bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019‒08‒18
sixty-two papers selected by
Gavin McStay
Staffordshire University
  1. HO-1 reduces heat stress-induced apoptosis in bovine granulosa cells by suppressing oxidative stress.
  2. Apigenin attenuates edifenphos-induced toxicity by modulating ROS-mediated oxidative stress, mitochondrial dysfunction and caspase signal pathway in rat liver and kidney.
  3. Berberine exhibits antioxidative effects and reduces apoptosis of the vaginal epithelium in bacterial vaginosis.
  4. Cadmium induces cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells.
  5. Melatonin Prevents Mice Cortical Astrocytes From Hemin-Induced Toxicity Through Activating PKCα/Nrf2/HO-1 Signaling in vitro.
  6. Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis.
  7. Studies on the Neuroprotection of Osthole on Glutamate-Induced Apoptotic Cells and an Alzheimer's Disease Mouse Model via Modulation Oxidative Stress.
  8. The Neuroprotective Role of Coenzyme Q10 Against Lead Acetate-Induced Neurotoxicity Is Mediated by Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities.
  9. Neuroprotective effects of increasing levels of HSP70 against neuroinflammation in Parkinson's disease model by inhibition of NF-κB and STAT3.
  10. Peroxiredoxin 5 prevents diethylhexyl phthalate-induced neuronal cell death by inhibiting mitochondrial fission in mouse hippocampal HT-22 cells.
  11. Phosphocreatine attenuates Gynura segetum-induced hepatocyte apoptosis via a SIRT3-SOD2-mitochondrial reactive oxygen species pathway.
  12. The mycotoxin beauvericin induces oocyte mitochondrial dysfunction and affects embryo development in the juvenile sheep.
  13. Carbamazepine, a Histone Deacetylase Inhibitor Induces Apoptosis in Human Colon Adenocarcinoma Cell Line HT-29.
  14. Effect of M2 Macrophages on Injury and Apoptosis of Renal Tubular Epithelial Cells Induced by Calcium Oxalate Crystals.
  15. Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis.
  16. ROS-mediated JNK pathway critically contributes to PFOS-triggered apoptosis in SH-SY5Y cells.
  17. Overcoming multidrug resistance by activating unfolded protein response of the endoplasmic reticulum in cisplatin-resistant A2780/CisR ovarian cancer cells.
  18. MicroRNA-34a and MicroRNA-181a Mediate Visfatin-Induced Apoptosis and Oxidative Stress via NF-κB Pathway in Human Osteoarthritic Chondrocytes.
  19. ROS, not Ca2+ , mediates methotrexate-induced autophagy and apoptosis in spermatocyte cell line.
  20. Ivermectin induces apoptosis of porcine trophectoderm and uterine luminal epithelial cells through loss of mitochondrial membrane potential, mitochondrial calcium ion overload, and reactive oxygen species generation.
  21. Isopsoralen ameliorates H2O2-induced damage in osteoblasts via activating the Wnt/β-catenin pathway.
  22. Effects of inflammatory responses, apoptosis, and STAT3/NF-κB- and Nrf2-mediated oxidative stress on benign prostatic hyperplasia induced by a high-fat diet.
  23. Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K/AKT/mTOR pathway.
  24. Salidroside attenuates dextran sulfate sodium-induced colitis in mice via SIRT1/FoxOs signaling pathway.
  25. Effect of oocyte vitrification on DNA damage in metaphase II oocytes and the resulting preimplantation embryos.
  26. The conundrum of dietary antioxidants in cancer chemotherapy.
  27. Melatonin Improves the Fertilization Capacity of Sex-Sorted Bull Sperm by Inhibiting Apoptosis and Increasing Fertilization Capacitation via MT1.
  28. Oxidative stress induces apoptosis via calpain- and caspase-3- mediated cleavage of ATM in pancreatic acinar cells.
  29. Nephroprotective Effect of Moringa Oleifera Seed Oil on Gentamicin-Induced Nephrotoxicity in Rats: Biochemical Evaluation of Antioxidant, Anti-inflammatory, and Antiapoptotic Pathways.
  30. Ethanol exposure in prenatal and early postnatal induced cardiac injury in rats: involvement of oxidative stress, Hsp70, ERK 1/2, JNK, and apoptosis in a 3-month follow-up study.
  31. Choline, not folate, can attenuate the teratogenic effects ofdibutyl phthalate (DBP) during early chick embryo development.
  32. Aucubin, a natural iridoid glucoside, attenuates oxidative stress-induced testis injury by inhibiting JNK and CHOP activation via Nrf2 up-regulation.
  33. Alyssin and Iberin in Cruciferous Vegetables Exert Anticancer Activity in HepG2 by Increasing Intracellular Reactive Oxygen Species and Tubulin Depolymerization.
  34. Tris(1,3-dichloro-2-propyl) Phosphate (TDCPP) disturbs mouse embryonic development by inducing apoptosis and abnormal DNA methylation.
  35. Nox2 and Nox4 Participate in ROS-Induced Neuronal Apoptosis and Brain Injury During Ischemia-Reperfusion in Rats.
  36. Protective Effects of Naringenin in a Rat Model of Sepsis-Triggered Acute Kidney Injury via Activation of Antioxidant Enzymes and Reduction in Urinary Angiotensinogen.
  37. The protective effect of klotho against contrast-associated acute kidney injury via the anti-oxidative effect.
  38. ROS-Responsive Blended Nanoparticles: Cascade-Amplifying Synergistic Effects of Sonochemotherapy with On-demand Boosted Drug Release During SDT Process.
  39. Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening.
  40. Puerarin protects pulmonary arteries from hypoxic injury through the BMPRII and PPARγ signaling pathways in endothelial cells.
  41. Ferulic acid ameliorates pentylenetetrazol-induced seizures by reducing neuron cell death.
  42. Knockdown of TRIM32 Protects Hippocampal Neurons from Oxygen-Glucose Deprivation-Induced Injury.
  43. Bisdemethoxycurcumin protects cardiomyocyte mainly depends on Nrf2/HO-1 activation mediated by PI3K/AKT pathway.
  44. Reduction of miR-29a-3p induced cardiac ischemia reperfusion injury in mice via targeting Bax.
  45. The Stability and Activity Changes of Apigenin and Luteolin in Human Cervical Cancer Hela Cells in Response to Heat Treatment and Fe2+/Cu2+ Addition.
  46. MiR-34c acts as a tumor suppressor in non-small cell lung cancer by inducing endoplasmic reticulum stress through targeting HMGB1.
  47. Eco-friendly green synthesis of silver nanoparticles and their potential applications as antioxidant and anticancer agents.
  48. Co-enzyme Q10 protects primary chicken myocardial cells from heat stress by upregulating autophagy and suppressing the PI3K/AKT/mTOR pathway.
  49. Protective Role of Epigallocatechin Gallate in a Rat Model of Cisplatin-Induced Cerebral Inflammation and Oxidative Damage: Impact of Modulating NF-κB and Nrf2.
  50. Protective effect of Ganoderma atrum polysaccharide on acrolein-induced macrophage injury via autophagy-dependent apoptosis pathway.
  51. Platinum(ii) complexes showing high cytotoxicity toward A2780 ovarian carcinoma cells.
  52. Radioprotective effect of olanzapine as an anti-psychotic drug against genotoxicity and apoptosis induced by ionizing radiation on human lymphocytes.
  53. Atorvastatin Induces Hepatotoxicity in Diabetic Rats via Oxidative Stress, Inflammation, and Anti-Apoptotic Pathway.
  54. CIRP downregulation renders cardiac cells prone to apoptosis in heart failure.
  55. LncRNA-ROR is involved in cerebral hypoxia/reoxygenation-induced injury via regulating miR-135a-5p/ROCK1/2.
  56. Therapeutic efficacy of Phyllanthus emblica-coated iron oxide nanoparticles in A549 lung cancer cell line.
  57. TIGAR promotes growth, survival and metastasis through oxidation resistance and AKT activation in glioblastoma.
  58. Effects of ginsenoside Rb1 on spinal cord ischemia-reperfusion injury in rats.
  59. Activation of the NLRP3 and AIM2 inflammasomes in a mouse model of Schistosoma mansoni infection.
  60. Fas-associated factor 1 Mediates NADPH Oxidase-Induced Reactive Oxygen Species Production and Proinflammatory Responses in Macrophages against Listeria Infection.
  61. (Pro)renin receptor contributes to renal mitochondria dysfunction, apoptosis and fibrosis in diabetic mice.
  62. The role of ferroptosis in digestive system cancer.
  1. Aging (Albany NY). 2019 Aug 12. 11
    HO-1 reduces heat stress-induced apoptosis in bovine granulosa cells by suppressing oxidative stress.
    Yiru Wang, Caixia Yang, Nahla Abdalla Hassan Elsheikh, Chengmin Li, Fangxiao Yang, Genlin Wang, Lian Li.
      Heat stress negatively affects reproduction in cattle by disrupting the normal function of ovarian granulosa cells (GCs), ultimately leading to oxidative damage and cell death via apoptosis. Heme oxygenase-1(HO-1) is a member of the heat shock protein family, which are associated with cellular antioxidant defenses and anti-apoptotic functions. Recent studies demonstrated that HO-1 is upregulated in heat-stressed cells. In the present study, we investigated the expression of HO-1 in bovine GCs transiently exposed to heat stress and characterized the expression and activity of key oxidative stress enzymes and molecules. We show that heat stress induced oxidative stress and apoptosis, and enhanced Nrf2 and HO-1 expression in primary GC cultures. Knocking down HO-1 expression using siRNA exacerbated both oxidative stress and apoptosis, whereas pre-treating GCs with hemin, which induces HO-1 expression, partially prevented these effects. These findings demonstrate that HO-1 attenuates heat stress-induced apoptosis in bovine GCs by decreasing production of reactive oxygen species and activating the antioxidant response.
    Keywords:  HO-1; apoptosis; granulosa cells; heat stress; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.18632/aging.102136
  2. Pestic Biochem Physiol. 2019 Sep;pii: S0048-3575(19)30214-7. [Epub ahead of print]159 163-172
    Apigenin attenuates edifenphos-induced toxicity by modulating ROS-mediated oxidative stress, mitochondrial dysfunction and caspase signal pathway in rat liver and kidney.
    Ajaz Ahmad, Pooja Kumari, Masood Ahmad.
      Edifenphos (EDF) (O-ethyl-S, S-diphenyldithiophosphate) is an organophosphate pesticide that is extensively used as a fungicide in agricultural rice fields. However, EDF accumulated in various agricultural products and caused potential health hazards to human and other living organisms. Therefore, the present study was investigated to evaluate the ameliorative role of apigenin (APG); a natural antioxidant against EDF-induced hepato-renal toxicity in rats. Six groups with five male Wistar rats each, were used for this purpose; these groups included the control group (A) that received corn oil; (B) 10 mg/kg APG; (C) 10 mg/kg EDF; (D) 25 mg/kg EDF; (E) 10 mg/kg APG pretreatment for 1 h then 10 mg/kg EDF; (F) 10 mg/kg APG pretreatment for 1 h then 25 mg/kg EDF for 14 consecutive days. Oral administration of EDF led to disruption of the intracellular antioxidant machinery which cause the generation of intracellular reactive oxygen species (ROS). However, EDF promotes deleterious effects like oxidative stress, DNA damage, reduced mitochondrial membrane potential, generation of ROS production, activation of caspase 3/9 activities and causing hepato-renal histopathological changes. However, the pretreatment of APG ameliorated the EDF-induced oxidative damage and apoptosis, through their antioxidant activity or by directly scavenging free radical property. Overall, these results suggest that EDF exerts oxidative stress, and APG could be a potent dietary anti-oxidant regimen against EDF-induced toxicity.
    Keywords:  Apigenin; Apoptosis; DNA damage; Edifenphos; Intracellular reactive oxygen species; Toxicity
    DOI:  https://doi.org/10.1016/j.pestbp.2019.06.010
  3. Exp Ther Med. 2019 Sep;18(3): 2122-2130
    Berberine exhibits antioxidative effects and reduces apoptosis of the vaginal epithelium in bacterial vaginosis.
    Xiuzhen Ma, Junfeng Deng, Xinmu Cui, Qi Chen, Weihua Wang.
      Bacterial vaginosis (BV) is a common type of vaginitis. Berberine is a natural alkaline product that reduces oxidative stress and apoptosis in cells. The aim of the present study was to investigate the effects of berberine on oxidative stress and apoptotic rates of BV. Vaginal epithelial and discharge samples were obtained from 60 healthy individuals and 180 patients with BV before and after one month of berberine treatment. Clinical observation was documented for all patients before and after treatment for comparison. Additionally, an in vitro study was performed; the samples were divided into groups the following groups: Control, model (H2O2-treated), LT (low-dose berberine), MT (medium-dose berberine) and HT (high-dose berberine). Expression levels of the oxidative stress related proteins were detected by western blotting. Clinical symptoms of patients with BV significantly improved following berberine treatment. Oxidative stress in vaginal discharge was significantly lower following treatment, indicated by the increased activity of superoxide dismutase (SOD) and catalase, as well as the reduced levels of malondialdehyde and H2O2. Apoptosis of the vaginal epithelial cells was also reduced, which was indicated by the reduced expression of apoptosis proteins caspase-3, cytochrome C, capase-12 and Bax, and increased expression of Bcl-2. The results of the in vitro experiments demonstrated a dose-dependent decrease in apoptosis with berberine treatment compared with levels before treatment. Oxidative stress relief was demonstrated by the reduced reactive oxygen species level and increased SOD and endothelial nitric oxide synthase levels, whereas suppression of apoptosis was further supported by the reduction in apoptotic proteins, as well as a decreased Bax/Bcl-2 ratio. Berberine exhibited effects on lowering oxidative stress in vaginal discharge and reducing oxidative damage, as well as apoptosis of the vaginal epithelium, which are beneficial to patients with bacterial vaginosis.
    Keywords:  apoptosis; bacterial vaginosis; berberine; hydrogen peroxide; oxidative stress
    DOI:  https://doi.org/10.3892/etm.2019.7772
  4. Toxicol In Vitro. 2019 Aug 13. pii: S0887-2333(19)30377-7. [Epub ahead of print] 104625
    Cadmium induces cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells.
    Jionghan Zhuang, Gaohui Nie, Fan Yang, Xueyan Dai, Huabin Cao, Chenghong Xing, Guoliang Hu, Caiying Zhang.
      Cadmium (Cd) is a well studied nephrotoxic metal element. To investigate the effects of Cd-induced cytotoxicity on oxidative stress-mediated apoptosis in primary renal tubular epithelial cells of duck. Shaoxing duck (Anas platyrhyncha) renal tubular epithelial cells were cultured in medium in absence and presence of 3CdSO4·8H2O (1.25, 2.5, 5.0 μM Cd), in N-acetyl-l-cysteine (NAC) (100 μM), and the combination of Cd and NAC for 12 h. After 12 h exposure, morphologic observation and function, reactive oxygen species (ROS) level, antioxidant indices, the activity of ATPase, intracellular pH and [Ca2+]i, mitochondrial membrane potential (MMP), and apoptosis-related genes mRNA were determined. The results showed that Cd exposure could induce release of intracellular lactate dehydrogenase (LDH), simultaneously, enhance the ROS generation, acidification, malondialdehyde (MDA) and [Ca2+]i, decrease glutathione (GSH), Na+, K+-ATPase, Ca2+-ATPase, catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activities as well as MMP, upregulated Bak-1, Bax and Caspase-3 mRNA expression, inhibited Bcl-2 mRNA expression, and induced cell apoptosis. The toxicity of Cd to cells showed a dose-dependent manner. Antioxidant NAC could efficiently alleviate Cd-induced the cytotoxicity. Taken together, these results suggest that Cd exposure cause cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells.
    Keywords:  Apoptosis; Cadmium; Mitochondrion; Oxidative stress; Renal tubular epithelial cell
    DOI:  https://doi.org/10.1016/j.tiv.2019.104625
  5. Front Neurosci. 2019 ;13 760
    Melatonin Prevents Mice Cortical Astrocytes From Hemin-Induced Toxicity Through Activating PKCα/Nrf2/HO-1 Signaling in vitro.
    Xiao Chen, Zhiyu Xi, Huaibin Liang, Yuhao Sun, Zhihong Zhong, Baofeng Wang, Liuguan Bian, Qingfang Sun.
      Secondary injuries mediated by oxidative stress lead to deterioration of neurological functions after intracerebral hemorrhage (ICH). Cortical astrocytes are among the most important cells in the central nervous system (CNS), and play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemin is a product of hemoglobin degradation, which has strong toxicity and can induce reactive oxygen species (ROS). Melatonin (Mel) and its metabolites are well tolerated without toxicity, prevent tissue damage as well as effectively assist in scavenging free radicals. We evaluated the hemin neurotoxicity to astrocytes and the resistance of Mel-treated astrocytes to hemin neurotoxicity. And we found Mel induced PKCα phosphorylation (p-PKC), nuclear translocation of Nrf2 in astrocytes, and upregulation of HO-1, which contributed to the reduction of ROS accumulation and cell apoptosis. Nrf2 and HO1 protein expression upregulated by Mel were decreased after administration of PKC inhibitor, Ro 31-8220 (Ro 31). Luzindole (Luz), a melatonin receptor inhibitor, suppressed p-PKCα, HO-1, and Nrf2 expression upregulated by Mel and increased cell apoptosis rate. The upregulation of HO-1 induced by Mel was depressed by knocking down Nrf2 expression by siRNA, which also decreased the resistance of astrocytes to toxicity of hemin. Mel activates astrocytes through PKCα/Nrf2/HO-1 signaling pathway to acquire resistance to toxicity of hemin and resist from oxidative stress and apoptosis. The positive effect of Mel on PKCα/Nrf2/HO-1 signaling pathway may become a new target for neuroprotection after intracerebral hemorrhage.
    Keywords:  Nrf2; PKCα; hemin; intracerebral hemorrhage; melatonin; oxidative stress
    DOI:  https://doi.org/10.3389/fnins.2019.00760
  6. Int J Nanomedicine. 2019 ;14 5713-5728
    Regulating intracellular ROS signal by a dual pH/reducing-responsive nanogels system promotes tumor cell apoptosis.
    Kai Dong, Qiuya Lei, Runhao Guo, Xianglong Wu, Yanni Zhang, Ning Cui, Jian-Yu Shi, Tingli Lu.
      Purpose: The levels of reactive oxygen species (ROS) in tumor cells are much higher than that in normal cells, and rise rapidly under the influence of exogenous or endogenous inducing factors, eventually leading to the apoptosis of tumor cells. Therefore, this study prepared a dual pH/reducing-responsive poly (N-isopropylacrylamide-co-Cinnamaldehyde-co-D-α-tocopheryl polyethylene glycol 1000 succinate, PssNCT) nanogels, which employed two exogenous ROS inducers, cinnamaldehyde (CA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), to selectively induce apoptosis by regulating ROS levels in tumor cells. Methods: The PssNCT nanogels were prepared by the free radical precipitation polymerization under the crosslink between pH-sensitive hydrazone and reducing-sensitive disulfide bonds, followed by the physicochemical and morphological characteristics investigations. Plasma stability, dual pH/reducing responsive degradation and in vitro release were also assessed. In cell experiments, cytotoxicity in different cells were first detected. The intracellular ROS levels and mitochondrial functions of tumor cells were then evaluated. Moreover, the apoptosis and western-blot assays were employed to verify the association between ROS levels elevation and apoptosis in tumor cells. Results: The nanogels exhibited a round-like hollow structure with the diameter smaller than 200nm. The nanogels were stable in plasma, while showed rapid degradation in acidic and reducing environments, thus achieving significant release of CA and TPGS in these media. Furthermore, the sufficient amplification of ROS signals was induced by the synergistically function of CA and TPGS on mitochondria, which resulted in the opening of the mitochondrial apoptotic pathway and enhanced cytotoxicity on MCF-7 cells. However, nanogels barely affected L929 cells owing to their lower intracellular ROS basal levels. Conclusion: The specific ROS regulation method achieved by these nanogels could be explored to selectively kill tumor cells according to the difference of ROS signals in different kinds of cells.
    Keywords:  TPGS; cinnamaldehyde; nanogels; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.2147/IJN.S208089
  7. Appl Biochem Biotechnol. 2019 Aug 13.
    Studies on the Neuroprotection of Osthole on Glutamate-Induced Apoptotic Cells and an Alzheimer's Disease Mouse Model via Modulation Oxidative Stress.
    Qiubo Chu, Yanfeng Zhu, Tianjiao Cao, Yi Zhang, Zecheng Chang, Yan Liu, Jiahui Lu, Yizhi Zhang.
      In the present study, the neuroprotection of osthole (OST) was confirmed. In L-glutamic acid (L-Glu)-damaged HT22 cells, a 3-h pre-incubation with OST-enhanced cell viability suppressed the apoptosis rate; inhibited the activities of caspase-3, caspase-8, and caspase-9; reduced the over-accumulation of intracellular reactive oxygen species; restored the dissipated mitochondrial membrane potential; and regulated the expression levels of B cell lymphoma-2 (Bcl-2), Bax, cleaved poly (ADP-ribose) polymerase (PARP), NF-E2p45-related factor 2 (Nrf2), and its downstream proteins. In amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, an 8-week OST administration improved the pathological behaviors related to memory and cognition, and reduced the expression levels of 4-hydroxynonenal, the deposition of β-amyloid peptides and neuronal fiber tangles formed by the high phosphor-Tau in the brain. OST enhanced the expression levels of Nrf2 and its downstream proteins including superoxide dismutase-1 (SOD-1) and heme oxygenase-1 (HO-1). The present data confirmed the protection of OST against AD-like symptoms via modulating oxidative stress, especially Nrf2 signaling.
    Keywords:  Alzheimer’s disease; Apoptosis; Nrf2; Osthole; Oxidative stress
    DOI:  https://doi.org/10.1007/s12010-019-03101-2
  8. Int J Environ Res Public Health. 2019 Aug 13. pii: E2895. [Epub ahead of print]16(16):
    The Neuroprotective Role of Coenzyme Q10 Against Lead Acetate-Induced Neurotoxicity Is Mediated by Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities.
    Al Omar S Yousef, Alkhuriji A Fahad, Ahmed E Abdel Moneim, Dina M Metwally, Manal F El-Khadragy, Rami B Kassab.
      Heavy metal exposure, in lead (Pb) particularly, is associated with severe neuronal impairment though oxidative stress mediated by reactive oxygen species, and antioxidants may be used to abolish these adverse effects. This study investigated the potential neuroprotective role of coenzyme Q10 (CoQ10) against lead acetate (PbAc)-induced neurotoxicity. Twenty-eight male Wistar albino rats were divided into four equal groups (n = 7) and treated as follows: the control group was injected with physiological saline (0.9% NaCl); the CoQ10 group was injected with CoQ10 (10 mg/kg); PbAc group was injected with PbAc (20 mg/kg); PbAc + CoQ10 group was injected first with PbAc, and after 1 h with CoQ10. All groups were injected intraperitoneally for seven days. PbAc significantly increased cortical lipid peroxidation, nitrate/nitrite levels, and inducible nitric oxide synthase expression, and decreased glutathione content, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase activity and mRNA expression, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and homoxygenase-1 (HO-1) expression. PbAc also promoted the secretion of interleukin-1ß and tumor necrosis factor-α, inhibited interleukin-10 production, triggered the activation of pro-apoptotic proteins, and suppressed anti-apoptotic proteins. Additionally, PbAc increased the cortical levels of serotonin, dopamine, norepinephrine, GABA, and glutamate, and decreased the level of ATP. However, treatment with CoQ10 rescued cortical neurons from PbAc-induced neurotoxicity by restoring the balance between oxidants and antioxidants, activating the Nrf2/HO-1 pathway, suppressing inflammation, inhibiting the apoptotic cascade, and modulating cortical neurotransmission and energy metabolism. Altogether, our findings indicate that CoQ10 has beneficial effects against PbAc-induced neuronal damage through its antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities.
    Keywords:  Nrf2/HO-1 pathway; apoptosis; brain; coenzyme Q10; inflammation; lead; neurotransmission
    DOI:  https://doi.org/10.3390/ijerph16162895
  9. Life Sci. 2019 Aug 10. pii: S0024-3205(19)30674-5. [Epub ahead of print] 116747
    Neuroprotective effects of increasing levels of HSP70 against neuroinflammation in Parkinson's disease model by inhibition of NF-κB and STAT3.
    Haining Li, Juan Yang, Yanbai Wang, Qiang Liu, Jiang Cheng, Feng Wang.
      AIMS: The present study was aimed to investigate the neuroprotective effect of HSP70 against neuroinflammation in a rotenone-induced Parkinson's disease model.MATERIALS AND METHODS: In the present study, SH-SY5Y cells were treated with HSP70 (5-20 mg/L) for 72 h. Cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), levels of oxidative markers, mitochondrial fragmentation, apoptosis, and mRNA and protein expressions of signal transducer and activator of transcription (STAT)-3 and nuclear factor-kappa B (NF-κB) were assessed.
    KEY FINDINGS: Cells treated with 5, 10, 15, and 20 mg/L of HSP70 exhibited increased, by 61.7%, 70.3%, 84.6%, and 96.7%, respectively, in cell viability. ROS and lipid peroxidation levels decreased following treatment with HSP70, and reductions in glutathione (GSH), catalase, glutathione peroxidase (Gpx), and superoxide dismutase (SOD) levels were reversed following treatment with HSP70. Additionally, MMP levels were reduced by 29.7, 46.4, 79.5, and 125.2 relative units following treatment with 5-20 mg/L of HSP70, respectively. HSP70 treatment also decreased levels of fragmented mitochondria and apoptosis, and mRNA and protein expressions of NF-κB and STAT3 were reduced by >25%.
    SIGNIFICANCE: Taken together, these findings indicate that supplementation with HSP70s recovered cell viability and MMP and reduced levels of ROS, apoptosis, and mitochondrial fragmentation. Additionally, supplementation with HSP70 significantly reduced the expressions of STAT3 and NF-κB.
    Keywords:  Apoptosis; Cell viability; HSP70; Parkinson's disease; SH-SY5Y cells
    DOI:  https://doi.org/10.1016/j.lfs.2019.116747
  10. Neurotoxicology. 2019 Aug 10. pii: S0161-813X(19)30079-8. [Epub ahead of print]
    Peroxiredoxin 5 prevents diethylhexyl phthalate-induced neuronal cell death by inhibiting mitochondrial fission in mouse hippocampal HT-22 cells.
    Dong Gil Lee, Kyung-Min Kim, Hyun-Shik Lee, Yong Chul Bae, Jae-Won Huh, Sang-Rae Lee, Dong-Seok Lee.
      Diethylhexyl phthalate (DEHP) is used in many plastic products, such as perfumes, lunch boxes, bags, and building materials. As DEHP is not covalently bound to the plastic, humans can be easily exposed to it. DEHP induces neurobehavioral changes and neuronal cell death; however, the exact mechanism behind this is still unclear. We hypothesized that the neurotoxic mechanism is related to DEHP-induced oxidative stress leading to apoptosis through mitochondrial fission. We demonstrated that DEHP-induced oxidative stress triggers neuronal cell death via mitochondrial fission in mouse hippocampal HT-22 cells. Furthermore, we identified that peroxiredoxin 5 (Prx5), an antioxidant enzyme induced by DEHP, prevents DEHP-induced mitochondrial fission by inhibiting the production of reactive oxygen species. We conclude that Prx5 may be a promising therapeutic target for mitigating DEHP-induced neuronal cell death.
    Keywords:  Diethylhexyl phthalate; Mitochondrial dynamics; Neurotoxicity; Oxidative stress; Peroxiredoxin 5
    DOI:  https://doi.org/10.1016/j.neuro.2019.08.003
  11. Drug Des Devel Ther. 2019 ;13 2081-2096
    Phosphocreatine attenuates Gynura segetum-induced hepatocyte apoptosis via a SIRT3-SOD2-mitochondrial reactive oxygen species pathway.
    Dong-Ping Li, Ying-Ling Chen, Hong-Yue Jiang, Yun Chen, Xiao-Qing Zeng, Li-Li Xu, Yang Ye, Chang-Qiang Ke, Ge Lin, Ji-Yao Wang, Hong Gao.
      Purpose: To investigate the mitochondria-related mechanism of Gynura segetum (GS)-induced apoptosis and the protective effect of phosphocreatine (PCr), a mitochondrial respiration regulator. Methods: First, the mechanism was explored in human hepatocyte cell line. The mitochondrial oxidative stress was determined by fluorescence assay. The level of sirtuin 3 (SIRT3), acetylated superoxide dismutase 2 (Ac-SOD2), SOD2, and apoptosis were detected by Western blotting. Mito-TEMPO and cell lines of viral vector-mediated overexpression of SIRT3 and SIRT3H248Y were used to further verify the mechanism of GS-induced apoptosis. GS-induced liver injury mice models were built by GS through intragastric administration and interfered by PCr through intraperitoneal injection. A total of 30 C57BL/6J mice were assigned to 5 groups and treated with either saline, PCr (100 mg/kg), GS (30 g/kg), or PCr (50 or 100 mg/kg)+GS (30 g/kg). Liver hematoxylin and eosin (HE) staining, immunohistochemical analysis, and blood biochemical evaluation were performed. Results: GS induced hepatocyte apoptosis and elevated levels of mitochondrial ROS in L-02 cells. The expression of SIRT3 was decreased. Downregulation of SIRT3 was associated with increased levels of Ac-SOD2, which is the inactivated enzymatic form of SOD2. Conversely, when overexpressing SIRT3 in GS-treated cells, SOD2 activity was restored, and mitochondrial ROS levels and hepatocyte apoptosis declined. Upon administration of PCr to GS-treated cells, they exhibited a significant upregulation of SIRT3 and were protected against apoptosis. In animal experiments, serum ALT level and mitochondrial ROS of the mice treated with GS and 50 mg/kg PCr were significantly attenuated compared with only GS treated. The changes in SIRT3 expression were also consistent with the in vitro results. In addition, immunohistochemical analysis of the mouse liver showed that Ac-SOD2 was decreased in the PCr and GS co-treated group compared with GS treated group. Conclusion: GS caused liver injury by dysregulating mitochondrial ROS generation via a SIRT3-SOD2 pathway. PCr is a potential agent to treat GS-induced liver injury by mitochondrial protection.
    Keywords:  Gynura segetum; ROS; SIRT3; apoptosis; mitochondrial; phosphocreatine
    DOI:  https://doi.org/10.2147/DDDT.S203564
  12. Mol Reprod Dev. 2019 Aug 13.
    The mycotoxin beauvericin induces oocyte mitochondrial dysfunction and affects embryo development in the juvenile sheep.
    Antonella Mastrorocco, Nicola Antonio Martino, Giuseppina Marzano, Giovanni Michele Lacalandra, Elena Ciani, Bernard A J Roelen, Maria Elena Dell'Aquila, Fiorenza Minervini.
      Beauvericin (BEA) is a mycotoxin produced by Beauveria bassiana and Fusarium species recently reported as toxic on porcine oocyte maturation and embryo development. The aim of this study was to assess, in the juvenile sheep, whether its effects are due to alterations of oocyte and/or embryo bioenergetic/oxidative status. Cumulus-oocyte-complexes (COCs) were exposed to BEA during in vitro maturation (IVM), evaluated for cumulus cell (CC) apoptosis, oocyte maturation and bioenergetic/oxidative status or subjected to in vitro fertilization (IVF) and embryo culture (IVEC). Oocyte nuclear maturation and embryo development were assessed after Hoechst staining and CC apoptosis was analysed by terminal deoxynucleotidyl transferase-mediated dUTP nick-End labeling assay and chromatin morphology after Hoechst staining by epifluorescence microscopy. Oocyte and blastocyst bioenergetic/oxidative status were assessed by confocal microscopy after mitochondria and reactive oxygen species labelling with specific probes. BEA showed various toxic effects, that is, short-term effects on somatic and germinal compartment of the COC (CCs and the oocyte) and long-term carry-over effects on developing embryos. In detail, at 5 µM, it significantly reduced oocyte maturation and immature oocytes showed increased late-stage (Type C) CC apoptosis and DNA fragmentation while matured oocytes showed unaffected CC viability but abnormal mitochondrial distribution patterns. At lower tested concentrations (3-0.5 µM), BEA did not affect oocyte maturation, but matured oocytes showed reduced mitochondrial activity. At low concentrations, BEA impaired embryo developmental capacity and blastocyst quality after IVF and IVEC. In conclusion, in the juvenile sheep, COC exposure to BEA induces CC apoptosis and oocyte mitochondrial dysfunction with negative impact on embryo development.
    Keywords:  bioenergetic/oxidative status; embryo; mycotoxin beauvericin; oocyte; sheep
    DOI:  https://doi.org/10.1002/mrd.23256
  13. J Gastrointest Cancer. 2019 Aug 13.
    Carbamazepine, a Histone Deacetylase Inhibitor Induces Apoptosis in Human Colon Adenocarcinoma Cell Line HT-29.
    Sohaib M, Ezhilarasan D.
      BACKGROUND AND AIM: Colon cancer ranks fourth and is responsible for causing 10% cancer-related mortality in western countries. Its incidence is rising in many countries due to widespread adoption of the Western diet and lifestyle. Carbamazepine (CBZ) is a FDA-approved antiepileptic drug and a histone deacetylase inhibitor. The aim of this study is to evaluate the cytotoxic potentials of CBZ in human colon cancer cells (HT-29 cells).METHODS: HT-29 cells were treated with 36 and 76 μg/ml of CBZ for 24 h. The cytotoxic effect was evaluated by MTT assay. The intracellular reactive oxygen species (ROS) expression was evaluated through dichloro-dihydro-fluorescein diacetate staining. Morphological changes related to apoptosis were evaluated by dual staining with acridine orange and ethidium bromide. Mitochondrial membrane potential was evaluated by rhodamine 123 staining. Immunofluorescence analysis of caspase 3 was done with confocal microscopy.
    RESULTS: CBZ caused significant cytotoxicity in HT-29 cells and the effect was concentration dependent. CBZ treatments also caused significant expression of ROS in HT-29 cells. Dual staining showed early and late apoptotic cells and morphological alterations induced by the CBZ. Confocal microscopic studies confirmed the increased caspase 3 expression in CBZ-treated cells.
    CONCLUSION: CBZ induced apoptosis in HT-29 cell through ROS generation and caspase 3 expression and these results pave the way for further in vivo studies.
    Keywords:  Antiepileptics; Apoptosis; Caspase; Colon cancer; Cytotoxicity
    DOI:  https://doi.org/10.1007/s12029-019-00286-x
  14. Kidney Blood Press Res. 2019 08 13. 1-15
    Effect of M2 Macrophages on Injury and Apoptosis of Renal Tubular Epithelial Cells Induced by Calcium Oxalate Crystals.
    Quan Liu, Yunlong Liu, Xiaofeng Guan, Jihua Wu, Ziqi He, Juening Kang, Zhiwei Tao, Yaoliang Deng.
      BACKGROUND: M2 macrophages have important roles in diseases such as tumours, cardiovascular diseases and renal diseases. This study aimed to determine the effects and protective mechanism of M2 macrophages against oxidative stress injury and apoptosis induced by calcium oxalate crystals (CaOx) in renal tubular epithelial cells (HK-2) under coculture conditions.METHODS: THP-1 cells were induced to differentiate into M2 macrophages by using phorbol-12-myristate-13-acetate, IL-4 and IL-13. Morphological features were observed by microscopy. Phenotypic markers were identified by reverse transcription-polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay (ELISA). HK-2 cells were treated with 0.5 mg/mL CaOx crystals and co-cultured with M2 macrophages or apocynin. The viability of HK-2 cells was detected by CCK-8 assay. The lactate dehydrogenase (LDH) activity of HK-2 cells was analysed using a microplate reader. The apoptosis of HK-2 cells was examined by flow cytometry and Hoechst 33258 staining. Reactive oxygen species (ROS) expression and mitochondrial membrane potential in HK-2 cells were detected by a fluorescence microplate reader. Western blot analysis was conducted to detect the expression of p47phox, Bcl-2, cleaved caspase-3, cytochrome c, p38 MAPK, phospho-p38 MAPK, Akt and phospho-Akt.
    RESULTS: The results of morphology, reverse transcription-polymerase chain reaction, Western blot and ELISA showed that THP-1 cells were successfully polarised to M2 macrophages. The results of co-culture suggested that M2 macrophages or apocynin significantly increased the cell viability and decreased the LDH activity and apoptosis rate after HK-2 cells were challenged with CaOx crystals. The expression of the p47phox protein and the concentration of ROS were reduced, the release of mitochondrial membrane potential and the expression of the Bcl-2 protein were upregulated and the protein expression of cleaved caspase-3 and cytochrome c was downregulated. The expression of the phosphorylated form of p38 MAPK increased. Under coculture conditions with M2 macrophages, the Akt protein of HK-2 cells treated with CaOx crystals was dephosphorylated, but the phosphorylated form of Akt was not reduced by apocynin.
    CONCLUSIONS: M2 macrophages reduced the oxidative stress injury and apoptosis of HK-2 cells by downregulating the activation of NADPH oxidase, reducing the production of ROS, inhibiting the phosphorylation of p38 MAPK and enhancing the phosphorylation of Akt. We have revealed one of the possible mechanisms by which M2 macrophages reduce the formation of kidney stones.
    Keywords:  Apoptosis; Calcium oxalate crystals; M2 macrophages; Renal tubular epithelial cells
    DOI:  https://doi.org/10.1159/000501558
  15. Sci Rep. 2019 Aug 12. 9(1): 11701
    Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis.
    Somayeh Keshtkar, Maryam Kaviani, Zahra Jabbarpour, Bita Geramizadeh, Elahe Motevaseli, Saman Nikeghbalian, Alireza Shamsaeefar, Nasrin Motazedian, Ismail H Al-Abdullah, Mohammad Hossein Ghahremani, Negar Azarpira.
      Islets transplantation, as a treatment of type 1 diabetes, faces challenges, including the loss of islets in the process of isolation and pre-transplantation due to cellular stresses-induced apoptosis. Accordingly, the optimization of culture plays a decisive role in the transplantation success. In this study, we evaluated the effect of nobiletin on the cultured human islets. Isolated human islets were treated by different concentrations of nobiletin and cultured for 24 and 72 hours. Then, the islets viability, apoptosis, insulin and C-peptide secretion, and apoptosis markers were evaluated. Also, the production of reactive oxygen species (ROS), hypoxia inducible factor 1 alpha (HIF-1α), and its target genes in the islets were examined. Our findings showed that the islets were encountered with hypoxia and oxidative stress after isolation and during culture. These insults induced apoptosis and reduced viability during culture period. Moreover, the secretion of insulin and C-peptide decreased. Nobiletin treatments significantly improved the islets survival through reduction of HIF-1α and ROS production and suppression of apoptosis, along with increased islets function. Islet protective effect of nobiletin might be related to its anti-oxidant, anti-apoptotic and insulinotropic properties. Hence, in order to achieve viable and functional islets for clinical transplantation, the application of nobiletin during pre-transplantation period is useful.
    DOI:  https://doi.org/10.1038/s41598-019-48262-6
  16. Neurotoxicol Teratol. 2019 Aug 08. pii: S0892-0362(19)30046-7. [Epub ahead of print] 106821
    ROS-mediated JNK pathway critically contributes to PFOS-triggered apoptosis in SH-SY5Y cells.
    Pingping Sun, Lingqi Gu, Jiashan Luo, Yi Qin, Lingli Sun, Shengyang Jiang.
      Recent studies have indicated that perfluorooctane sulfonate (PFOS) and its derivatives can lead to neurotoxicity. In the present study, we showed that PFOS may trigger neuronal apoptosis through a c-Jun N-terminal kinase (JNK)-related mechanism. We revealed that c-Jun N-terminal kinase (JNK) was robustly activated in PFOS-exposed neuronal cells. The doses of PFOS that initiates JNK activation coincides with that inducing neuronal apoptosis, as confirmed by western blot, Annexin V-PE/7-AAD and TdT-mediated dUTP Nick-End Labeling (TUNEL) analyses. In addition, we found that reactive oxidative species (ROS) accumulation plays a casual role in PFOS-initiated JNK activation, as treatment with ROS scavenger N-acetyl-l-cysteine (NAC) abrogated PFOS-induced mitochondrial and nuclear translocation of phosphorylated JNK (p-JNK). In keeping with this notion, the expression of JNK downstream pro-apoptotic target Bim was increased following PFOS exposure in JNK- and ROS-dependent manners. Finally, Annexin V-PE/7-AAD analysis uncovered that treatment with NAC or SP600125 could significantly impair PFOS-induced neuronal apoptosis. These findings implicate that JNK signaling is critically involved in PFOS-induced neuronal death by virtue of mitochondrial translocation and the transcription of pro-apoptotic genes.
    Keywords:  Apoptosis; JNK; Neurotoxicity; Perfluorooctanesulfonate (PFOS); ROS
    DOI:  https://doi.org/10.1016/j.ntt.2019.106821
  17. BMB Rep. 2019 Aug 12. pii: 4615. [Epub ahead of print]
    Overcoming multidrug resistance by activating unfolded protein response of the endoplasmic reticulum in cisplatin-resistant A2780/CisR ovarian cancer cells.
    Euitaek Jung, Dongsoo Koh, Yoongho Lim, Soon Young Shin, Young Han Lee.
      Cisplatin is a widely used anti-cancer agent. However, the effectiveness of cisplatin has been limited by the commonly developed drug resistance. This study aimed to investigate the potential effects of endoplasmic reticulum (ER) stress to overcome drug resistance using the cisplatin-resistant A2780/CisR ovarian cancer cell model. The synthetic chalcone derivative (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop- 2-en-1-one (named DPP23) is an ER stress inducer. We found that DPP23 triggered apoptosis in both parental cisplatinsensitive A2780 and cisplatin-resistant A2780/CisR ovarian cancer cells due to activation of reactive oxygen species (ROS)-mediated unfolded protein response (UPR) pathway in the endoplasmic reticulum. This result suggests that ROSmediated UPR activation is potential in overcoming drug resistance. DPP23 can be used as a target pharmacophore for the development of novel chemotherapeutic agents capable of overcoming drug resistance in cancer cells, particularly ovarian cancer cells.
  18. Cells. 2019 Aug 11. pii: E874. [Epub ahead of print]8(8):
    MicroRNA-34a and MicroRNA-181a Mediate Visfatin-Induced Apoptosis and Oxidative Stress via NF-κB Pathway in Human Osteoarthritic Chondrocytes.
    Sara Cheleschi, Sara Tenti, Nicola Mondanelli, Claudio Corallo, Marcella Barbarino, Stefano Giannotti, Ines Gallo, Antonio Giordano, Antonella Fioravanti.
      Current evidence suggests a complex interaction between adipokines and microRNA (miRNA) in osteoarthritis (OA) pathogenesis. The present study explored the role of miR-34a and miR-181a in regulating apoptosis and oxidative stress induced by visfatin in human OA chondrocytes. Chondrocytes were transfected with miR-34a and miR-181a inhibitors and stimulated with visfatin for 24 h, in the presence of nuclear factor (NF)-κB inhibitor (BAY-11-7082, 2 h pre-incubation). Apoptosis and reactive oxygen species (ROS) production were detected by cytometry, miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2 and B-cell lymphoma (BCL)2 expressions by quantitative real time polymerase chain reaction (real time PCR) and western blot. P50 NF-κB subunit was measured by immunofluorescence. Visfatin significantly induced apoptosis and superoxide anion production, increased miR-34a, miR-181a, superoxide dismutase (SOD)-2, catalase (CAT), NRF2 and decreased BCL2 gene and protein expression in OA chondrocytes. All the visfatin-caused effects were suppressed by using miR-34a and miR-181a inhibitors. Pre-incubation with BAY-11-7082 counteracted visfatin-induced expression of miRNA, BCL2, SOD-2, CAT and NRF2. Inhibition of miR-34a and miR-181a significantly reduced the activation of p50 NF-κB. Visfatin confirms its ability to induce apoptosis and oxidative stress in human OA chondrocytes; these effects appeared mediated by miR-34a and miR-181a via NF-κB pathway. We highlight the relevance of visfatin as potential therapeutic target for OA treatment.
    Keywords:  NF-κB; apoptosis; chondrocytes; miR-181a; miR-34a; microRNA; osteoarthritis; oxidative stress; visfatin
    DOI:  https://doi.org/10.3390/cells8080874
  19. Basic Clin Pharmacol Toxicol. 2019 Aug 17.
    ROS, not Ca2+ , mediates methotrexate-induced autophagy and apoptosis in spermatocyte cell line.
    Suping Xiong, Dandan Song, Yang Xiang, Yanting Li, Yuanyuan Zhong, Hongjin Li, Peng Zhang, Wenwen Zhou, Xuhui Zeng, Xiaoning Zhang.
      Methotrexate (MTX) is widely used to treat cancers and systemic autoimmune diseases. However, it is severely toxic to healthy cells, especially those of the reproductive system, and therefore poses a great risk to patient fertility. In addition, the underlying mechanism of MTX-induced reproductive toxicity has not yet been fully elucidated. Here, a spermatocyte cell line (GC2) was used as an in vitro model system to determine whether MTX induces autophagy and apoptosis, and to elucidate the role of reactive oxygen species (ROS) and Ca2+ in these two processes. Treatment with MTX resulted in a dramatic decrease in cell viability, inhibition of cell proliferation, collapse of the mitochondrial membrane potential and activation of Caspase 3, suggesting that MTX induced apoptosis. Moreover, MTX activated autophagy, as indicated by conversion of LC3-I to LC3-II (microtubule-associated protein 1 light chain 3) and an increase in the number of LC3 puncta. Furthermore, MTX triggered ROS overproduction, rather than a Ca2+ burst. Intriguingly, eliminating excess ROS significantly alleviated MTX-induced apoptosis and autophagy. In addition, inhibiting autophagy significantly reversed apoptosis and promoted cell survival, indicating that autophagy aggravated MTX-induced apoptosis in GC2 cells. Taken together, these results suggest that ROS signalling, not Ca2+ , is critical in mediating MTX-induced autophagy and apoptosis and autophagy serves as a promoted partner of apoptosis to deteriorate MTX-induced cytotoxicity in GC2 cells. The findings from this study provide new perspectives for evaluating the reproductive toxicity of MTX. This article is protected by copyright. All rights reserved.
    Keywords:   MTX ; ROS ; Ca2+; apoptosis; autophagy; reproductive toxicity
    DOI:  https://doi.org/10.1111/bcpt.13306
  20. Pestic Biochem Physiol. 2019 Sep;pii: S0048-3575(19)30029-X. [Epub ahead of print]159 144-153
    Ivermectin induces apoptosis of porcine trophectoderm and uterine luminal epithelial cells through loss of mitochondrial membrane potential, mitochondrial calcium ion overload, and reactive oxygen species generation.
    Jin-Young Lee, Whasun Lim, Jiyeon Ham, Jinyoung Kim, Seungkwon You, Gwonhwa Song.
      Ivermectin is a pesticide that has been used for over 30 years in livestock. Although there are a number of studies on the therapeutic potential of ivermectin, little is known about the effects of the drug during the early stage of pregnancy. In this study, we investigated the detrimental effects of ivermectin on porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. Ivermectin not only inhibited the proliferation of both cells via the regulation of cell cycle-associated genes, but also induced apoptosis in pTr and pLE cells. We also verified its effect on mitochondrial dysfunction as shown by loss of mitochondrial membrane potential, mitochondrial Ca2+ overload, and reactive oxygen species (ROS) generation in pTr and pLE cells. As a mechanistic approach, we evaluated ivermectin-mediated cell signaling interactions including PI3K, AKT and MAPK pathways. Overall, our results suggest that constant exposure to and accumulation of ivermectin may cause abnormal fetal morphogenesis and placentation during the early stages of pregnancy. Our results may further provide a comprehensive understanding of the detrimental effects of ivermectin during pregnancy and will contribute to the establishment of a complete safety profile for ivermectin and its association with environmental pollution and public health in humans and livestock.
    Keywords:  Apoptosis; Ivermectin; Pig; Trophoblast; Uterine luminal epithelium
    DOI:  https://doi.org/10.1016/j.pestbp.2019.06.009
  21. Exp Ther Med. 2019 Sep;18(3): 1899-1906
    Isopsoralen ameliorates H2O2-induced damage in osteoblasts via activating the Wnt/β-catenin pathway.
    Yu-Peng Li, Bin Wu, Jie Liang, Fei Li.
      Osteoporosis is a disease with a worldwide prevalence that involves a severe loss of bone mineral density and decreased microarchitecture, which increases the risk of bone fracture. The present study evaluated the effects of isopsoralen on osteoblastic OB-6 cells following hydrogen peroxide (H2O2)-induced damage and investigated the molecular mechanisms involved in this process. For in vitro experiments, OB-6 osteoblasts were treated with H2O2 or H2O2 + isopsoralen then the cell viability, apoptosis, reactive oxygen species (ROS) production and calcium accumulation were determined. Results demonstrated that treatment with H2O2 reduced cell viability, runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) expression levels, and calcium deposition, whilst markedly increasing cell apoptosis and ROS production. However, isopsoralen (1 µM) provided significant protection against H2O2-induced alterations in osteoblasts. In addition, isopsoralen effectively upregulated protein expression of tankyrase and β-catenin which are the main transductors of the Wnt/β-catenin pathway. Of note, the protective effects of isopsoralen against H2O2-induced damage were attenuated in OB-6 cells treated with tankyrase inhibitor XAV-939. In conclusion, the present findings provided evidence that isopsoralen attenuated oxidative stress-induced injury in osteoblasts via the Wnt/β-catenin signaling pathway.
    Keywords:  Wnt/β-catenin pathway; isopsoralen; osteoblast; oxidative stress
    DOI:  https://doi.org/10.3892/etm.2019.7741
  22. Aging (Albany NY). 2019 Aug 14. 11
    Effects of inflammatory responses, apoptosis, and STAT3/NF-κB- and Nrf2-mediated oxidative stress on benign prostatic hyperplasia induced by a high-fat diet.
    Yongzhi Li, Benkang Shi, Fengming Dong, Xingwang Zhu, Bing Liu, Yili Liu.
      This study determined whether or not benign prostatic hyperplasia (BPH) induced by a high-fat diet (HFD) is involved in inflammatory responses, apoptosis, and the signal transducer and activator of transcription (STAT3)/nuclear factor-kappa B (NF-κB)- and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress pathways. Forty rats were divided into four groups: control; HFD; testosterone; and HFD+testosterone. Hematoxylin and eosin (HE) staining was used to assess histologic changes. An enzyme-linked immunosorbent assay and Western blot analysis were used to detect levels of related proteins. Compared with the control group, the prostate levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), transforming growth factor-β1 (TGF-β1), and monocyte chemotactic protein-1 (MCP-1) were significantly increased, while the levels of glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione (GSH), and superoxide dismutase (SOD) were decreased. The TNF-κB, Bcl-2, and caspase-3 levels were increased, while the Bax level was markedly decreased. The cytoplasmic expression of STAT3 and NF-κB was increased, while the nuclear expression of Nrf2 was markedly decreased compared with the control group. In summary, our results demonstrated that a long-term HFD might cause changes in inflammatory responses, apoptosis, and oxidative stress, thus contributing to prostatic hyperplasia. The underlying mechanisms might be related to the STAT3/NF-κB- and Nrf2-mediated oxidative stress pathway.
    Keywords:  apoptosis; benign prostatic hyperplasia; high-fat diet; inflammatory responses; oxidative stress
    DOI:  https://doi.org/10.18632/aging.102138
  23. Life Sci. 2019 Aug 11. pii: S0024-3205(19)30675-7. [Epub ahead of print] 116748
    Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K/AKT/mTOR pathway.
    Peng Guan, Zhi-Min Sun, Na Wang, Jian Zhou, Li-Fei Luo, Ya-Shuo Zhao, En-Sheng Ji.
      AIMS: Resveratrol is a polyphenolic compound that has received much attention for its use in ameliorating various systemic pathological conditions. The present study was performed to investigate whether the resveratrol alleviated cardiac hypertrophy and functional remodelling by regulating autophagy.MATERIALS AND METHODS: Male rats were exposed to CIH 8 h/day for five weeks and/or intragastric administration of resveratrol daily. The morphological and echocardiography were used to evaluate the cardiac protective effects. The apoptosis was detected by TUNEL staining. The biochemical assessments were used to evaluate oxidative stress. Further, the effect of resveratrol on autophagy and PI3K/AKT/mTOR pathway was investigated.
    KEY FINDINGS: The CIH group exhibited increased heart weight/body weight and left ventricle weight/body weight ratios, which was accompanied by left ventricular remodelling. Echocardiography analysis showed that CIH-treated rats had significantly higher left ventricular posterior wall thickness, ejection fraction and fractional shortening than those of controls. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group versus the control. The autophagy marker Beclin-1 was elevated, while p62 was decreased by CIH treatment. Resveratrol treatment significantly improved cardiac function and alleviated cardiac hypertrophy, oxidative stress, and apoptosis in CIH rats. Further results indicated that PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway played a role in the activation of autophagy by resveratrol after CIH stimulation.
    SIGNIFICANCE: In conclusion, resveratrol supplementation during CIH upregulates autophagy by targeting the PI3K/AKT/mTOR pathway, which appears to be beneficial for resisting cardiac hypertrophy.
    Keywords:  Cardiac hypertrophy; Chronic intermittent hypoxia; Resveratrol; mTOR
    DOI:  https://doi.org/10.1016/j.lfs.2019.116748
  24. Eur J Pharmacol. 2019 Aug 08. pii: S0014-2999(19)30543-6. [Epub ahead of print]861 172591
    Salidroside attenuates dextran sulfate sodium-induced colitis in mice via SIRT1/FoxOs signaling pathway.
    Huimin Li, Lei Shen, Tingting Lv, Ru Wang, Na Zhang, Hao Peng, Wenxiu Diao.
      Salidroside (Sal), the active ingredient of Rhodiola rosea L, has various pharmacological activities, including antioxidant, anti-inflammatory and anti-tumor activities. Recently, studies have shown that oxidative stress and apoptosis are related to the pathogenesis of inflammatory bowel disease. Therefore, we evaluated the effects of Sal on oxidative stress and apoptosis in colitis mice through the SIRT1/FoxOs pathway. To induce the colitis model, mice continuously consumed water containing 3% DSS for 7 days; some mice were also treated with Sal and the SIRT1/FoxOs pathway blocker selisistat (Ex527). Changes in body weight, DAI, colon length and colon tissue histology as well as SOD, GSH-Px and CAT activities were measured. The expression of SIRT1, FoxO1, FoxO3a, FoxO4, caspase-3, cleaved-caspase-3, Bax and Bcl-2 in colorectal tissues was detected by RT-PCR and Western blotting. The study showed that Sal decreased the DAI score, weight loss, colon shortening and colon tissue damage in colitis mice. Sal inhibited oxidative stress by upregulating SOD, GSH-Px and CAT while suppressing colonic apoptosis by downregulating the expression of Bax, caspase-3, and cleaved-caspase-3 and upregulating the expression of Bcl-2. Sal also activated SIRT1/FoxOs signaling, which increased the expression of SIRT1, FoxO1, FoxO3a and FoxO4 in colon tissue. Furthermore, SIRT1/FoxOs pathway inhibition using Ex527 partially eliminated the effect of Sal on colitis mice. The study manifested that Sal may protect colitis mice by activating the SIRT1/FoxOs pathway, which is related to oxidative stress and apoptosis in colon tissues.
    Keywords:  Apoptosis; Colitis; Oxidative stress; SIRT1/FoxOs pathway; Salidroside
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172591
  25. Mol Reprod Dev. 2019 Aug 13.
    Effect of oocyte vitrification on DNA damage in metaphase II oocytes and the resulting preimplantation embryos.
    Haoya Chang, Huanhuan Chen, Lei Zhang, Yile Wang, Xiaogang Xie, Yong Zhang, Fusheng Quan.
      As an assisted reproduction technology, vitrification has been widely used for oocyte and embryo cryopreservation. Many studies have indicated that vitrification affects ultrastructure, gene expression, and epigenetic status. However, it is still controversial whether oocyte vitrification could induce DNA damage in metaphase II (MII) oocytes and the resulting early embryos. This study determined whether mouse oocytes vitrification induce DNA damage in MII oocytes and the resulting preimplantation embryos, and causes for vitrification-induced DNA damage. The effects of oocyte vitrification on reactive oxygen species (ROS) levels, γ-H2AX accumulation, apoptosis, early embryonic development, and the expression of DNA damage-related genes in early embryos derived by in vitro fertilization were examined. The results indicated that vitrification significantly increased the number of γ-H2AX foci in zygotes and two-cell embryos. Trp53bp1 was upregulated in zygotes, two-cell embryos and four-cell embryos in the vitrified group, and Brca1 was increased in two-cell embryos after vitrification. Vitrification also increased the ROS levels in MII oocytes, zygotes, and two-cell embryos and the apoptotic rate in blastocysts. Resveratrol (3,5,4'-trihydroxystilbene) treatment decreased the ROS levels and the accumulation of γ-H2AX foci in zygotes and two-cell embryos and the apoptotic rate in blastocysts after vitrification. Overall, vitrification-induced abnormal ROS generation, γ-H2AX accumulation, an increase in the apoptotic rate and the disruption of early embryonic development. Resveratrol treatment could decrease ROS levels, γ-H2AX accumulation, and the apoptotic rate and improve early embryonic development. Vitrification-associated γ-H2AX accumulation is at least partially due to abnormal ROS generation.
    Keywords:  DNA damage; early embryonic development; mouse oocyte; vitrification
    DOI:  https://doi.org/10.1002/mrd.23247
  26. Nutr Rev. 2019 Aug 13. pii: nuz027. [Epub ahead of print]
    The conundrum of dietary antioxidants in cancer chemotherapy.
    Roghayeh Ilghami, Abolfazl Barzegari, Mohammad Reza Mashayekhi, Didier Letourneur, Michel Crepin, Graciela Pavon-Djavid.
      Although chemotherapy succeeds in reducing tumor burden, the efficacy is limited due to acquired drug resistance and often irreparable side effects. Studies show that antioxidants may influence the response to chemotherapy and its side effects, although their use remains controversial. The evidence shows that some chemo-drugs induce oxidative stress and lead to normal tissue apoptosis and the entry of cancer cells to a dormant G0 state. Through the suppression of oxidative stress, antioxidants could protect normal cells and bring the tumor out of dormancy so as to expose it to chemotherapies. This review is focused on the redox biology of cancer/normal cells and association of reactive oxygen species with drug resistance, cancer dormancy, and side effects. To this end, evidence from cellular, animal, and clinical studies is provided to better understand the conundrum of dietary antioxidants in cancer chemotherapy.
    Keywords:  antioxidants; cancer chemotherapy; carotenoids; oxidative stress; side effect
    DOI:  https://doi.org/10.1093/nutrit/nuz027
  27. Int J Mol Sci. 2019 Aug 12. pii: E3921. [Epub ahead of print]20(16):
    Melatonin Improves the Fertilization Capacity of Sex-Sorted Bull Sperm by Inhibiting Apoptosis and Increasing Fertilization Capacitation via MT1.
    Chong-Yang Li, Hai-Sheng Hao, Ya-Han Zhao, Pei-Pei Zhang, Hao-Yu Wang, Yun-Wei Pang, Wei-Hua Du, Shan-Jiang Zhao, Yan Liu, Jin-Ming Huang, Jing-Jing Wang, Wei-Min Ruan, Tong Hao, Russel J Reiter, Hua-Bin Zhu, Xue-Ming Zhao.
      Little information is available regarding the effect of melatonin on the quality and fertilization capability of sex-sorted bull sperm, and even less about the associated mechanism. Sex-sorted sperm from three individual bulls were washed twice in wash medium and incubated in a fertilization medium for 1.5 h, and each was supplemented with melatonin (0, 10-3 M, 10-5 M, 10-7 M, and 10-9 M). The reactive oxygen species (ROS) and endogenous antioxidant activity (glutathione peroxidase (GPx); superoxide dismutase (SOD); catalase (CAT)), apoptosis (phosphatidylserine [PS] externalization; mitochondrial membrane potential (Δψm)), acrosomal integrity events (malondialdehyde (MDA) level; acrosomal integrity), capacitation (calcium ion [Ca2+]i level; cyclic adenosine monophosphate (cAMP); capacitation level), and fertilization ability of the sperm were assessed. Melatonin receptor 1 (MT1) and 2 (MT2) expression were examined to investigate the involvement of melatonin receptors on sex-sorted bull sperm capacitation. Our results show that treatment with 10-5 M melatonin significantly decreased the ROS level and increased the GPx, SOD, and CAT activities of sex-sorted bull sperm, which inhibited PS externalization and MDA levels, and improved Δψm, acrosomal integrity, and fertilization ability. Further experiments showed that melatonin regulates sperm capacitation via MT1. These findings contribute to improving the fertilization capacity of sex-sorted bull sperm and exploring the associated mechanism.
    Keywords:  bull; fertilization; melatonin; sex-sorted; sperm
    DOI:  https://doi.org/10.3390/ijms20163921
  28. Free Radic Res. 2019 Aug 12. 1-241
    Oxidative stress induces apoptosis via calpain- and caspase-3- mediated cleavage of ATM in pancreatic acinar cells.
    Soon Ok Cho, Joo Weon Lim, Hyeyoung Kim.
      Oxidative stress-induced DNA cleavage and apoptosis in pancreatic acinar cells has been implicated in the pathogenesis of acute pancreatitis. Thus, an efficient DNA repair process is key to prevention of apoptotic pancreatic acinar cell death. Ataxia telangiectasia mutated (ATM), a sensor of DNA breaks, functions by recruiting DNA repair proteins to initiate the DNA repair process. In the present study, we investigated whether H2O2 produced by the action of glucose oxidase on α-D-glucose (G/GO) induces apoptosis in pancreatic acinar AR42J cells through an alteration of the level of ATM. As a result, G/GO induced apoptosis by promoting a loss of cell viability, increase in Bax, decrease in Bcl-2, cleavage of poly (ADP-ribose) polymerase (PARP) and fragmentation of DNA. In addition, ATM cleavage along with elevated levels of calpain and caspase-3 activity was induced by G/GO. By using ATM siRNA, we demonstrated that reduction in ATM levels enhanced G/GO-induced apoptosis. Moreover, inhibition of calpain activity by calpeptin or calpatatin, or by inhibition of caspase-3 with z-DEVD, suppressed G/GO-induced apoptosis and ATM cleavage. Collectively, these findings suggest that proteolysis of ATM is the underlying mechanism of apoptosis of pancreatic acinar cells caused by exposure to oxidative stress.
    Keywords:  Ataxia telangiectasia mutated; calpain; caspase-3; glucose/glucose oxidase; pancreatic acinar cells
    DOI:  https://doi.org/10.1080/10715762.2019.1655145
  29. J Am Coll Nutr. 2019 Aug 12. 1-9
    Nephroprotective Effect of Moringa Oleifera Seed Oil on Gentamicin-Induced Nephrotoxicity in Rats: Biochemical Evaluation of Antioxidant, Anti-inflammatory, and Antiapoptotic Pathways.
    C O Edeogu, Michael E Kalu, Ademola C Famurewa, Nnaemeka T Asogwa, Gertrude N Onyeji, Kelechi O Ikpemo.
      Objective: Gentamicin is an efficacious aminoglycoside antibiotic widely used to treat life-threatening Gram-negative bacteria infections. However, its specific non-targeted induction of nephrotoxicity is a worrying clinical challenge. The study explored the nephroprotective effect of Moringa oleifera seed oil (MOO) against gentamicin-induced oxidative nephrotoxicity, pro-inflammation, and apoptosis in male Wistar rats. Method: Twenty-four rats divided into 4 groups (n = 6) were administered MOO (5 ml/kg) for 16 days and/or gentamicin (100 mg/kg bw/d, ip) injected from day 11 to day 16. The renal antioxidant enzyme activities reduced glutathione, lipid peroxidation, and serum renal markers. Urea and creatinine levels were estimated. The renal expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) were determined. Renal levels of inducible nitric oxide synthase (iNOS), nuclear factor-ĸB (NF-ĸB), and caspase-3 were determined to detect possible mechanism of inflammation and apoptosis with histology. Results: MOO prominently reduced serum creatinine and urea levels with amelioration of histopathological abrasions induced by gentamicin (GM). It significantly depressed oxidative stress through lowering of renal malondialdehyde (MDA) and elevation of renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and reduced glutathione (GSH) level. MOO restored renal content of IL-1β, IL-6, TNF-α, and NO, coupled with the mechanistic downregulation of NF-ĸB, iNOS, and caspase-3 activities. The histopathological alterations were ameliorated by MOO. Conclusions: MOO possesses marked nephroprotective effect against GM-induced renal damage via modulating oxidative stress, inflammation, and apoptosis in Wistar rats.
    Keywords:  Gentamicin; Moringa oil; apoptosis; nephrotoxicity; oxidative stress
    DOI:  https://doi.org/10.1080/07315724.2019.1649218
  30. Cell Stress Chaperones. 2019 Aug 13.
    Ethanol exposure in prenatal and early postnatal induced cardiac injury in rats: involvement of oxidative stress, Hsp70, ERK 1/2, JNK, and apoptosis in a 3-month follow-up study.
    Alireza Shirpoor, Reza Gaderi, Roya Naderi.
      Alcohol exposure during pregnancy induces a wide range of structural and functional abnormalities in the fetal heart. However, the underlying mechanism of this phenomenon is not well known. This study was undertaken to elucidate probable mechanisms of myocardial damage induced by prenatal and early postnatal ethanol treatment. Pregnant Wistar rats received ethanol 4.5 g/kg BW once per day from the seventh day of gestation (GD7) throughout lactation. The oxidative stress injury of the myocardium in pups was evaluated by measuring levels of oxidative stress biomarkers. Histopathological examinations and Western blot were performed to evaluate histological features, apoptosis, and molecular alterations in the myocardial tissue of male pups on the postnatal day 21 (PN-21) and postnatal day 90 (PN-90). The results showed that maternal ethanol consumption caused oxidative stress (impaired total antioxidant capacity and malondialdehyde), histological changes, and apoptosis of the myocardium in the pups on PN-21 and PN-90. At the molecular levels, Western blot analysis revealed that ethanol modulated the protein expression of p-ERK1/2, p-JNK, and Hsp70 in the myocardial tissue of the pups after 21 and 90 days of birth compared with the controls. These findings revealed that maternal ethanol intake induced cardiac toxicity in part, mediated by oxidative stress and apoptosis in the pups. A further mechanism study revealed that ethanol enhanced ERK1/2 and JNK phosphorylation and Hsp70 protein expression.
    Keywords:  ERK1/2; Ethanol; Heart; Hsp70; JNK; Offspring
    DOI:  https://doi.org/10.1007/s12192-019-01015-w
  31. Environ Sci Pollut Res Int. 2019 Aug 12.
    Choline, not folate, can attenuate the teratogenic effects ofdibutyl phthalate (DBP) during early chick embryo development.
    Rui Wang, Da-Guang Sun, Ge Song, Chun Yi Guan, Yi Cui, Xu Ma, Hong-Fei Xia.
      Dibutyl phthalate (DBP), a persistent environmental pollutant, can induce neural tube abnormal development in animals. The possible effects of DBP exposure on human neural tube defects (NTDs) remain elusive. In this study, the distribution of DBP in the body fluid of human NTDs was detected by GC-MS. Then, chick embryos were used to investigate the effects of DBP on early embryonic development. Oxidative stress indicators in chick embryos and the body fluid of human NTDs were detected by ELISA. The cell apoptosis and total reactive oxygen species (ROS) level in chick embryos were detected by whole-mount TUNEL and oxidized DCFDA, respectively. The study found that the detection ratio of positive DBP and its metabolites in maternal urine was higher in the NTD population than that in normal controls. 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA) were evidently upregulated and superoxide dismutase (SOD) was observably downregulated in amniotic fluid and urine. Animal experiments indicated that DBP treatment induced developmental toxicity in chick embryos by enhancing the levels of oxidative stress and cell apoptosis. MDA was increased and SOD was decreased in DBP-treated embryos. Interestingly, the supplement of high-dose choline (100 μg/μL), not folic acid, could partially restore the teratogenic effects of DBP. Our data collectively suggest that the incidence of NTDs is closely associated with DBP exposure. This study may provide new insight for NTD prevention.
    Keywords:  Body fluid; Chick embryo; Choline; Dibutyl phthalate; Human neural tube defects; Oxidative stress
    DOI:  https://doi.org/10.1007/s11356-019-06087-w
  32. Phytomedicine. 2019 Jul 27. pii: S0944-7113(19)30223-5. [Epub ahead of print]64 153057
    Aucubin, a natural iridoid glucoside, attenuates oxidative stress-induced testis injury by inhibiting JNK and CHOP activation via Nrf2 up-regulation.
    Bo Ma, Jie Zhang, Zhiming Zhu, Xiaowen Bao, Mingya Zhang, Chaoxing Ren, Qi Zhang.
      BACKGROUND: Eucommia ulmoides has been used for many years as a successful strategy to treat male infertility. Aucubin (AU) is the active ingredient extracted from Eucommia ulmoides. However, its protective action and exact mechanism on testicular injury is not yet known.PURPOSE: Here, the protective effect and the mechanism of action of AU on testis damage under oxidative stress was investigated in vivo and in vitro.
    METHODS: As regard the in vivo experiment, male mice were divided into five groups and testicular injury model was established by Triptolide (TP) (120 μg/kg) intraperitoneal injection for two weeks. Animals in the treatment group were pretreated with an intraperitoneal injection of AU at different doses (5, 10 and 20 mg/kg) for 1 h and subsequently treated with TP (120 μg/kg). At the end of the experimental period, the testis was collected for biochemical and histological examination. As regard the in vitro experiment, Sertoli cells (SCs) were used to investigate the protective effect and mechanism of action of AU against disruption of the blood-testis-barrier (BTB) and apoptosis induced by TP via apoptosis detection, western blot, immunofluorescence analysis, and siRNA transient transfection.
    RESULTS: TP-treated animals showed testicular atrophy, BTB disruption, increased ROS levels and spermatogenic dysfunction. Pre-administration of AU resulted in a significant protection on keeping a normal testicular weight, sperm morphology, BTB integrity, and a normal level of oxidative stress markers and antioxidants. Furthermore, AU prevented apoptosis through an effective inhibition of PERK/CHOP and JNK dependent apoptosis pathway, as well as protected the integrity of BTB by up-regulating the expression of tight junction proteins (ZO-1, Occludin, Claudin-11) and gap junction protein (Cx43). The mechanistic study revealed that AU significantly triggered Nrf2 translocation, thus increasing nuclear Nrf2 accumulation and then induced antioxidant enzymes expression in the testis and SCs. Furthermore, Nrf2 silencing unsuccessfully reversed the increased CHOP and p-JNK expression induced by TP, abolishing the protective effect of AU.
    CONCLUSION: These results indicate that AU might be considered as a potential protective agent against testicular injury.
    Keywords:  Aucubin (AU); Blood-testis-barrier (BTB); NF-E2-related factor 2 (Nrf2); Sertoli cells (SCs); Testicular injury
    DOI:  https://doi.org/10.1016/j.phymed.2019.153057
  33. Biomol Ther (Seoul). 2019 Aug 13.
    Alyssin and Iberin in Cruciferous Vegetables Exert Anticancer Activity in HepG2 by Increasing Intracellular Reactive Oxygen Species and Tubulin Depolymerization.
    Piman Pocasap, Natthida Weerapreeyakul, Kanjana Thumanu.
      To determine the chemopreventive potential of alyssin and iberin, the in vitro anticancer activities and molecular targets of isothiocyanates (ITCs) were measured and compared to sulforaphane in hepatocellular carcinoma cell HepG2. The SR-FTIR spectra observed a similar pattern vis-à-vis the biomolecular alteration amongst the ITCs-treated cells suggesting a similar mode of action. All of the ITCs in this study cause cancer cell death through both apoptosis and necrosis in concentration dependent manner (20-80 µM). We found no interactions of any of the ITCs studied with DNA. Notwithstanding, all of the ITCs studied increased intracellular reactive oxygen species (ROS) and suppressed tubulin polymerization, which led to cell-cycle arrest in the S and G2/M phase. Alyssin possessed the most potent anticancer ability; possibly due to its ability to increase intracellular ROS rather than tubulin depolymerization. Nevertheless, the structural influence of alkyl chain length on anticancer capabilities of ITCs remains inconclusive. The results of this study indicate an optional, potent ITC (viz., alyssin) because of its underlying mechanisms against hepatic cancer. As a consequence, further selection and development of effective chemotherapeutic ITCs is recommended.
    Keywords:  Alyssin; HepG2; Iberin; Isothiocyanates; Reactive oxygen species; Tubulin depolymerization
    DOI:  https://doi.org/10.4062/biomolther.2019.027
  34. Environ Mol Mutagen. 2019 Aug 14.
    Tris(1,3-dichloro-2-propyl) Phosphate (TDCPP) disturbs mouse embryonic development by inducing apoptosis and abnormal DNA methylation.
    Shu-Yuan Yin, Li Chen, Dan-Ya Wu, Tao Wang, Li-Jun Huo, Shuhong Zhao, Jilong Zhou, Xia Zhang, Yi-Liang Miao.
      Tris (1, 3-dichloro-2-propyl) Phosphate (TDCPP) is a kind of additive flame retardants (FR) and was found to affect early embryonic development in zebrafish; however, there are few studies to investigate whether TDCPP will disturb the development of early mouse embryos. In our studies, we used mouse embryos as models to study the toxicology of TDCPP on the early embryos. The results showed that TDCPP disturbed the development of early mouse embryos in a dose-dependent manner. 10 μM TDCPP decreased the blastocyst formation and 100 μM TDCPP was a lethal concentration for the mouse embryos. We proved that TDCPP was detrimental to embryonic development potential by increasing the reactive oxygen species (ROS) level and inducing early apoptosis. Furthermore, TDCPP changed the DNA methylation patterns of imprinted genes in treated blastocysts. The methylation of H19 and Snrpn promoter regions were increased from 37.67% to 46.00% and 31.56% to 44.38% in treated groups, respectively. In contrast, Peg3 promoter region methylation was declined from 86.55% to 73.27% in treated embryos. Taken together, our results demonstrated that TDCPP could adversely impair the early embryonic development in mouse. This article is protected by copyright. All rights reserved.
    Keywords:  TDCPP; development toxicity; embryo; mouse
    DOI:  https://doi.org/10.1002/em.22322
  35. Acta Neurochir Suppl. 2020 ;127 47-54
    Nox2 and Nox4 Participate in ROS-Induced Neuronal Apoptosis and Brain Injury During Ischemia-Reperfusion in Rats.
    Jinjin Wang, Yin Liu, Haitao Shen, Haiying Li, Zhong Wang, Gang Chen.
      BACKGROUND: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats.METHODS: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats.
    RESULTS: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage.
    CONCLUSION: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.
    Keywords:  Cerebral ischemia-reperfusion; Middle cerebral artery occlusion; Nox2; Nox4; Reactive oxygen species
    DOI:  https://doi.org/10.1007/978-3-030-04615-6_8
  36. Med Sci Monit. 2019 Aug 11. 25 5986-5991
    Protective Effects of Naringenin in a Rat Model of Sepsis-Triggered Acute Kidney Injury via Activation of Antioxidant Enzymes and Reduction in Urinary Angiotensinogen.
    Lin Mu, Guoxin Hu, Jian Liu, Yan Chen, Wenjuan Cui, Lujun Qiao.
      BACKGROUND Sepsis is a devastating medical condition. In the USA, about 745 000 people are diagnosed with sepsis annually. Although many anti-inflammatory drugs have been used to manage sepsis, the treatment success rate is very low. This study was undertaken to examine the protective effects of naringenin on sepsis-induced kidney injury in rats. MATERIAL AND METHODS Sepsis was induced in Wistar albino rats by cecal ligation and puncture methods. Histological analysis was performed with hematoxylin and eosin (HE) staining. Reactive oxygen species (ROS) levels were determined by flow cytometery. TUNEL assay was used to demonstrate apoptosis. Sandwich ELISA method was used for the determination of urinary angiotensinogen, and protein expression was determined by Western blot analysis. RESULTS We found that naringenin decreased atrophy in the glomerulus and enabled maintenance of the capsule area and normal tubular cavity of the septic rats. Admistration of naringenin at the dosage of 10 and 20 mg/kg to sepsis rats caused significant reduction in the sepsis-induced apoptosis of kidney cells, accompanied by decrease in Bax and increase in Bcl-2 expression. Moreover, naringenin also decreased the ROS levels in septic rats and downregulated the expression of SOD, CAT, and APX. The effects of naringenin were also examined on the levels of urinary angiotensinogen in sepsis rats. We found that naringenin caused a significant decrease in urinary angiotensinogen levels of septic rats. CONCLUSIONS Naringenin appears to have potential in the treatment of sepsis.
    DOI:  https://doi.org/10.12659/MSM.916400
  37. Am J Physiol Renal Physiol. 2019 Aug 14.
    The protective effect of klotho against contrast-associated acute kidney injury via the anti-oxidative effect.
    Hyung Jung Oh, Hyewon Oh, Bo Young Nam, Je Sung You, Dong-Ryeol Ryu, Shin-Wook Kang, Yong Eun Chung.
      As oxidative stress is one major factor behind contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of klotho against CA-AKI via the anti-oxidative effect. In in vitro experiments, cells (NRK-52E) were divided into three groups; the control, iopamidol, or iopamidol+recombinant klotho (rKL) group. Moreover, cell viability was measured with the CCK-8 assay, and oxidative stress was examined with H2DCFDA fluorescence intensity. RT-PCR and Western blotting were performed to assess klotho expression and the Bax/Bcl-2 and apoptosis ratios were evaluated with AnnexinV/PI and Hochest33342 staining. Furthermore, we knocked down the klotho gene using siRNA to verify the endogenous effect of klotho. In in vivo experiment, oxidative stress was evaluated with the TBARS assay and apoptosis was evaluated with the Bax/Bcl-2 ratio and cleaved caspase-3 immunohistochemistry. Additionally, cell and tissue morphology were investigated with TEM. In both in vitro and in vivo experiments, the mRNA and protein expressions of klotho significantly decreased in CA-AKI mice compared with the controls, whereas oxidative stress and apoptosis markers significantly increased in CA-AKI mice. However, rKL supplementation mitigated the elevated apoptotic markers and oxidative stress in the CA-AKI mice model and improved cell viability. In contrast, oxidative stress and apoptotic markers were more aggravated when the klotho gene was knocked down. Moreover, we found more cytoplasmic vacuoles in the CA-AKI mice model using TEM, but fewer cytoplasmic vacuoles in the rKL supplemented cells. This study showed that klotho in the proximal tubular cells can protect against CA-AKI via the anti-oxidative effect.
    Keywords:  Acute kidney injury; Oxidative stress; apoptosis
    DOI:  https://doi.org/10.1152/ajprenal.00297.2018
  38. Adv Healthc Mater. 2019 Aug 13. e1900720
    ROS-Responsive Blended Nanoparticles: Cascade-Amplifying Synergistic Effects of Sonochemotherapy with On-demand Boosted Drug Release During SDT Process.
    Pengying Wu, Wei Dong, Xuyan Guo, Xiaoyang Qiao, Shifang Guo, Lei Zhang, Mingxi Wan, Yujin Zong.
      Sonodynamic therapy (SDT) not only has greater tissue-penetrating depth compared to photo-stimulated therapies, but also can also trigger rapid drug release to achieve synergistic sonochemotherapy. Here, reactive oxygen species (ROS)-responsive IR780/PTL- nanoparticles (NPs) are designed by self-assembly, which contain ROS-cleavable thioketal linkers (TL) to promote paclitaxel (PTX) release during SDT. Under ultrasound (US) stimulation, IR780/PTL-NPs produce high amounts of ROS, which not only induces apoptosis in human glioma (U87) cells but also boosts PTX released by decomposing the ROS-sensitive TL. In the U87 tumor-bearing mouse model, the IR780/PTL-NPs releases the drug at the target sites in a controlled manner upon US irradiation, which significantly inhibits tumor growth and induces apoptosis in the tumor tissues with no obvious toxicity. Taken together, the IR780/PTL-NPs are a novel platform for sonochemotherapy, and can control the spatio-temporal release of chemotherapeutic drugs during SDT.
    Keywords:  ROS-responsive nanoparticles; cascade-amplifying synergistic effects; on-demand drug release; sonochemotherapy
    DOI:  https://doi.org/10.1002/adhm.201900720
  39. Redox Biol. 2019 Aug 02. pii: S2213-2317(19)30657-3. [Epub ahead of print]26 101288
    Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening.
    Chandrika Canugovi, Mark D Stevenson, Aleksandr E Vendrov, Takayuki Hayami, Jacques Robidoux, Han Xiao, You-Yi Zhang, Daniel T Eitzman, Marschall S Runge, Nageswara R Madamanchi.
      Aging is characterized by increased aortic stiffness, an early, independent predictor and cause of cardiovascular disease. Oxidative stress from excess reactive oxygen species (ROS) production increases with age. Mitochondria and NADPH oxidases (NOXs) are two major sources of ROS in cardiovascular system. We showed previously that increased mitochondrial ROS levels over a lifetime induce aortic stiffening in a mouse oxidative stress model. Also, NADPH oxidase 4 (NOX4) expression and ROS levels increase with age in aortas, aortic vascular smooth muscle cells (VSMCs) and mitochondria, and are correlated with age-associated aortic stiffness in hypercholesterolemic mice. The present study investigated whether young mice (4 months-old) with increased mitochondrial NOX4 levels recapitulate vascular aging and age-associated aortic stiffness. We generated transgenic mice with low (Nox4TG605; 2.1-fold higher) and high (Nox4TG618; 4.9-fold higher) mitochondrial NOX4 expression. Young Nox4TG618 mice showed significant increase in aortic stiffness and decrease in phenylephrine-induced aortic contraction, but not Nox4TG605 mice. Increased mitochondrial oxidative stress increased intrinsic VSMC stiffness, induced aortic extracellular matrix remodeling and fibrosis, a leftward shift in stress-strain curves, decreased volume compliance and focal adhesion turnover in Nox4TG618 mice. Nox4TG618 VSMCs phenocopied other features of vascular aging such as increased DNA damage, increased premature and replicative senescence and apoptosis, increased proinflammatory protein expression and decreased respiration. Aortic stiffening in young Nox4TG618 mice was significantly blunted with mitochondrial-targeted catalase overexpression. This demonstration of the role of mitochondrial oxidative stress in aortic stiffness will galvanize search for new mitochondrial-targeted therapeutics for treatment of age-associated vascular dysfunction.
    DOI:  https://doi.org/10.1016/j.redox.2019.101288
  40. Pharmacol Rep. 2019 May 07. pii: S1734-1140(18)30613-3. [Epub ahead of print]71(5): 855-861
    Puerarin protects pulmonary arteries from hypoxic injury through the BMPRII and PPARγ signaling pathways in endothelial cells.
    Tianyi Yuan, Huifang Zhang, Di Chen, Yucai Chen, Yang Lyu, Lianhua Fang, Guanhua Du.
      BACKGROUND: Recent evidence indicates that Puerarin has a protective effect on pulmonary arteries. In the present study, we aimed to investigate whether Puerarin could protect pulmonary arterial endothelial cells from hypoxic injury and determine its potential targets.METHODS: In our study, human pulmonary arterial endothelial cells (HPAECs) were injured by hypoxic (1% O2) incubation. Cell viability was detected by a cell counting kit (CCK8). The production of nitric oxide (NO) was detected by Griess reagent and endothelin-1 (ET-1) was detected by the ELISA method. Oxidative stress was measured by a fluorescence microscope via the fluorescent probe DCFH-DA. Western blotting was employed for studying the mechanism.
    RESULTS: The results show that Puerarin protects HPAECs from hypoxia-induced apoptosis and slightly improves cell viability. Puerarin increases NO and decreases ET-1 to prevent the imbalance between vasoactive substances induced by hypoxia in HPAECs. Puerarin also inhibits the oxidative stress induced by hypoxia. The results from the Western blot show that Puerarin activates the BMPRII/Smad and PPARγ/PI3K/Akt signaling pathways.
    CONCLUSION: In conclusion, Puerarin protects HPAECs from hypoxic injury through the inhibition of oxidative stress and the activation of the BMPRII and PPARγ signaling pathways. This work provides insight into the development of Puerarin as a treatment for hypoxic pulmonary hypertension.
    Keywords:  BMPRII; Hypoxia; PPARγ; Puerarin; Pulmonary arterial endothelial cells
    DOI:  https://doi.org/10.1016/j.pharep.2019.05.002
  41. Epilepsy Res. 2019 Aug 05. pii: S0920-1211(19)30204-9. [Epub ahead of print]156 106183
    Ferulic acid ameliorates pentylenetetrazol-induced seizures by reducing neuron cell death.
    Shu-Hong Zhang, Donghai Liu, Qingyun Hu, Jinling Zhu, Shuqiu Wang, Shaobo Zhou.
      To investigate the neuroprotective effect of ferulic acid (FA) in a pentylenetetrazol (PTZ)-induced seizures model in rat, the motor response, spatial learning ability and memory capability of the rats were assessed. Both the antioxidation and anti-apoptosis pathways were also investigated. In this study, male Wistar rats were randomly divided into 3 groups (n = 12 in each group). For 28 days, the rats were administered saline alone (i.p. normal saline, NS group), PTZ (40 mg/kg, i.p., PTZ group) once daily to induce seizures, or FA (i.p. 60 mg/kg) 20 min before being given PTZ (40 mg/kg, i.p., FA + PTZ group) to assess the neuroprotective effect of FA. The motor response of the rats was analysed with the Racine scale. The spatial learning and memory capacity of the rats were assessed by the Morris water maze test. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured, and both in situ staining with the DNA-binding bisbenzimide Hoechst 33258 and TUNEL assays were used to assess apoptosis. Western blotting was used to further analyse the expression of Apaf-1, caspase-9, caspase-3, Bcl-2, Bid, Bax, cleaved caspase-3 and cytochrome c. The results showed that compared to the those of the PTZ group, FA pre-treatment significantly (p <  0.01) reduced the Racine scores starting at day 4, prolonged the latency of the onset of seizure at day 28, reduced the escape latency period starting at day 2, increased the frequency of crossing the platform location, increased the SOD activity, reduced the MDA content and apoptosis percentage, and upregulated the Bcl-2 levels whilst downregulating the Bax, cytochrome c, Apaf-1, caspase-9, caspase-3, cleaved caspase-3 and Bid expression levels. This study demonstrated that pre-treatment with FA exerts strong neuroprotective effects by reducing the motor response and by improving spatial learning ability and memory capacity. The neuroprotective effect may be a result of a reduction in neuron cell death that occurs via the antioxidative and anti-apoptotic pathways.
    Keywords:  Apoptosis; Epilepsy; Ferulic acid; Memory capacity; Oxidative stress; Spatial learning
    DOI:  https://doi.org/10.1016/j.eplepsyres.2019.106183
  42. Neurochem Res. 2019 Aug 13.
    Knockdown of TRIM32 Protects Hippocampal Neurons from Oxygen-Glucose Deprivation-Induced Injury.
    Liang Wei, Jian-Shui Zhang, Sheng-Feng Ji, Hao Xu, Zhao-Hua Zhao, Li Zhang, Long Pang, Jun-Feng Zhang, Peng-Bo Yang, Hai Ma.
      Tripartite motif 32 (TRIM32) is a member of TRIM family that plays a potential role in neural regeneration. However, the biological function of TRIM32 in cerebral ischemia reperfusion injury has not been investigated. In the present study, we evaluated the expression level of TRIM32 in hippocampal neurons following oxygen-glucose deprivation/reperfusion (OGD/R). The results showed that TRIM32 expression was significantly elevated in hippocampal neurons subjected to OGD/R as compared to the neurons cultured in the normoxia condition. To further evaluate the role of TRIM32, hippocampal neurons were transfected with TRIM32 small interfering RNA (si-TRIM32) to knock down TRIM32. We found that knockdown of TRIM32 improved cell viability of OGD/R-stimulated hippocampal neurons. Generation of reactive oxygen species was decreased, while contents of superoxide dismutase and glutathione peroxidase were increased after si-TRIM32 transfection. Knockdown of TRIM32 suppressed cell apoptosis, as proved by the increased bcl-2 expression along with decreased bax expression and caspase-3 activity. We also found that TRIM32 knockdown enhanced OGD/R-induced activation of Nrf2 signaling pathway in hippocampal neurons. Furthermore, siRNA-Nrf2 was transfected to knock down Nrf2. SiRNA-Nrf2 transfection reversed the protective effects of TRIM32 knockdown on neurons. These data suggested that knockdown of TRIM32 protected hippocampal neurons from OGD/R-induced oxidative injury through activating Nrf2 signaling pathway.
    Keywords:  Cerebral ischemia reperfusion (I/R) injury; Hippocampal neurons; Nrf2 signaling pathway; Oxidative stress; Oxygen–glucose deprivation/reperfusion (OGD/R); Tripartite totif 32 (TRIM32)
    DOI:  https://doi.org/10.1007/s11064-019-02857-7
  43. Chem Res Toxicol. 2019 Aug 12.
    Bisdemethoxycurcumin protects cardiomyocyte mainly depends on Nrf2/HO-1 activation mediated by PI3K/AKT pathway.
    Xing Li, Cong Huo, Yuan Xiao, Rong Xu, Yan Liu, Xin Jia, Xiaoming Wang.
      Bisdemethoxycurcumin (BDMC) is one of three curcuminoids extracted from turmeric. Unlike the dominant ingredient curcumin with some intensive investigations, BDMC was recently reported to possess potent anti-tumor, anti-inflammatory, anti-atherosclerosis, anti-obesity and anti-ageing effects. Considering its pharmacological effects in inflammation, atherosclerosis and obesity, this study was designed to examine if BDMC displays cardioprotective property. In this study, staurosporine (STS) was used to establish cardiomyocyte injury model. Our data revealed that BDMC significantly inhibited myocardial apoptosis, improved cell survival, reduced caspase-3 activity and diminished reactive oxygen species (ROS) production. BDMC enhanced phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) and up-regulated the expression of HO-1. Inhibition of HO-1 activity by using tin-protoporphyrin (SnPPIX) can restrain the anti-apoptotic effect of BDMC. Furthermore, translocation of Nrf2 from cytoplasm to nucleus was ablated by LY294002, although only partially by PD98059. Up-regulation of HO-1 was weakly suppressed by PD98059 but strongly inhibited by LY294002. Unlike PD98059, LY294002 negated the protective effect of BDMC. These findings indicated that BDMC possessed favorable cardioprotection in a Nrf2 / HO-1-dependent manner. Activation of Nrf2 /HO-1 mainly depended on PI3K / AKT but not MEK/ERK signaling.
    DOI:  https://doi.org/10.1021/acs.chemrestox.9b00222
  44. Exp Ther Med. 2019 Sep;18(3): 1729-1737
    Reduction of miR-29a-3p induced cardiac ischemia reperfusion injury in mice via targeting Bax.
    Liang Zhang, Jian Zhang, Qiguang Tong, Guannan Wang, Hongling Dong, Zhonglu Wang, Qi Sun, Hangyu Wu.
      The current study mainly aimed to evaluate the expression and the potential mechanism of miR-29a-3p in the hearts of mice after cardiac ischemia reperfusion (CIR) injury. Quantitative PCR was carried out to assess the relative levels of miR-29a-3p in the hearts of a CIR injury mouse model. To the best of our knowledge, the current study is the first to show that the level of miR-29a-3p was significantly decreased in the hearts of CIR injury mouse models compared with that of sham controls. Moreover, the authors found that decreased miR-29a-3p levels enhanced the production of reactive oxygen species in cardiomyocytes. Meanwhile, the inhibition of miR-29a-3p induced substantial cardiomyocyte apoptosis. Further study showed that the inhibition of miR-29a-3p decreased the activation of Akt and p38, suggesting a stress-induced self-regulatory mechanism after CIR injury in primary cardiomyocytes. A dual luciferase assay and western blot analysis showed that Bax was a target gene of miR-29a-3p. The authors also measured the level of miR-29a-3p in the plasma of 100 acute myocardial infarction (AMI) patients and found that circulating miR-29a-3p was significantly decreased in AMI patients. Receiver operating characteristic curve analysis showed that miR-29a-3p could be used to screen AMI patients from healthy controls. Hence, the authors of the current study propose that reduced miR-29a-3p levels in primary cardiomyocytes contribute to CIR injury-related apoptosis mainly by targeting Bax.
    Keywords:  Bax; cardiac ischemia reperfusion injury; cardiomyocyte apoptosis; microRNA-29a-3p
    DOI:  https://doi.org/10.3892/etm.2019.7722
  45. Foods. 2019 Aug 14. pii: E346. [Epub ahead of print]8(8):
    The Stability and Activity Changes of Apigenin and Luteolin in Human Cervical Cancer Hela Cells in Response to Heat Treatment and Fe2+/Cu2+ Addition.
    Wan-Ning Liu, Jia Shi, Yu Fu, Xin-Huai Zhao.
      Flavonoids are natural polyphenolic compounds with desired bio-functions but with chemical instability and sensitivity to temperature, oxygen, and other factors. Apigenin and luteolin, two flavones of the flavonoid family in plant foods, were; thus, assessed and compared for their stability, especially the changes in anti-cancer activity in response to the conducted heat treatments and the addition of ferrous or cupric ions. The two flavones in aqueous solutions showed first-order degradation at 20 and 37 °C. The addition of ferrous or cupric ions (except for Cu2+ at 37 °C) enhanced luteolin stability via forming the luteolin-metal complexes; however, Fe/Cu addition (especially at 37 °C) consistently impaired apigenin stability. Using the human cervical cancer Hela cells and two cell treatment times (24 and 48 h), it was evident that heat treatments (37 and 100 °C) or Fe/Cu addition could endow apigenin and luteolin with decreased activities in growth inhibition, DNA damage, intracellular reactive oxygen species (ROS) generation, and apoptosis induction. In general, higher temperature led to greater decrease in these activities, while Fe2+ was more effective than Cu2+ to decrease these activities. The correlation analysis also suggested that the decreased ROS generation of the two flavones in the Hela cells was positively correlated with their decreased apoptosis induction. It is; thus, concluded that the two treatments can influence the two flavones' stability and especially exert an adverse impact on their anti-cancer activities.
    Keywords:  apigenin; apoptosis; cervical cancer cells; cupric ions; degradation; ferrous ions; growth inhibition; luteolin
    DOI:  https://doi.org/10.3390/foods8080346
  46. Onco Targets Ther. 2019 ;12 5729-5739
    MiR-34c acts as a tumor suppressor in non-small cell lung cancer by inducing endoplasmic reticulum stress through targeting HMGB1.
    Li Tu, Xiang Long, Weidong Song, Zhongdong Lv, Huadong Zeng, Tiezhu Wang, Xianglu Liu, Juanni Dong, Ping Xu.
      Objective: To investigate the role of miR-34c in lung cancer.Methods: The levels of microRNA-34c (miR-34c) expression in non-small cell lung cancer (NSCLC) tissue and cell lines were examined by the qRT-PCR assay. High mobility group box 1 (HMGB1) expression in NSCLC was assessed by immunohistochemical analysis (IHC), qRT-PCR, and Western blot assays. The effects of miR-34c overexpression or HMGB1 knockdown on cell proliferation and apoptosis were evaluated by CCK-8 and flow cytometry analysis, respectively. Cellular reactive oxygen species (ROS) production in NSCLC cells was detected using a ROS kit. The levels of Bax, p-ERK, eIF2α, GADD153, and IRE1α expression in treated NSCLC cells were measured by Western blot assays. In addition, the interaction between miR-34c and HMGB1 was verified by the dual-luciferase reporter assay.
    Results: miR-34c was only slightly expressed, while HMGB1 was highly expressed in NSCLC tissues and cell lines. Overexpression of miR-34c or knockdown of HMGB1 inhibited cell proliferation, promoted cell apoptosis, and induced ER stress in NSCLC cells. In terms of mechanism, miR-34c negatively regulated HMGB1 expression by directly targeting the 3'-untranslated region (UTR) of HMGB1 mRNA. In addition, we proved that HMGB1 overexpression could block the effects of miR-34c on NSCLC cell proliferation, apoptosis, and ER stress.
    Conclusion: miR-34c may suppress NSCLC tumors by targeting HMGB1 mRNA, promoting endoplasmic reticulum stress, and increasing ROS levels. Our findings suggest that miR-34c has a role in NSCLC.
    Keywords:  endoplasmic reticulum stress, ER stress; high mobility group box 1; microRNA; non-small cell lung cancer
    DOI:  https://doi.org/10.2147/OTT.S206932
  47. Drug Dev Ind Pharm. 2019 Aug 13. 1-40
    Eco-friendly green synthesis of silver nanoparticles and their potential applications as antioxidant and anticancer agents.
    Muhammad Jamil Ahmed, Ghulam Murtaza, Faisal Rashid, Jamshed Iqbal.
      Eco-friendly green synthesis of nanoparticles using medicinal plants gained immense importance due to its potential therapeutic uses. In the current study, silver nanoparticles (AgNPs) were synthesized using water extract of Jurinea dolomiaea leaf and root at room temperature. MTT assay was used to study anticancer potential of AgNPs against cervical cancer cell line (HeLa), breast cancer cell lines (MCF-7) and mouse embryonic fibroblast (NIH-3 T3) cell line for toxicity evaluation. The antioxidant potential was evaluated using stable DPPH radicals. In addition, the apoptotic nuclear changes prompted by AgNPs in more susceptible HeLa cells were observed using fluorescence microscope through DAPI and PI staining. Physiochemical properties of biosynthesized AgNPs were characterized using various techniques. AgNPs were formed in very short time and UV-Vis spectra showed characteristic absorption peak of AgNPs. SEM and TEM showed spherical shape of AgNPs and XRD revealed their crystalline nature. EDX analysis revealed high percentage of silver in green synthesized AgNPs. FTIR analysis indicated involvement of secondary metabolites in fabrication of AgNPs. In vitro cytotoxic and antioxidant study revealed that herb and biosynthesized AgNPs exhibited significant dose dependent and time dependent anticancer and antioxidant potential. Furthermore, study on normal cell line and microscopic analysis of apoptosis revealed that AgNPs exhibited good safety profile as compared to cisplatin and induces significant apoptosis effect. Based on the current findings, it is strongly believe that use of J. dolomiaea offers large scale production of biocompatible AgNPs that can be used as alternative anticancer agents against cancer cell lines tested.
    Keywords:  Green synthesis; anticancer activity; apoptosis; silver nanoparticles; spectroscopy analysis
    DOI:  https://doi.org/10.1080/03639045.2019.1656224
  48. Cell Stress Chaperones. 2019 Aug 10.
    Co-enzyme Q10 protects primary chicken myocardial cells from heat stress by upregulating autophagy and suppressing the PI3K/AKT/mTOR pathway.
    Jiao Xu, Bei Huang, Shu Tang, Jiarui Sun, Endong Bao.
      In this study, we investigated the function of co-enzyme Q10 (Q10) in autophagy of primary chicken myocardial cells during heat stress. Cells were treated with Q10 (1 μΜ, 10 μΜ, and 20 μM) before exposure to heat stress. Pretreatment of chicken myocardial cells with Q10 suppressed the decline in cell viability during heat stress and suppressed the increase in apoptosis during heat stress. Treatment with 20 μM Q10 upregulated autophagy-associated genes during heat stress. The expression of LC3-II was highest in cells treated with 20 μM Q10. Pretreatment with Q10 decreased reactive oxygen species (ROS) levels during heat stress. The number of autophagosomes was significantly increased by 20 μM Q10 treatment, as demonstrated by electron microscopy or monodansylcadaverine (MDC) fluorescence. SQSTM1 accumulation was diminished by Q10 treatment during heat stress, and the number of LC3II puncta was increased. Treatment with 20 μM Q10 also decreased the activation of the PI3K/Akt/mTOR pathway. Our results showed that co-enzyme Q10 can protect primary chicken myocardial cells by upregulating autophagy and suppressing the PI3K/Akt/mTOR pathway during heat stress.
    Keywords:  Autophagy; Chicken; Co-enzyme Q10; Heat stress; Myocardial cells
    DOI:  https://doi.org/10.1007/s12192-019-01029-4
  49. Neurotox Res. 2019 Aug 13.
    Protective Role of Epigallocatechin Gallate in a Rat Model of Cisplatin-Induced Cerebral Inflammation and Oxidative Damage: Impact of Modulating NF-κB and Nrf2.
    Manar Hamed Arafa, Hebatallah Husseini Atteia.
      Cisplatin is a widely used chemotherapeutic agent in treating various types of cancers. However, it can induce neurotoxicity and nephrotoxicity, limiting its dose and clinical use. Although previous studies indicated the direct link between cisplatin-induced central neurotoxicity and oxidative stress, the exact mechanism is not completely understood. Therefore, herein we investigated the effects of prophylactic and concurrent treatment with (-)-epigallocatechin-3-gallate (EGCG), a natural polyphenolic neuroprotective antioxidant, on cisplatin-induced brain toxicity in rats to delineate its molecular mechanism of action. We found that cisplatin initiated a cascade of genetic, biological, and histopathological changes in the brain cortex, inducing inflammatory cytokines, appearance of scattered inflammatory cells, nitro-oxidative stress, and apoptotic proteins in the cerebral cortex. However, EGCG not only protected against cisplatin-induced inflammatory burden but also ameliorated the induction of nitro-oxidative stress and apoptotic proteins triggered by cisplatin in the cerebral cortex of pre- and co-treated rats with respect to their unprotected counterparts. EGCG anti-inflammatory effect here may be attributed to the downregulation of nuclear factor kappa B (NF-κB). Additionally, this natural polyphenol significantly ameliorated cisplatin-elicited reduction in cerebral cortex brain-derived neurotrophic factor and acetylcholine esterase. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream heme oxygenase-1 (HO-1) by EGCG prophylactic and concurrent administration here seems also to play a key role in the protective impact of EGCG against cisplatin toxicity through enhancing total antioxidant capacity. Thus, EGCG can be used as a promising prophylactic adjuvant for preventing the development of brain inflammation and oxidative damage associated with cisplatin chemotherapy.
    Keywords:  (−)-Epigallocatechin-3-gallate; Acetylcholine esterase; Apoptosis; Brain-derived neurotrophic factor (BDNF); Cisplatin; Oxidative damage; Proinflammatory cytokines
    DOI:  https://doi.org/10.1007/s12640-019-00095-x
  50. Food Chem Toxicol. 2019 Aug 10. pii: S0278-6915(19)30547-2. [Epub ahead of print] 110757
    Protective effect of Ganoderma atrum polysaccharide on acrolein-induced macrophage injury via autophagy-dependent apoptosis pathway.
    Kunyou Hou, Qiang Yu, Xiaoyi Hu, Xiaomeng Ding, Jiaqian Hong, Yi Chen, Jianhua Xie, Shaoping Nie, Mingyong Xie.
      The study aimed to investigate the protective effect and underlying mechanism of Ganoderma atrum (G. atrum) polysaccharide (PSG-1) on macrophage injury induced by acrolein. The results showed that PSG-1 restored the cell viability damaged by acrolein. In addition, PSG-1 significantly reduced the acrolein-induced occurrence of apoptosis via increase of Bcl-2 expression, mitochondrial membrane potential (MMP), decrease of ROS, cytochrome c (Cyt-C), caspase-3, caspase-9. Moreover, the overexpressions of autophagy-related proteins (LC3, Beclin-1, Atg7 and Atg5) were suppressed by PSG-1, which demonstrated that PSG-1 inhibited autophagy in acrolein treated macrophage. Beside, PSG-1 significantly elevated the expression level of p-mTOR, suggested that PSG-1 mediated autophagy through mTOR pathway. Furthermore, inhibitor of autophagy could inhibit apoptosis in acrolein-induced macrophage, suggesting that autophagy may be involved in the regulation of apoptosis. In summary, the present study demonstrated that PSG-1 protected acrolein-induced macrophage injury via autophagy-dependent apoptosis.
    Keywords:  Acrolein; Apoptosis; Autophagy; Ganoderma atrum polysaccharide; Macrophage
    DOI:  https://doi.org/10.1016/j.fct.2019.110757
  51. Dalton Trans. 2019 Aug 14.
    Platinum(ii) complexes showing high cytotoxicity toward A2780 ovarian carcinoma cells.
    Katarzyna Choroba, Barbara Machura, Luis R Raposo, Jan G Małecki, Slawomir Kula, Michał Pająk, Karol Erfurt, Anna M Maroń, Alexandra R Fernandes.
      2,6-Bis(thiazol-2-yl)pyridines functionalized with 9-anthryl (L1), 9-phenanthryl (L2), and 1-pyrenyl (L3) groups were used for the preparation of [Pt(Ln)Cl]CF3SO3 (1-3). The constitution of the Pt(ii) complexes was determined by 1H and 13C NMR spectroscopy, HR-MS spectrometry, elemental analysis and X-ray analysis (for (1)). The electrochemical and photophysical properties of [Pt(Ln)Cl]CF3SO3 were compared with the behaviour of the Pt(ii) complexes with aryl-substituted 2,2':6',2''-terpyridine ligands. What is noteworthy is that the coordination ability of dtpy toward the Pt(ii) centre was investigated for the first time. All complexes were tested in vitro by MTS assay on four tumor cell lines, A2780 (ovarian carcinoma), HTC116 (colon rectal carcinoma), MCF7 (breast adenocarcinoma), and PC3 (prostate carcinoma) and on normal primary fibroblasts. Compounds (1-3) showed a dose dependent antiproliferative effect in the A2780 cell line with (3) > (2) > (1) and this loss of A2780 cell viability was due to a combination of an apoptotic cell death mechanism via mitochondria and autophagic cell death. Exposure to IC50 concentration of (2) induced an increase in the number of apoptotic nuclei and a depolarization of the mitochondrial membrane which is consistent with the induction of apoptosis while exposure to IC50 concentration of (3) showed an increase in the apoptotic nuclei with a slight hyperpolarization of the mitochondrial membrane that might indicate an initial step of apoptosis induction. The complexes (2) and (3) induce an increase in the production of intracellular ROS which is associated with the trigger of the apoptotic pathways. The ROS production was augmented by the presence of oxidants and correlated with an increase of oxygen radicals. The IC50 of (2) and (3) (4.4 μM and 2.9 μM, respectively) was similar to the IC50 of cisplatin (3.4 μM) in the A2780 cell line, which together with their low cytotoxicity in normal fibroblasts, demonstrates their potential for further studies.
    DOI:  https://doi.org/10.1039/c9dt02894c
  52. Mol Biol Rep. 2019 Aug 12.
    Radioprotective effect of olanzapine as an anti-psychotic drug against genotoxicity and apoptosis induced by ionizing radiation on human lymphocytes.
    Mohammad Asghari, Zahra Shaghaghi, Soghra Farzipour, Arash Ghasemi, Seyed Jalal Hosseinimehr.
      Olanzapine (OLA), is prescribed as an anti-psychotic medicine in schizophrenia patients. In this study, the protective effect of OLA against genotoxicity and apoptosis induced by ionizing radiation in human healthy lymphocytes was evaluated. At first, the antioxidant activities of OLA were assayed by two different methods as free radical scavenging with DPPH (2,2-diphenyl-1-picryl-hydrazyl) and ferric reducing power methods. In in vitro experiment, human blood samples were treated with OLA at various concentrations (0.25-20 μM) for 3 h and then were exposed to X-ray at a dose of 150 cGy. The genotoxicity was assessed in binucleated human lymphocytes with micronuclei assay. The apoptotic lymphocytes were assessed by flow cytometry in OLA treated and/or irradiated lymphocytes. OLA exhibited free radical scavenging and reducing power activities more than ascorbic acid. The results showed that the lymphocytes treated with OLA and later exposed to IR presented lower frequencies of micronuclei and apoptosis compared to the control sample which was irradiated and not treated to OLA. The maximum radioprotection was observed at 20 μM of OLA with 83% of efficacy. The present study suggested the protective role for OLA in protection radiation-induced genetic damage and apoptosis induced by ionizing irradiation in human normal cells.
    Keywords:  Apoptosis; Genotoxicity; Ionizing radiation; Olanzapine; Radioprotective
    DOI:  https://doi.org/10.1007/s11033-019-05024-x
  53. Med Sci Monit. 2019 Aug 17. 25 6165-6173
    Atorvastatin Induces Hepatotoxicity in Diabetic Rats via Oxidative Stress, Inflammation, and Anti-Apoptotic Pathway.
    Hanqing Zeng, Zhongtao Liu.
      BACKGROUND Patients with diabetes mellitus (DM) commonly receive statins to suppress vulnerability to adverse cardiovascular events. It has been clinically proven that hepatotoxicity is one of the most severe adverse effects of statins. MATERIAL AND METHODS We constructed diabetic rat models by feeding rats with high-fat food and by injection of low-dose STZ. Rats were randomized into 2 groups: a DM group (n=10) and a control (CON) group (n=5). CON rats received a normal diet, whereas DM rats ate high-fat food. Rats in the DM group underwent intraperitoneal STZ (35 mg/kg) injection following 6-week diet restriction. On the seventh day following STZ or blank injection, rats with FBG concentration over 11.1 mM were regarded as successfully established models and were used for further research. RESULTS We showed that severe liver injury occurred in diabetic rats treated with 20 mg/kg atorvastatin, as evidenced by attenuation of liver enzyme activities, elevation of bilirubin levels, and alterations in the hepatic architecture, including hepatocyte death by necrosis, lymphocyte infiltration, and fibrosis. We also found that atorvastatin increased the secretion of pro-inflammatory factors such as L-1, TNF, IL-6, and IL-18 by enhancing activation of the NF-B signal pathway in the livers of diabetic rats. Atorvastatin elevated the levels of ROS and reduced the antioxidant enzyme (SOD and CAT) activities. Atorvastatin also increased the expression of anti-apoptotic protein BCL2 and decreased the expression of pro-apoptotic protein BAX in the livers of diabetic rats. CONCLUSIONS Atorvastatin exerts potentially hepatotoxic effects on diabetic rats by modulating oxidative/antioxidative status, pro-inflammatory cytokine production, and apoptosis inhibition.
    DOI:  https://doi.org/10.12659/MSM.915790
  54. Biochem Biophys Res Commun. 2019 Aug 09. pii: S0006-291X(19)30880-0. [Epub ahead of print]
    CIRP downregulation renders cardiac cells prone to apoptosis in heart failure.
    Minxiao Chen, Hui Fu, Jingjing Zhang, He Huang, Peng Zhong.
      OBJECTIVES: Cold-inducible RNA binding protein (CIRP) is a stress protein which is involved in regulating multiple cellular processes. However, its role in pathological heart diseases is still unknown. Our current study was aimed at addressing the response and functional role of CIRP in heart failure.METHODS: CIRP protein level was evaluated in heart samples from patients with heart failure and mice with post-myocardial infarction (post-MI). Cardiac-derived H9C2 cells were utilized to test the effects of CIRP deficiency on cell survival and apoptosis in response to H2O2 treatment.
    RESULTS: Reduced expression of cardiac CIRP was observed in patients with heart failure, mice with post-MI. In addition, knockdown of CIRP exacerbated cell apoptosis and cell death in response to H2O2 treatment, suggesting a protective role of CIRP in cell apoptosis induced by oxidative stress in the heart.
    CONCLUSIONS: Our findings suggest that altered expression of CIRP may be involved in the pathogenesis of heart failure and downregulation of CIRP may render cardiac cells prone to apoptosis in heart failure.
    Keywords:  CIRP; Cardiac pathology; Cell apoptosis; Heart failure; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbrc.2019.05.012
  55. Exp Mol Pathol. 2019 Aug 13. pii: S0014-4800(19)30406-X. [Epub ahead of print] 104298
    LncRNA-ROR is involved in cerebral hypoxia/reoxygenation-induced injury via regulating miR-135a-5p/ROCK1/2.
    Hong Chen, Xiaoming Li.
      Ischemic stroke is a common cerebrovascular disease with high mortality, disability and morbidity. LncRNAs was involved in ischemia/reperfusion injury. The present study aims to investigate whether LncRNA-ROR can promote the cerebral hypoxia/reoxygenation (H/R) injury in vitro, a cellular model of cerebral ischemia/reperfusion injury, through inhibiting the expression of miR-135a-5p through upregulating the expression of ROCK1 and ROCK2. Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was used to detect the LncRNA-ROR expression in PC12 cells induced by H/R and verify the transfection effect. ROS, LDH, SOD and MDA levels were detected by respective kits. CCK-8 assay and flow cytometry analysis were respectively used to detect the cell viability and cell apoptosis. Western blot analysis was to analyze the expression of apoptosis-related proteins (Bcl-2, Bax, cleaved caspase3). Immunofluorescent staining was detecting the ROCK1/2 expression. As a result, LncRNA-ROR expression was increased in the PC12 cells induced by H/R. LncRNA-ROR overexpression could aggravate injury of PC12 cells induced by H/R. And, LncRNA-ROR overexpression could decrease viability and promote apoptosis of PC12 cells induced by H/R. In addition, miR-135a-5p was demonstrated to be a target of LncRNA-ROR and LncRNA-ROR improved H/R injury in PC12 cells by up-regulated the expression of miR-135a-5p via down-regulation of ROCK1/2. In conclusion, this study indicated that LncRNA-ROR could promote the cerebral H/R injury by inhibiting the expression of miR-135a-5p through upregulating the expression of ROCK1/2. And, miR-135a-5p overexpression could improve the cerebral H/R injury by inhibiting the expression of ROCK1/2.
    Keywords:  Cerebral injury; Ischemia/reperfusion; LncRNA-ROR; miR-135a-5p
    DOI:  https://doi.org/10.1016/j.yexmp.2019.104298
  56. Nanomedicine (Lond). 2019 Aug 15.
    Therapeutic efficacy of Phyllanthus emblica-coated iron oxide nanoparticles in A549 lung cancer cell line.
    Shivani Thoidingjam, Ashu Bhan Tiku.
      Aim: Present work was undertaken to fabricate iron oxide nanoparticles (IONPs) using a green approach for increased therapeutic efficacy. Materials & methods: Two types of IONPs were synthesized, one without any coating (IONPUC) and other coated with Phyllanthus emblica (Amla) fruit extract (IONPA). Both the IONPs were characterized using different techniques and therapeutic efficacy was evaluated in A549 human lung cancer cell line. Results: IONPA were smaller in size with better dispersibility compared with IONPUC. They induced increased reactive oxygen species production, higher DNA damage and apoptosis, which resulted in increased toxicity to cancer cells in comparison to IONPUC. Conclusion: Higher uptake of IONPA and active components coating the surface, may be responsible for the increased therapeutic efficacy in cancer cells.
    Keywords:  amla extract; green synthesis; iron oxide; iron oxide nanoparticle; lung cancer; nanoparticle; nanotherapy; phytochemical screening; reactive oxygen species
    DOI:  https://doi.org/10.2217/nnm-2019-0111
  57. Oncol Lett. 2019 Sep;18(3): 2509-2517
    TIGAR promotes growth, survival and metastasis through oxidation resistance and AKT activation in glioblastoma.
    Zhi Tang, Zhengwen He.
      Glioblastoma has a poor prognosis and is one of the most lethal types of cancer in the world. TP53 induced glycolysis regulatory phosphatase (TIGAR) is upregulated in various types of cancer. Therefore, the present study investigated the role of TIGAR in glioblastoma. TIGAR expression was measured in glioma samples and cell lines using immunohistochemistry and western blotting. Reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione, malondialdehyde and intracellular reactive oxygen species levels were detected to measure oxidative stress in U-87MG cells following short hairpin RNA (shRNA)-mediated knockdown of TIGAR. Cell viability was determined using an MTT assay for TIGAR-overexpression vector- and TIGAR-shRNA-transfected U-87MG cells. Apoptosis was assessed to evaluate whether TIGAR knockdown sensitized cells to the antitumor effects of temozolomide (TMZ). Migration, invasion and epithelial-mesenchymal transition (EMT) were further assessed using Transwell and western blotting assays. A co-immunoprecipitation assay was used to detect the interaction between TIGAR and protein kinase B (AKT). The results of the present study revealed that TIGAR was positively associated with poor survival and was upregulated in glioblastoma. TIGAR knockdown significantly increased oxidative stress, decreased cell proliferation and exacerbated TMZ-induced apoptosis in U-87MG cells. Additionally, TIGAR knockdown decreased migration, invasion and EMT, and treatment of TIGAR-shRNA-transfected cells with NADPH had no effect on metastasis. In addition, TIGAR promoted AKT activation and bound to AKT. In conclusion, the present study demonstrated that TIGAR may promote glioblastoma growth and progression through oxidation resistance and AKT activation.
    Keywords:  TP53 induced glycolysis regulatory phosphatase; glioblastoma; metastasis; oxidative stress; proliferation
    DOI:  https://doi.org/10.3892/ol.2019.10574
  58. J Orthop Surg Res. 2019 Aug 14. 14(1): 259
    Effects of ginsenoside Rb1 on spinal cord ischemia-reperfusion injury in rats.
    Jin-Tao Ye, Feng-Tao Li, Sheng-Li Huang, Jian-Li Xue, Yirixiati Aihaiti, Hao Wu, Ruo-Xi Liu, Bin Cheng.
      BACKGROUND: The aim of this study was to evaluate the effects of different doses of ginsenoside Rb1 (GRb1) pretreatment on spinal cord ischemia-reperfusion (SCII) in rats and explore the potential mechanisms about the expression of survivin protein after the intervention.METHODS: A total of 90 healthy adult Sprague-Dawley (SD) rats were randomly divided into six groups: sham-operated (n = 15), SCII model (n = 15), and GRb1-treated groups (n = 60). The GRb1-treated group was divided into four subgroups: 10 mg/kg, 20 mg/kg, 40 mg/kg, and 80 mg/kg (n = 15). The corresponding dose of GRb1 was injected intraperitoneally 30 min before operation and every day after operation. Forty-eight hours after model establishment, the neurological function of hind limbs was measured with Basso, Beattie, and Bresnahan (BBB) scale. The superoxide dismutase (SOD) and malondialdehyde (MDA) levels in serum and spinal cord tissue were detected respectively. The expression of survivin protein was observed by immunofluorescence staining. HE and TUNEL staining were used to observe neural cell injury and apoptosis, respectively, in the spinal cord of rats with SCII.
    RESULTS: The intervention of different doses of GRb1 could increase SOD activity and decrease MDA content in serum and spinal cord tissue, increase survivin protein expression, and decrease neuronal apoptosis. It was dose-dependent, but there was no significant change between 40 mg/kg and 80 mg/kg.
    CONCLUSIONS: GRb1 could reduce the cell apoptosis induced by SCII through inhibiting oxidative stress. It can also inhibit apoptosis by promoting the expression of Survivin protein. Ginsenoside Rb1 had a dose-dependent protective effect on SCII in the dose range of 10 mg/kg-40 mg/kg.
    Keywords:  Ginsenoside Rb1; Ischemia-reperfusion Injury; Oxidative stress; Spinal cord Injury; Survivin protein
    DOI:  https://doi.org/10.1186/s13018-019-1299-2
  59. J Helminthol. 2019 Aug 15. 1-9
    Activation of the NLRP3 and AIM2 inflammasomes in a mouse model of Schistosoma mansoni infection.
    T T W Chen, P C Cheng, K C Chang, J P Cao, J L Feng, C C Chen, H Y P Lam, S Y Peng.
      Schistosomiasis is an inflammatory disease that occurs when schistosome species eggs are deposited in the liver, resulting in fibrosis and portal hypertension. Schistosomes can interact with host inflammasomes to elicit host immune responses, leading to mitochondrial damage, generation of high levels of reactive oxygen species (ROS) and activation of apoptosis during inflammation. This study aims to examine whether ROS and NF-κB (p65) expression elicited other types of inflammasome activation in Schistosoma mansoni-infected mouse livers. We examine the relationship between inflammasome activation, mitochondrial damage and ROS production in mouse livers infected with S. mansoni. We demonstrate a significant release of ROS and superoxides and increased NF-κB (p65) in S. mansoni-infected mouse livers. Moreover, activation of the NLRP3 and AIM2 inflammasomes was triggered by S. mansoni infection. Stimulation of HuH-7 hepatocellular carcinoma cells with soluble egg antigen induced activation of the AIM2 inflammasome pathway. In this study, we demonstrate that S. mansoni infection promotes both NLRP3 and AIM2 inflammasome activation.
    Keywords:  Inflammasome; ROS; SEA; schistosomes
    DOI:  https://doi.org/10.1017/S0022149X19000622
  60. PLoS Pathog. 2019 Aug 14. 15(8): e1008004
    Fas-associated factor 1 Mediates NADPH Oxidase-Induced Reactive Oxygen Species Production and Proinflammatory Responses in Macrophages against Listeria Infection.
    Tae-Hwan Kim, Hyun-Cheol Lee, Jae-Hoon Kim, C Y Hewawaduge, Kiramage Chathuranga, W A Gayan Chathuranga, Pathum Ekanayaka, H M S M Wijerathne, Chul-Joong Kim, Eunhee Kim, Jong-Soo Lee.
      Fas-associated factor 1 is a death-promoting protein that induces apoptosis by interacting with the Fas receptor. Until now, FAF1 was reported to interact potentially with diverse proteins and to function as a negative and/or positive regulator of several cellular possesses. However, the role of FAF1 in defense against bacterial infection remains unclear. Here, we show that FAF1 plays a pivotal role in activating NADPH oxidase in macrophages during Listeria monocytogenes infection. Upon infection by L. monocytogenes, FAF1 interacts with p67phox (an activator of the NADPH oxidase complex), thereby facilitating its stabilization and increasing the activity of NADPH oxidase. Consequently, knockdown or ectopic expression of FAF1 had a marked effect on production of ROS, proinflammatory cytokines, and antibacterial activity, in macrophages upon stimulation of TLR2 or after infection with L. monocytogenes. Consistent with this, FAF1gt/gt mice, which are knocked down in FAF1, showed weaker inflammatory responses than wild-type mice; these weaker responses led to increased replication of L. monocytogenes. Collectively, these findings suggest that FAF1 positively regulates NADPH oxidase-mediated ROS production and antibacterial defenses.
    DOI:  https://doi.org/10.1371/journal.ppat.1008004
  61. Sci Rep. 2019 Aug 12. 9(1): 11667
    (Pro)renin receptor contributes to renal mitochondria dysfunction, apoptosis and fibrosis in diabetic mice.
    Caixia Li, Luis C Matavelli, Safia Akhtar, Helmy M Siragy.
      Recently we demonstrated that increased renal (Pro)renin receptor (PRR) expression in diabetes contributes to development of diabetic kidney disease. However, the exact mechanisms involving PRR activity and diabetic kidney dysfunction are unknown. We hypothesized that PRR is localized in renal mitochondria and contributes to renal fibrosis and apoptosis through oxidative stress-induced mitochondria dysfunction. Controls and streptozotocin-induced diabetic C57BL/6 mice were injected with scramble shRNA and PRR shRNA and followed for a period of eight weeks. At the end of study, diabetic mice showed increased expressions of PRR and NOX4 in both total kidney tissue and renal mitochondria fraction. In addition, renal mitochondria of diabetic mice showed reduced protein expression and activity of SOD2 and ATP production and increased UCP2 expression. In diabetic kidney, there was upregulation in the expressions of caspase3, phos-Foxo3a, phos-NF-κB, fibronectin, and collagen IV and reduced expressions of Sirt1 and total-FOXO3a. Renal immunostaining revealed increased deposition of PRR, collagen and fibronectin in diabetic kidney. In diabetic mice, PRR knockdown decreased urine albumin to creatinine ratio and the renal expressions of PRR, NOX4, UCP2, caspase3, phos-FOXO3a, phos-NF-κB, collagen, and fibronectin, while increased the renal mitochondria expression and activity of SOD2, ATP production, and the renal expressions of Sirt1 and total-FOXO3a. In conclusion, increased expression of PRR localized in renal mitochondria and diabetic kidney induced mitochondria dysfunction, and enhanced renal apoptosis and fibrosis in diabetes by upregulation of mitochondria NOX4/SOD2/UCP2 signaling pathway.
    DOI:  https://doi.org/10.1038/s41598-019-47055-1
  62. Oncol Lett. 2019 Sep;18(3): 2159-2164
    The role of ferroptosis in digestive system cancer.
    Yan Song, Hu Yang, Rui Lin, Kui Jiang, Bang-Mao Wang.
      Ferroptosis is a type of regulated cell death dependent on iron and reactive oxygen species. Ferroptosis is distinct from other cell death modalities, including apoptosis, autophagy and necrosis. Dysregulated ferroptosis has been implicated in a number of diseases, including neuropathy, ischemia reperfusion injury, acute kidney failure and cancer. The digestive system consists of several organs. The morbidity and mortality rates of digestive system cancer are high. The current review summarizes the role of ferroptosis in digestive system cancer. A large number of molecules, including tumor protein p53, retinoblastoma protein, nuclear factor E2-related factor 2, KH RNA binding domain containing signal transduction associated 1, cysteine dioxygenase type 1, metallothionein-1G, nuclear receptor coactivator 4, CDGSH iron sulfur domain 1, heat shock protein family A (Hsp70) member 5 and acyl-CoA synthetase long chain family member 4, regulate ferroptosis in digestive system cancer. Drugs such as cisplatin, baicalein, haloperidol, artesunate, piperlongumine, saponin and bromelain may cause cancer cell death by inducing ferroptosis. An improved understanding of ferroptosis in digestive system cancer may give rise to novel diagnostic and making therapeutic strategies.
    Keywords:  digestive cancer; ferroptosis; regulated cell death
    DOI:  https://doi.org/10.3892/ol.2019.10568
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