In this study, we explore the effects and mechanisms of mitochondria-targeted peptide SS31 on renal tubulointerstitial injury in DN.
    Method: 40 C57BL/6 mice were randomly divided into control group, STZ group, STZ+SS31 group, and STZ+normal saline group. SS31 was intraperitoneally injected to the mice every other day for 24 weeks. Renal lesions and the expression of Drp1, Mfn1, Bcl-2, Bax, Caspase1, IL-1β, and FN were detected. In in vitro studies, HK-2 cells were incubated with different concentrations of D-glucose (5, 30 mM) or combined with SS31 and Drp1 inhibitor Midivi1. Mitochondrial ROS, membrane potential, and morphology have been detected to evaluate the mitochondrial function.
    Results: Compared with diabetic mice, the levels of serum creatinine and microalbuminuria were significantly decreased in the SS31 group. Renal tubulointerstitial fibrosis, oxidative stress, and apoptosis were observed in diabetic mice, while the pathological changes were reduced in the SS31-treatment group. SS31 could decrease the expression of Drp1, Bax, Caspase1, IL-1β, and FN in the renal tissue of diabetic mice, while increasing the expression of Mfn1. Additionally, mitochondria exhibit focal enlargement and crista swelling in renal tubular cells of diabetic mice, while SS31 treatment could partially block these changes. An in vitro study showed that pretreatment with SS31 or Drp1 inhibitor Mdivi1 could restore the level of mitochondrial ROS, the membrane potential levels, and the expressions of Drp1, Bax, Caspase1, IL-1β, and FN in HK-2 cells under high-glucose conditions.
    Conclusion: SS31 protected renal tubulointerstitial injury in diabetic mice through a decrease in mitochondrial fragmentation via suppressing the expression of Drp1 and increasing the expression of Mfn1.
    DOI:  https://doi.org/10.1155/2019/2346580
  62. Eur Rev Med Pharmacol Sci. 2019 Jul;pii: 18344. [Epub ahead of print]23(13): 5980-5986
    Protective effect of remifentanil on myocardial ischemia-reperfusion injury through Fas apoptosis signaling pathway.
    Z-Ju Qu, Z-Ji Qu, H-B Zhou, C-S Xu, D-Z Zhang, G Wang.
       OBJECTIVE: The aim of this study was to investigate the protective effect of remifentanil (RFT) on myocardial ischemia-reperfusion (IR) injury through Fas apoptosis signaling pathway.
    MATERIALS AND METHODS: A total of 36 Sprague-Dawley (SD) rats were randomly divided into 3 groups, including the sham operation (Sham) group, IR model (IR) group and RFT pretreatment (RFT) group, with 12 rats in each group. Myocardial tissues of rats in each group were collected. Hematoxylin and eosin (H&E) staining was used to examine the pathological differences of the myocardium in the three groups. The levels of lactate dehydrogenase (LDH), creatine kinase (CK), superoxide dismutase (SOD) and malondialdehyde (MDA) in the serum of rats in each group were detected by enzyme-linked immunosorbent assay (ELISA). Meanwhile, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was adopted to detect the apoptosis level of myocardial cells in each group. Furthermore, Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting were applied to measure the mRNA and protein expression levels of Fas and its pathway indexes, respectively.
    RESULTS: Compared with the Sham group, LDH and CK activities and MDA level in the IR group were significantly increased, whereas the level of SOD was remarkably decreased (p<0.05). Compared with the IR group, RFT pretreatment could significantly reduce the release of LDH and CK-muscle/brain (CK-MB), increase SOD level and decrease MDA level (p<0.05). TUNEL results manifested that the apoptosis rate of myocardial cells in the IR group was markedly increased than that of the Sham group (p<0.05). Meanwhile, the apoptosis rate of myocardial cells in the RFT group was notably decreased when compared with that of the IR group (p<0.05). ELISA results demonstrated that the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) proteins in the RTF group were significantly lower than those of the IR group (p<0.05). RT-PCR and Western blotting results indicated that the expressions of Fas, Fas ligand (FasL), and Fas-associated protein with death domain (FADD) in IR and RFT groups were significantly higher than those of the Sham group (p<0.05). However, RTF pretreatment could markedly reduce the levels of Fas, FasL, and FADD (p<0.05).
    CONCLUSIONS: RFT can reduce the apoptosis of myocardial cells as well as IR-induced oxidative stress and inflammation by inhibiting the Fas/FasL signal transduction pathway.
    DOI:  https://doi.org/10.26355/eurrev_201907_18344
  63. Eur Rev Med Pharmacol Sci. 2019 Jun;pii: 18219. [Epub ahead of print]23(12): 5495-5502
    22-oxacalcitriol protects myocardial ischemia-reperfusion injury by suppressing NF-κB/TNF-α pathway.
    C-N Zhou, W Yao, Y-N Gong, Y Li, C-H Wang, Y-F Huo.
       OBJECTIVE: The aim of this study was to explore whether 22-oxacalcitriol could protect inflammatory response induced by ischemia-reperfusion injury (IRI) in rats, and to investigate its underlying mechanism.
    MATERIALS AND METHODS: 24 male Sprague Dawley rats were randomly assigned into the sham group, the IRI group and the 22-oxacalcitriol group, with 8 rats in each group. Serum and heart samples of each rat were collected 10 days after the animal procedure. The serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in each rat were detected by relative commercial kits. Pathological lesions in rat myocardium were observed by hematoxylin and eosin (HE) staining. Cardiomyocyte apoptosis in rat heart was accessed by TUNEL staining. Meanwhile, the serum levels of tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), and KC-GRO were detected by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR). Also, the protein expression levels of NF-κB, TNF-α, VCAM-1, ICAM-1, and MCP-1 in rat myocardium were detected by Western blot and immunohistochemistry.
    RESULTS: The serum levels of CK-MB and LDH in rats of the IRI group were significantly higher than those of the sham group. 22-oxacalcitriol treatment remarkably decreased the serum levels of CK-MB and LDH when compared with the IRI group. However, cardiomyocyte apoptosis of the 22-oxacalcitriol group was markedly less than the IRI group. The activities of SOD, GSH, CAT and T-AOC in the cardiac homogenate of the 22-oxacalcitriol group were significantly elevated than those of the IRI group. Meanwhile, malondialdehyde (MDA) and reactive oxygen species (ROS) levels were remarkably decreased by 22-oxacalcitriol treatment. Furthermore, the serum levels of TNF-α, IL-1β, IL-6 and KC-GRO were significantly downregulated in the 22-oxacalcitriol group. Western blot results showed that the protein expression levels of NF-κB, TNF-α, VCAM-1, ICAM-1 and MCP-1 in the 22-oxacalcitriol group were significantly lower than those of the IRI group.
    CONCLUSIONS: 22-oxacalcitriol inhibits the inflammatory response in the myocardium by suppressing NF-kB/TNF-α pathway, thereby protecting myocardial ischemia-reperfusion injury in rats.
    DOI:  https://doi.org/10.26355/eurrev_201906_18219
  64. Biosci Rep. 2019 Jul 08. pii: BSR20190578. [Epub ahead of print]
    Tension induces intervertebral disc degeneration via endoplasmic reticulum stress-mediated autophagy.
    Jiangwei Chen, Zunwen Lin, Kui Deng, Bin Shao, Dong Yang.
      Intervertebral disc degeneration is a common degenerative disease. This study aimed to explore the role and mechanism of tension-induced endoplasmic reticulum stress in intervertebral disc degeneration. Intervertebral disc degeneration models of SD rat were analyzed for apoptosis, the expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP using immunohistochemistry, qPCR and Western blot analysis. Annulus fibrosus cells of intervertebral disc were isolated, subjected to cyclic deformation stress and analyzed for ROS and apoptosis, lysosome activity and expression of genes. The cells were knockdown with siRNA or treated with endoplasmic reticulum stress inhibitor 4-PBA and assayed for ROS, apoptosis, lysosome activity and gene expression. Compared with the controls, intervertebral disc degeneration was observed through X-rays examination and HS staining. Apoptosis and expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP were significantly increased in the intervertebral disc tissue of the models. In mechanic mimic experiments, the primary annulus fibrosus cells were subjected to 18% cyclic deformation, ROS and apoptosis as well as the activity of lysosome were increased. Similarly, the expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP was also increased significantly after deformation treatment. On other hand, when the cells were treated with 9 mM 4-PBA and/or CHOP-siRNA4, the apoptosis rate, ROS level, lysosome activity and expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP were significantly reduced. Autophagy reaction mediated by endoplasmic reticulum stress plays important rale in tension-induced intervertebral disc degeneration. Intervertebral disc degeneration likely results from interactions between autophagy, apoptosis and reticulum stress, and is ROS-dependent.
    Keywords:  autophagy; cyclic deformation; endoplasmic reticulum stress; intervertebral disc degeneration
    DOI:  https://doi.org/10.1042/BSR20190578
  65. Environ Monit Assess. 2019 Jul 11. 191(8): 490
    Cadmium induces GAPDH- and- MDH mediated delayed cell aging and dysfunction in Candida tropicalis 3Aer.
    Zaman Khan, Muhammad Atif Nisar, Saima Muzammil, Saima Zafar, Inga Zerr, Abdul Rehman.
      Eukaryotes employ various mechanisms to survive environmental stress conditions. Multicellular organisms eliminate permanently damaged cells by apoptosis, while unicellular eukaryotes like yeast react by decelerating cell aging. In the present study, transcriptomic and proteomic approaches were employed to elucidate the underlying mechanism of delayed apoptosis. Our findings suggest that Candida tropicalis 3Aer has a set of tightly controlled genes that are activated under Cd+2 exposition. Acute exposure to Cd+2 halts the cell cycle at the G2/M phase checkpoint and activates multiple cytoplasmic proteins that overcome effects of Cd+2-induced reactive oxygen species. Prolonged Cd+2 stress damages DNA and initiates GAPDH amyloid formation. This is the first report that Cd+2 challenge initiates dynamic redistribution of GAPDH and MDH and alters various metabolic pathways including the pentose phosphate pathway. In conclusion, the intracellular redistribution of GAPDH and MDH induced by prolonged cadmium stress modulates various cellular reactions, which facilitate delayed aging in the yeast cell.
    Keywords:  Apoptosis; Candida tropicalis 3Aer; Cd+2 stress; Cell cycle; Non-protein thiols
    DOI:  https://doi.org/10.1007/s10661-019-7631-9
  66. Eur J Nutr. 2019 Jul 06.
    Beneficial effects of δ-tocotrienol against oxidative stress in osteoblastic cells: studies on the mechanisms of action.
    Lavinia Casati, Francesca Pagani, Patrizia Limonta, Claudia Vanetti, Giovanni Stancari, Valeria Sibilia.
       PURPOSE: Natural antioxidants are considered as promising compounds in the prevention/treatment of osteoporosis. We studied the ability of purified δ-tocotrienol (δ-TT) isolated from a commercial palm oil (Elaeis guineensis) fraction to protect osteoblast MC3T3-E1 and osteocyte MLO-Y4 cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage and the mechanisms involved in its protective action in MC3T3-E1.
    METHODS: MC3T3-E1 and MLO-Y4 cells were treated with δ-TT (1.25-20 µg/ml for 2 h) followed by t-BHP at 250 µM or 125 µM for 3 h, respectively. MTT test was used to measure cell viability. Apoptotic cells were stained with Hoechst-33258 dye. Intracellular ROS levels were measured by dichlorofluorescein CM-DCFA. The OPT fluorimetric assay was used to detect the reduced glutathione to oxidized glutathione ratio (GSH/GSSG) contents.
    RESULTS: δ-TT significantly prevented the effects of t-BHP on cell viability and apoptosis reaching a maximum protective activity at 10 and 5 µg/ml in MC3T3-E1 and MLO-Y4 cells, respectively. This protective effect was due to a reduction of intracellular ROS levels and an increase in the defense systems shown by the increase in the GSH/GSSG. GSH loss induced by an inhibitor of GSH synthesis significantly reduced the δ-TT-positive effect on ROS levels. δ-TT prevention of oxidative damage was completely removed by combined treatment with the specific inhibitors of PI3K/AKT (LY294002) and Nrf2 (ML385).
    CONCLUSIONS: The δ-TT protective effect against oxidative damage in MC3T3-E1 cells is due to a reduction of intracellular ROS levels and an increase of the GSH/GSSG ratio, and involves an interaction between the PI3K/Akt-Nrf2 signaling pathways.
    Keywords:  MC3T3-E1 cells; MLO-Y4 cells; Oxidative stress; Signaling pathways; Tocotrienol
    DOI:  https://doi.org/10.1007/s00394-019-02047-9
  67. Sci Total Environ. 2019 Jul 02. pii: S0048-9697(19)33095-5. [Epub ahead of print]690 158-166
    Shape-dependent toxicity of alumina nanoparticles in rat astrocytes.
    Li Dong, Song Tang, Fuchang Deng, Yufeng Gong, Kangfeng Zhao, Jianjun Zhou, Donghai Liang, Jianlong Fang, Markus Hecker, John P Giesy, Xuetao Bai, Hongwei Zhang.
      Nanosized alumina (Al2O3-NPs), a widely used nanoparticle in numerous commercial applications, is released into environment posing a threat to the health of wildlife and humans. Recent research has revealed essential roles of physicochemical properties of nanoparticles in determining their toxicity potencies. However, influence of shape on neurotoxicity induced by heterogeneous Al2O3-NPs remains unknown. We herein compared the neurotoxicity of two shapes of γ-Al2O3-NPs (flake versus rod) and their effects on metabolic profiles of astrocytes in rat cerebral cortex. While exposed to both shapes caused significant cytotoxicity and apoptosis in a dose-dependent manner after 72 h exposure, a significantly stronger response was observed for nanorods than for nanoflakes. These effects were associated with significantly greater ROS accumulation and inflammation induction, as indicated by increased concentrations of IL-1β, IL-2 and IL-6. Using untargeted metabolomics, significant alternations in metabolism of amino acids, lipids and purines, and pyrimidines were observed after exposure to both types. Moreover, changes in the metabolome caused by nanorods were significantly greater than those by nanoflakes as also indicated by physiological stress responses to ROS, inflammation, and apoptosis. Taken together, these findings demonstrated the critical role of morphology in determining toxic potencies of nano-alumina and its underlying mechanisms of toxic actions.
    Keywords:  Apoptosis; Brain; Inflammation; Morphology; Nanoparticles; Oxidative stress; Pathway analysis; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.scitotenv.2019.06.532
  68. Redox Biol. 2019 Jun 28. pii: S2213-2317(19)30446-X. [Epub ahead of print]26 101261
    Self-defense of macrophages against oxidative injury: Fighting for their own survival.
    László Virág, Rafael I Jaén, Zsolt Regdon, Lisardo Boscá, Patricia Prieto.
      Activated macrophages play a central role in both the development and resolution of inflammation. These immune cells need to be functional in harmful conditions with high levels of reactive oxygen and nitrogen species that can damage their basic cell components, which may alter their metabolism. An excessive accumulation of these cell alterations drives macrophages inexorably to cell death, which has been associated to the development of several inflammatory diseases and even with aging in a process termed as "immunosenescence". Macrophages, however, exhibit a prolonged survival in this hostile environment because they equip themselves with a complex network of protective mechanisms. Here we provide an overview of these self-defense mechanisms with special attention being paid to bioactive lipid mediators, NRF2 signaling and metabolic reprogramming.
    Keywords:  Aging; Antioxidant; Apoptosis; Eicosanoids; FOXO; HO-1; Immunity; Inflammation; Macrophage; Metabolism; NRF2; Oxidative burst; PARP1; Parthanatos; Senescence; Specialized pro-resolving mediators
    DOI:  https://doi.org/10.1016/j.redox.2019.101261
  69. Front Pharmacol. 2019 ;10 700
    Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract.
    Li Lin, Gang Hou, Dan Han, Jian Kang, Qiuyue Wang.
      Background: We found previously that ursolic acid (UA) administration could alleviate cigarette smoke-induced emphysema in rats partly through the unfolded protein response (UPR) PERK-CHOP and Nrf2 pathways, thus alleviating endoplasmic reticulum stress (ERS)-associated oxidative stress and cell apoptosis. We hypothesized that other UPR pathways may play similar roles in cigarette smoke extract (CSE)-induced emphysema. So, we sought to investigate the dynamic changes and effects of UPR and the downstream apoptotic pathways. Further, we investigated whether UA could alleviate CSE-induced emphysema and airway remodelling in rats, whether and when it exerts its effects through UPR pathways as well as Smads pathways. Methods: One hundred eight Sprague Dawley (SD) rats were randomly divided into three groups: Sham group, CSE group, and UA group, and each group was further divided into three subgroups, administered CSE (vehicle) for 2, 3, or 4 weeks; each subgroup had 12 rats. We examined pathological changes, analyzed the three UPR signaling pathways and subsequent ERS, intrinsic and extrinsic apoptotic pathway indicators, as well as activation of Smad2,3 molecules in rat lungs. Results: Exposure to CSE for 3 or 4 weeks could apparently induce emphysema and airway remodeling in rats, including gross and microscopic changes, alteration of mean alveolar number (MAN), mean linear intercept (MLI), and mean airway thickness in lung tissue sections. UA intervention could significantly alleviate CSE-induced emphysema and airway remodeling in rats. UA exerted its effects through ameliorating apoptosis by down regulating UPR signalling pathways and subsequent apoptosis pathways, as well as, downregulating p-Smad2 and p-Smad3 molecules. Conclusions: UA attenuated CSE-induced emphysema and airway remodeling, exerting its effects partly through regulation of three UPR pathways, amelioration downstream apoptotic pathways, and alleviating activation of Smad2 and Smad3.
    Keywords:  airway remodeling; chronic obstructive pulmonary disease; cigarette smoke extract; endoplasmic reticulum stress; ursolic acid
    DOI:  https://doi.org/10.3389/fphar.2019.00700
  70. Aging (Albany NY). 2019 Jul 13. 11
    Tea polyphenol protects against cisplatin-induced meiotic defects in porcine oocytes.
    Changyin Zhou, Xue Zhang, Xiayan ShiYang, Huili Wang, Bo Xiong.
      DDP (cisplatin), a DNA cross-linking agent, is one of the most common chemotherapeutic drugs that have been widely used in the treatment of sarcomas and germ cell tumors. DDP treatment exhibits severe side effects including renal toxicity, ototoxicity and embryo-toxicity. Women of reproductive age treated with DDP may lead to loss of primordial follicles, resulting in the depletion of the ovarian reserve and consequent premature ovarian failure. However, the influence of DDP on the oocyte quality and the strategy to prevent it has not yet fully clarified. Here, we report that DDP exposure resulted in the oocyte meiotic failure via disrupting the meiotic organelle dynamics and arrangement, exhibiting a prominently impaired cytoskeleton assembly, including spindle formation and actin polymerization. In addition, exposure to DDP led to the abnormal distribution of mitochondrion and cortical granules, two indicators of cytoplasmic maturation of oocytes. Conversely, TP (tea polyphenols) supplementation partially restored all of the meiotic defects resulted from DDP exposure through suppressing the increase of ROS level and the occurrence of DNA damage as well as apoptosis.
    Keywords:  cisplatin; meiotic failure; oocyte quality; organelle dynamics; tea polyphenol
    DOI:  https://doi.org/10.18632/aging.102084
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