bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2018–12–02
47 papers selected by
Gavin McStay, Staffordshire University
  1. Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells.
  2. Protective effects of anthocyanin against apoptosis and oxidative stress induced by arsanilic acid in DF-1 cells.
  3. Attenuation of autophagy flux by 6-shogaol sensitizes human liver cancer cells to TRAIL-induced apoptosis via p53 and ROS.
  4. PINK1 Protects Against Gentamicin-Induced Sensory Hair Cell Damage: Possible Relation to Induction of Autophagy and Inhibition of p53 Signal Pathway.
  5. Mechanisms underlying nickel nanoparticle induced reproductive toxicity and chemo-protective effects of vitamin C in male rats.
  6. Blocking REDD1/TXNIP axis ameliorates LPS-induced vascular endothelial cell injury through repressing oxidative stress and apoptosis.
  7. Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2/HO-1 pathway.
  8. Green Platinum Nanoparticles Interaction With HEK293 Cells: Cellular Toxicity, Apoptosis, and Genetic Damage.
  9. Radiofrequency radiation at 2.856 GHz does not affect key cellular endpoints in neuron-like PC12 cells.
  10. Alpha-Lipoic Acid Preconditioning and Ischaemic Postconditioning Synergistically Protect Rats from Cerebral Injury Induced by Ischemia and Reperfusion Partly via Inhibition TLR4/MyD88/ NF-κB Signaling Pathway.
  11. Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro.
  12. Oxymatrine Attenuates Aβ1-42-Induced Neurotoxicity in Primary Neuronal Cells and Memory Impairment in Rats.
  13. p110α and p110β isoforms of PI3K are involved in protection against H2O2 induced oxidative stress in cancer cells.
  14. Use of DNA-generated gold nanoparticles to radiosensitize and eradicate radioresistant glioma stem cells.
  15. Effects of Acute Fluorene-9-Bisphenol Exposure on Mouse Oocyte in vitro Maturation and Its Possible Mechanisms.
  16. N-myristoylation of Antimicrobial Peptide CM4 Enhances Its Anticancer Activity by Interacting With Cell Membrane and Targeting Mitochondria in Breast Cancer Cells.
  17. Microcystin-LR induces angiodysplasia and vascular dysfunction through promoting cell apoptosis by the mitochondrial signaling pathway.
  18. Levistolide A synergistically enhances doxorubicin‑induced apoptosis of k562/dox cells by decreasing MDR1 expression through the ubiquitin pathway.
  19. Suppression of Apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) by Klotho Protein is Associated with Reduced Endoplasmic Reticulum Oxidative Stress and Activation of the PI3K/AKT Pathway.
  20. The effects of Para-phenylenediamine (PPD) on the skin fibroblast cells.
  21. Silencing Astrocyte Elevated Gene-1 Attenuates Lipopolysaccharide-induced Inflammation and Mucosal Barrier Injury in NCM460 Cells by Suppressing the Activation of NLRP3 Inflammasome.
  22. Melatonin Rescue Oxidative Stress-Mediated Neuroinflammation/ Neurodegeneration and Memory Impairment in Scopolamine-Induced Amnesia Mice Model.
  23. [Effects of endotoxin/lipopolysaccharide on early apoptosis of human neutrophil through PIM3].
  24. Oxidants-Antioxidants Profile in the Breast Cancer Cell Line MCF-7
  25. Does Oxidation of Mitochondrial Cardiolipin Trigger a Chain of Antiapoptotic Reactions?
  26. Synthesis of 3-Arylaminopropenone Linked 2-Arylbenzo[d]imidazo[2,1-b]thiazole Conjugates as Anticancer and Apoptotic Inducing Agents.
  27. Ethanol Exacerbates Manganese-Induced Neurobehavioral Deficits, Striatal Oxidative Stress, and Apoptosis Via Regulation of p53, Caspase-3, and Bax/Bcl-2 Ratio-Dependent Pathway.
  28. Protective effect of sesamin in lipopolysaccharide-induced mouse model of acute kidney injury via attenuation of oxidative stress, inflammation, and apoptosis.
  29. Galangin Alleviates Liver Ischemia-Reperfusion Injury in a Rat Model by Mediating the PI3K/AKT Pathway.
  30. Sanguiin H-11 from Sanguisorbae radix protects HT22 murine hippocampal cells against glutamate-induced death.
  31. Integrating in situ formation of nanozymes with three-dimensional dendritic mesoporous silica nanospheres for hypoxia-overcoming photodynamic therapy.
  32. The chemical composition and events related to the cytotoxic effects of propolis on osteosarcoma cells: A comparative assessment of Colombian samples.
  33. Thermosensitive chitosan-gelatin-based hydrogel containing curcumin-loaded nanoparticles and latanoprost as a dual-drug delivery system for glaucoma treatment.
  34. Iodixanol supplementation during sperm cryopreservation improves protamine level and reduces reactive oxygen species of canine sperm.
  35. Resveratrol improves ex vivo expansion of CB-CD34+ cells via downregulating intracellular reactive oxygen species level.
  36. Long-term exposure to low level of fluoride induces apoptosis via p53 pathway in lymphocytes of aluminum smelter workers.
  37. Effects of long-term dehydration on oxidative stress, apoptotic markers and neuropeptides in the gastric mucosa of the dromedary camel.
  38. Cytokine augments the sorafenib-induced apoptosis in Huh7 liver cancer cell by inducing mitochondrial fragmentation and activating MAPK-JNK signalling pathway.
  39. Hydralazine protects against renal ischemia-reperfusion injury in rats.
  40. ROS-induced autophagy regulates porcine trophectoderm cell apoptosis, proliferation and differentiation.
  41. Taurine ameliorates oxidative stress induced inflammation and ER stress mediated testicular damage in STZ-induced diabetic Wistar rats.
  42. Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy.
  43. Rosiglitazone attenuates cell apoptosis through antioxidative and anti-apoptotic pathways in the hippocampi of spontaneously hypertensive rats.
  44. Soluble epoxide hydrolase inhibitor, APAU, protects dopaminergic neurons against rotenone induced neurotoxicity: Implications for Parkinson's disease.
  45. 7,8-Dihydroxyflavone Protects High Glucose-Damaged Neuronal Cells against Oxidative Stress.
  46. SkQ1 Controls CASP3 Gene Expression and Caspase-3-Like Activity in the Brain of Rats under Oxidative Stress.
  47. The role of mitochondria in systemic lupus erythematosus: A glimpse of various pathogenetic mechanisms.
  1. Chem Biol Interact. 2018 Nov 24. pii: S0009-2797(17)31159-6. [Epub ahead of print]
    Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells.
    Haoran Wang, Bing Shao, Hongyan Yu, Feibo Xu, Peiyan Wang, Kaiyuan Yu, Yanfei Han, Miao Song, Yanfei Li, Zheng Cao.
      Many reports demonstrated that aluminum maltolate (Almal) has potential toxicity to human and animal. Our study has demonstrated that Almal can induce oxidative damage and apoptosis in PC12 cells and SH-SY5Y Cells, two in vitro models of neuronal cells. Hyperforin (HF) is a well-known antioxidant, anti-inflammatory, anti-amyloid and anti-depressant compound extracted from Hypericum perforatum extract. Here, we investigated the neuroprotective effect of HF against Almal-induced neurotoxicity in cultured PC12 cells and SH-SY5Y cells, mainly caused by oxidative stress. In the present study, HF significantly inhibited the formation of reactive oxygen species (ROS), decreased the level of lipid peroxide and enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) compared with Almal group in PC12 cells and SH-SY5Y cells. Additionally, HF suppressed the reduction of the mitochondrial membrane potential (MMP), cytochrome c (Cyt-c) release, activation of caspase-3, and the down-regulation of Bcl-2 expression and up-regulation of Bax expression induced by Almal in PC12 cells and SH-SY5Y cells. In summary, HF protects PC12 cells and SH-SY5Y cells from damage induced by Almal through reducing oxidative stress and preventing of mitochondrial-mediated apoptosis.
    Keywords:  Aluminum maltolate; Hyperforin; Mitochondrial-mediated apoptosis; Neuroprotective; Oxidative damage; PC12 cells and SH-SY5Y cells
    DOI:  https://doi.org/10.1016/j.cbi.2018.11.016
  2. Mol Biol Rep. 2018 Nov 28.
    Protective effects of anthocyanin against apoptosis and oxidative stress induced by arsanilic acid in DF-1 cells.
    Ning Xie, Na Geng, Dong Zhou, Yuliang Xu, Kangping Liu, Yongxia Liu, Jianzhu Liu.
      Anthocyanin is a natural plant pigment that acts as an antioxidant and scavenges free radicals. This study aimed to investigate the potential protective role of nightshade anthocyanin (NA), a natural flavonoid compound, against the arsanilic acid (ASA)-induced cell death of DF-1 cells. DF-1 cells were initially exposed to ASA, and then NA was applied to the treated cells. Cell viability, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis were examined. Results showed that NA inhibited the ASA-induced decrease in cell viability, increase in ROS, and loss of MMP in DF-1 cells. Moreover, caspase-3 activation was inhibited by ASA supplementation and NA attenuated the ASA-induced increase in the percentage of apoptotic cells. In summary, our study suggested that NA can enhance ASA-induced cytotoxicity and apoptosis, thereby providing a basis for the molecular mechanisms of NA-mediated protection.
    Keywords:  Anthocyanin; Apoptosis; Arsanilic acid; DF-1 cells
    DOI:  https://doi.org/10.1007/s11033-018-4472-5
  3. Int J Mol Med. 2018 Nov 21.
    Attenuation of autophagy flux by 6-shogaol sensitizes human liver cancer cells to TRAIL-induced apoptosis via p53 and ROS.
    Uddin Md Nazim, Sang-Youel Park.
      Tumor necrosis factor (TNF)‑related apoptosis‑inducing ligand (TRAIL) is a member of the TNF superfamily and is an antitumor drug that induces apoptosis in tumor cells with minimal or no effects on normal cells. Here, it is demonstrated that 6‑shogaol (6‑sho), a bioactive component of ginger, exerted anti‑inflammatory and anticancer properties, attenuated tumor cell propagation and induced TRAIL‑mediated cell death in liver cancer cells. The current study identified a potential pathway by revealing that TRAIL and 6‑sho or chloroquine acted together to trigger reactive oxygen species (ROS) production, to upregulate tumor‑suppressor protein 53 (p53) expression and to change the mitochondrial transmembrane potential (MTP). Treatment with N‑acetyl‑L‑cysteine reversed these effects, restoring the MTP and attenuated ROS production and p53 expression. Interestingly, treatment with 6‑sho increased p62 and microtubule‑associated proteins 1A/1B light chain 3B‑II levels, indicating an inhibited autophagy flux. In conclusion, attenuation of 6‑sho‑induced autophagy flux sensitized cells to TRAIL‑induced apoptosis via p53 and ROS, suggesting that the administration of TRAIL in combination with 6‑sho may be a suitable therapeutic method for the treatment of TRAIL‑resistant Huh7 liver cells.
    DOI:  https://doi.org/10.3892/ijmm.2018.3994
  4. Front Mol Neurosci. 2018 ;11 403
    PINK1 Protects Against Gentamicin-Induced Sensory Hair Cell Damage: Possible Relation to Induction of Autophagy and Inhibition of p53 Signal Pathway.
    Qianqian Yang, Yiwei Zhou, Haiyan Yin, Hongrui Li, Meijuan Zhou, Gaoying Sun, Zhixin Cao, Rongjun Man, Haibo Wang, Jianfeng Li.
      Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is a gatekeeper of mitochondrial quality control. The present study was aimed to examine whether PINK1 possesses a protective function against gentamicin (GM)-induced sensory hair cell (HC) damage in vitro. The formation of parkin particles (a marker revealing the activation of PINK1 pathway which is a substrate of PINK1 and could signal depolarized mitochondria for clearance) and autophagy were determined by immunofluorescence staining. The expressions of PINK1, LC3B, cleaved-caspase 3 and p53 were measured by Western blotting. The levels of reactive oxygen species (ROS) and apoptosis were respectively evaluated by DCFH-DA staining, Annexin V Apoptosis Detection Kit and TUNEL staining. Cell viability was tested by a CCK8 kit. We found that treatment of 400 μM GM elicited the formation of ROS, which, in turn, led to PINK1 degradation, parkin recruitment, autophagy formation, an increase of p53 and cleaved-caspase 3 in HEI-OC1 cells and murine HCs. In contrast, co-treatment with ROS scavenger N-acetyl-L-cysteine (NAC) inhibited parkin recruitment, alleviated autophagy and p53 pathway-related damaged-cell elimination. Moreover, PINK1 interference contributed to a decrease of autophagy but an increase of p53 level in HEI-OC1 cells in response to GM stimulus. Findings from this work indicate that PINK1 alleviates the GM-elicited ototoxicity via induction of autophagy and resistance the increase of p53 in HCs.
    Keywords:  ROS; autophagy; gentamicin (GM); p53; phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)
    DOI:  https://doi.org/10.3389/fnmol.2018.00403
  5. Chemosphere. 2018 Nov 20. pii: S0045-6535(18)32235-5. [Epub ahead of print]218 259-265
    Mechanisms underlying nickel nanoparticle induced reproductive toxicity and chemo-protective effects of vitamin C in male rats.
    Lu Kong, Wangcheng Hu, Chuncheng Lu, Keping Cheng, Meng Tang.
      The purpose of this research is to go a step further study on the reproductive toxicities and the underlying mechanisms induced by nickel nanoparticles (NiNPs), and the possible protective action of vitamin C. Animal experiment was designed according to the one-generation reproductive toxicity standard, and rats were exposed to NiNPs through gavage. Ultrastructural, reactive oxygen species (ROS), oxidant and antioxidant enzymes, and cell apoptosis-related factors in the testicular tissue were analyzed. In contrast with the control group, the activity of surperoxide dismutase (SOD), catalase (CAT) and gonad-stimulating hormone (GSH) was reduced, while the content of nitric oxide (NO), malondialdehyde (MDA) and ROS was increased in the NiNPs treated animals. As the doses of NiNPs increase, the mRNA of apoptotic related factor Caspase-9, Caspase-8 and Caspase-3 showed an obviously upregulation. Protein expression of Bcl-2-associated X Protein (Bax) and apoptosis inducing factor (AIF) was significantly unregulated. After addition of antioxidants-vitamin C, the toxicity was reduced. Injured testicular tissue indicated that NiNPs exposure could damage the reproductive system. Our results suggest that NiNPs induce significant reproductive toxicities. The cellular apoptosis might be induced by caspase family proteinases, but the regulator factor (factor associated suicide (Fas), B-cell lymphoma-2 (Bcl-2), Bax, BH3-interacting domain death agonist (Bid) and AIF protein) might not be involved in this process. Thus, the mechanism of reproductive toxicity of NiNPs on rat testes involves in the induction of oxidative stress, which further results in cell apoptosis. Antioxidants-vitamin C shows a significant inhibition on the reproductive toxicities induced by NiNPs.
    Keywords:  Apoptosis; Chemo-protection; Nickel nanoparticles; Oxidative stress; Rat; Reproductive toxicity; Vitamin C
    DOI:  https://doi.org/10.1016/j.chemosphere.2018.11.128
  6. Am J Physiol Cell Physiol. 2018 Nov 28.
    Blocking REDD1/TXNIP axis ameliorates LPS-induced vascular endothelial cell injury through repressing oxidative stress and apoptosis.
    Xuhui Hou, Songbai Yang, Jian Yin.
      The aim of the present study was to investigate the potential role of REDD1 (Regulated in development and DNA damage response 1) on LPS-induced vascular endothelial injury by using human umbilical vein endothelial cells (HUVECs). We observed that REDD1 expression was apparently elevated in HUVECs after exposure to LPS. Additionally, elimination of REDD1 strikingly attenuated the secretion of pro-inflammatory cytokines TNF-α, IL-6, IL-1β and MCP-1 and endothelial cell adhesion markers ICAM-1 and VCAM-1 that was induced by LPS stimulation. Subsequently, knockdown of REDD1 augmented cell viability but ameliorated LDH release in HUVECs stimulated with LPS. Meanwhile, depletion of REDD1 effectively restricted LPS-induced HUVEC apoptosis, as exemplified by reduced DNA fragmentation, and it also elevated anti-apoptotic Bcl-2 protein, concomitant with reduced levels of pro-apoptotic proteins Bax and C-caspase-3. Furthermore, repression of REDD1 remarkably alleviated LPS-trigged intracellular ROS generation accompanied by decreased MDA content and increased the activity of endogenous antioxidant enzymes SOD, CAT and GPx. Most important, depletion of REDD1 protected HUVECs against inflammation-mediated apoptosis and oxidative damage partly through TXNIP. Collectively, these findings indicate that the blocking REDD1/TXNIP axis repressed the inflammation-mediated vascular injury process, which may be closely related to oxidative stress and apoptosis in HUVECs, implying that REDD1/TXNIP axis may be a new target for preventing endothelial cell injury process.
    DOI:  https://doi.org/10.1152/ajpcell.00313.2018
  7. Life Sci. 2018 Nov 24. pii: S0024-3205(18)30774-4. [Epub ahead of print]
    Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2/HO-1 pathway.
    Runxiao Lv, Lili Du, Lixin Zhang, Zhiqiang Zhang.
       AIMS: Spinal cord injury (SCI) is one of the most devastating central lesions, resulting in serious locomotor deficit. Polydatin is a glucoside of resveratrol with proven anti-cardiovascular, anti-inflammatory and anti-oxidative properties. The main purpose of this study was to investigate whether polydatin could alleviate SCI in rats and explore the underlying mechanisms.
    MATERIALS AND METHODS: SCI rats induced by a weight-drop device were treated with intraperitoneal injection of 20 or 40 mg/kg polydatin. Then the locomotor function of SCI rats was evaluated by the Basso, Beattie and Bresnahan locomotor rating scale, spinal cord edema was measured by the wet/dry weight method, oxidative stress markers were detected by commercial kits and cell apoptosis status was measured by TUNEL staining. In addition, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) production and apoptosis status were detected in murine microglia BV2 cells treated with 100 ng/ml lipopolysaccharides (LPS) and 4.0 μM polydatin. The expression of apoptosis-related proteins involved in nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was measured by western blot.
    KEY FINDINGS: Our data showed that polydatin treatment improved locomotor performance of SCI rats, as well as reduced oxidative stress and inhibited apoptosis by enhancing Nrf2/HO-1 signaling. In addition, polydatin was found to up-regulate Nrf2 activity and the inhibitory effects of polydatin on oxidative stress and apoptosis in LPS-stimulated BV2 microglia was neutralized by silencing Nrf2 using specific siRNA.
    SIGNIFICANCE: We demonstrate that polydatin may protect the spinal cord from SCI by suppression of oxidative stress and apoptosis via improving Nrf2/HO-1 signaling in microglia.
    Keywords:  Microglia; Nrf2; Oxidative stress; Polydatin; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.lfs.2018.11.053
  8. Dose Response. 2018 Oct-Dec;16(4):16(4): 1559325818807382
    Green Platinum Nanoparticles Interaction With HEK293 Cells: Cellular Toxicity, Apoptosis, and Genetic Damage.
    Rafa S Almeer, Daoud Ali, Saud Alarifi, Saad Alkahtani, Mansour Almansour.
      Metal nanoparticles are widely used in industry, agriculture, textiles, drugs, and so on. The adverse effect of green platinum nanoparticles on human embryonic kidney (HEK293) cells is not well established. In the current study, green platinum nanoparticles were synthesized using leaf extract of Azadirachta indica L. Green platinum nanoparticles were characterized by dynamic light scattering and transmission electron microscope. The cytotoxicity of green platinum nanoparticle was observed in HEK293 cells by applying 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and Neutral red uptake (NRU) assays. Cell viability of the cells was decreased in a concentration and duration-dependent manner. Generation of reactive oxygen species (ROS) in HEK293 cells due to green platinum nanoparticles was examined using fluorescent dye 2,7-dichlorofluorescein diacetate (DCFDA), and ROS was increased according to exposure pattern. The cytotoxicity of HEK293 cells was correlated with increased caspase 3, depolarization of mitochondrial membrane potential, and DNA fragmentation. The abovementioned finding confirmed that mitochondria play an important role in genotoxicity and cytotoxicity induced by nanoparticles in HEK293 cells. Further, we determined other oxidative stress biomarkers, lipid peroxide (LPO) and glutathione (GSH); LPO was increased and GSH was decreased in HEK293 cells. It is also important to indicate that HEK293 cells appear to be more susceptible to green platinum nanoparticles exposure after 24 hours. This result provides a dose- and time-dependent apoptosis and genotoxicity of green nanoparticles on HEK293 cells.
    Keywords:  HEK293 cells; cytotoxicity; green platinum nanoparticles; oxidative stress
    DOI:  https://doi.org/10.1177/1559325818807382
  9. Electromagn Biol Med. 2018 Nov 27. 1-9
    Radiofrequency radiation at 2.856 GHz does not affect key cellular endpoints in neuron-like PC12 cells.
    Hongmei Zhou, Guofu Dong, Wen Zheng, Shuiming Wang, Lifeng Wang, Weijia Zhi, Changzhen Wang.
      To investigate the potential cytotoxicity of radiofrequency (RF) radiation on central nervous system, rat pheochromocytoma (PC12) cells were exposed to 2.856 GHz RF radiation at a specific absorption rate (SAR) of 4 W/kg for 8 h a day for 2 days in 35 mm Petri dishes. During exposure, the real-time variation of the culture medium temperature was monitored in the first hour. Reactive oxygen species (ROS) production, intracellular Ca2+ concentration, and cell apoptosis rate were assessed immediately after exposure by flow cytometry. The results showed that the medium temperature raised about 0.93 °C, but no significant changes were observed in apoptosis, ROS levels or intracellular Ca2+ concentration after treatment. Although several studies suggested that RF radiation does indeed cause neurological effects, this study presented inconsistent results, indicating that 2.856 GHz RF radiation exposure at a SAR of 4 W/kg does not have a dramatic impact on PC12 cells, and suggests the need for further investigation on the key cellular endpoints of other nerve cells after exposure to RF radiation.
    Keywords:  Ca2+; PC12 cells; Radiofrequency radiation; apoptosis; reactive oxygen species
    DOI:  https://doi.org/10.1080/15368378.2018.1550787
  10. Cell Physiol Biochem. 2018 Nov 28. 51(3): 1448-1460
    Alpha-Lipoic Acid Preconditioning and Ischaemic Postconditioning Synergistically Protect Rats from Cerebral Injury Induced by Ischemia and Reperfusion Partly via Inhibition TLR4/MyD88/ NF-κB Signaling Pathway.
    Jing Zhang, Fan Xiao, Lieliang Zhang, Xifeng Wang, Xiaoyang Lai, Yunfeng Shen, Meiying Zhang, Bin Zhou, Haili Lang, Peng Yu, Fuzhou Hua.
       BACKGROUND/AIMS: A combination of alpha-lipoic acid preconditioning (ALAP) and ischaemic preconditioning (IPC) has not been tested in an in vivo rat cerebral ischaemia/reperfusion injury (I/RI) model, and the potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the role of the TLR4/ MyD88/ NF-κB signaling pathway in the synergistically neuroprotective and anti-inflammatory effects of ALAP and IPC.
    METHODS: One hundred and fifty male Sprague-Dawley rats, weighing 180-230 g, were randomly divided into the following 5 groups: 1) sham-operated control; 2) I/R; 3) I/R+ALAP; 4) I/R+IPC; 5) I/R+IPC+ALAP. After 2 h of reperfusion, the infarct size, neurological deficit scores, brain oedema, oxidative stress, and inflammatory and apoptotic biomarkers were assessed. In addition, reactive oxygen species (ROS) and cell apoptosis were detected by DHE staining and TUNEL staining, respectively.
    RESULTS: Both ALAP and IPC treatment attenuated the I/RI-induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores, brain oedema, lactate dehydrogenase (LDH) release and the inflammatory response, as well as decreased HMGB1, TLR4, MyD88, p65, C-Caspase 3 and Bax expression and increased IKB-α, HO-1, SOD-2 and Bcl-2 expression compared to that in the I/R group. Furthermore, the combination of the two strategies had synergistic anti-inflammatory effects and antioxidant benefits, ultimately limiting neuronal apoptosis.
    CONCLUSION: The 'cocktail' strategy exhibited a significant neuroprotection against I/RI by attenuating neuroinflammation via inhibition of the TLR4/MyD88/NF-κB signaling pathway.
    Keywords:  Alpha-lipoic acid preconditioning; Cerebral ischaemia/reperfusion injury; Inflammation; Ischaemic postconditioning; TLR4
    DOI:  https://doi.org/10.1159/000495593
  11. Biochem Biophys Res Commun. 2018 Nov 22. pii: S0006-291X(18)32535-X. [Epub ahead of print]
    Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro.
    Lin Ren, Zi-Jun Song, Qing-Wei Cai, Rui-Xin Chen, Yang Zou, Qiang Fu, Yuan-Yuan Ma.
      Age-related skeletal changes is closely associated with imbalanced bone remodeling characterized by elevated osteocyte apoptosis and osteoclast activation. Since osteocytes are the commander of bone remodeling, attenuating increased osteocyte apoptosis may improve age-related bone loss. Exosomes, derived from mesenchymal stem cells, hold promising potential for cell-free therapy due to multiple abilities, such as promoting proliferation and suppressing apoptosis. We aimed to explore the effect of exosomes derived from adipose mesenchymal stem cell (ADSCs-exo) on osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. The osteocyte-like cell line MLO-Y4 was used as a model, and apoptosis was induced by hypoxia and serum deprivation (H/SD). Our results showed that ADSCs-exo noticeably reduced H/SD-induced apoptosis in MLO-Y4 cells via upregulating the radio of Bcl-2/Bax, diminishing the production of reactive oxygen species and cytochrome c, and subsequent activation of caspase-9 and caspase-3. Additionally, ADSCs-exo lowered the expression of RANKL both at the mRNA and protein levels, as well as the ratio of RANKL/OPG at the gene level. As determined by tartrate-resistant acid phosphatase staining, reduced osteoclastogenesis was further validated in bone marrow monocytes cultured under conditioned medium from exosome-treated MLO-Y4. Together, ADSCs-exo could antagonize H/SD induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis, indicating the therapeutic potential of ADSCs-exo in age-related bone disease.
    Keywords:  Adipose-derived mesenchymal stem cells; Apoptosis; Exosomes; Osteoclastogenesis; Osteocyte
    DOI:  https://doi.org/10.1016/j.bbrc.2018.11.109
  12. Can J Physiol Pharmacol. 2018 Nov 28.
    Oxymatrine Attenuates Aβ1-42-Induced Neurotoxicity in Primary Neuronal Cells and Memory Impairment in Rats.
    Peiliang Dong, Xiaomeng Ji, Wei Han, Hua Han.
      Aβ1-42-induced oxidative stress causes the death of neuronal cells, which is involved in the development of Alzheimer's disease (AD). Oxymatrine (OMT) inhibits oxidative stress. In this study, we investigated the effect of OMT on Aβ1-42-induced neurotoxicity in vivo and in vitro. In the Morris water maze test, OMT significantly decreased the escape latency and increased the number of platform crossings. In vitro, OMT markedly increased cell viability and superoxide dismutase activity. Moreover, OMT decreased the lactate dehydrogenase leakage, malondialdehyde content, and reactive oxygen species in a dose-dependent manner. OMT upregulated the ratio of Bcl-2/Bax and downregulated the level of caspase-3. Furthermore, OMT inhibited the activation of MAPK (ERK 1/2, JNK) and NF-κB. In summary, OMT may be a potential compound for the treatment of AD.
    DOI:  https://doi.org/10.1139/cjpp-2018-0299
  13. Breast Cancer. 2018 Nov 29.
    p110α and p110β isoforms of PI3K are involved in protection against H2O2 induced oxidative stress in cancer cells.
    Paramjeet Singh, Nasima Bano, Md Mehedi Hossain, Rafia Basit, Mohd Jamal Dar.
       PURPOSE: Phosphatidylinositol-3 kinases (PI3Ks) are involved in regulating cell growth, proliferation, differentiation, apoptosis and survival. p110α and p110β, two ubiquitously expressed isoforms of PI3K signalling, are involved in growth factor mediated signaling and survival by generating second messengers. Earlier, we have generated GFP-fusion proteins of p110α and p110β and expressed them in normal and cancer cell-lines to investigate their subcellular localization and their role in various activities. Here, we sought to examine the role of p110α and p110β isoforms in protecting MCF-7 breast cancer cells against oxidative stress.
    MATERIAL METHODS: We performed cytotoxicity assays, DNA transfection, Plasmid DNA preparation, western blotting, flourscence microscopy and statistical analysis.
    RESULTS: To know whether p110α and p110β are involved in protecting MCF-7 breast cancer cells against oxidative stress, we subjected MCF-7 cells to H2O2 treatment and observed a dose dependent decrease in cell viability and a marked increase in the levels of pro-apoptotic markers which include PARP, Bcl-2, Bax and procaspase-9. We then over-expressed recombinant GFP-fusion p110α and p110β proteins in MCF-7 cells and observed a significant decrease in apoptosis and a concomitant increase in pAkt levels.
    CONCLUSION: We report the involvement of p110α and p110β isoforms of Class 1A PI3K signalling in rescue from oxidative stress-induced apoptosis in MCF-7 cells in Akt dependent manner.
    Keywords:  Akt; Apoptosis; Breast cancer; PI3K signalling
    DOI:  https://doi.org/10.1007/s12282-018-0933-x
  14. Nanotechnology. 2018 Nov 30. 30(5): 055101
    Use of DNA-generated gold nanoparticles to radiosensitize and eradicate radioresistant glioma stem cells.
    Tatsuki Kunoh, Tsutomu Shimura, Tomonari Kasai, Syuji Matsumoto, Hafizah Mahmud, Apriliana Cahya Khayrani, Masaharu Seno, Hitoshi Kunoh, Jun Takada.
      The surface reactivity of gold nanoparticles (AuNPs) is receiving attention as a radiosensitizer of cancer cells for radiation therapy and/or as a drug carrier to target cells. This study demonstrates the potential of DNA-AuNPs (prepared by mixing calf thymus DNA with HAuCl4 solution) as a radiosensitizer of human glioma cells that have cancer stem cell (CSC)-like properties, to reduce their survival. CSC-like U251MG-P1 cells and their parental glioblastoma U251MG cells are treated with a prepared DNA-AuNP colloid. The radiosensitivity of the resultant AuNP-associated cells are significantly enhanced. To reveal the mechanism by which survival is reduced, the generation of reactive oxygen species (ROS), apoptosis induction, or DNA damage in the cells is assayed using the fluorescent dye DCFDA, annexin V-FITC/PI, and foci formation of γ-H2AX, respectively. X-ray irradiation with administration of AuNPs overcomes the radioresistance of U251MG-P1 cells. It does not induce ROS generation or apoptosis in the cells but enhances the number of abnormal nuclei with abundant γ-H2AX foci, which is judged as cell death by mitotic catastrophe. The AuNP association with the cells effectively induces mitotic catastrophe in x-ray-irradiated CSC-like cells, implicating that DNA-AuNPs might be a promising tool to develop an efficient radiosensitizer against CSC.
    DOI:  https://doi.org/10.1088/1361-6528/aaedd5
  15. Environ Mol Mutagen. 2018 Nov 30.
    Effects of Acute Fluorene-9-Bisphenol Exposure on Mouse Oocyte in vitro Maturation and Its Possible Mechanisms.
    Xiao-Fei Jiao, Qiu-Man Liang, Di Wu, Zhi-Ming Ding, Jia-Yu Zhang, Fan Chen, Yong-Sheng Wang, Shou-Xin Zhang, Yi-Liang Miao, Li-Jun Huo.
      Fluorene-9-bisphenol (BHPF), a substitute of bisphenol A (BPA) used in the production of the so-called "BPA-free" plastics, has now been shown to be released from commercial plastic bottles into drinking water and has strong anti-estrogenic activity in mice, which suggests that BHPF is also an environmental toxin. However, whether BHPF exposure has effects on mouse oocyte development is unknown. In this study, the influence of acute exposure to BHPF (50-150 μM, 12 hr) on mouse oocyte maturation and its possible mechanisms were investigated. Of note, 50-μM BHPF had no effects on the maturation of mouse oocytes, whereas 100- and 150-μM BHPF significantly blocked germinal vesicle breakdown and led to the failure of first polar body extrusion. Particularly, 100-μM BHPF exposure severely decreased the cellular adenosine triphosphate in a time-dependent manner, which finally brought out the loss of spindles. In addition, the actin cytoskeleton was also impaired. The defective mitochondrial dynamics and decreased mitochondrial DNA implied the damage of mitochondria in BHPF-treated oocytes. Increased PINK1, Beclin1, and LC3B protein level and decreased TOMM20 and TOMM17A protein level illustrated that mitophagy was induced, which also confirmed that BHPF exposure impaired the cellular mitochondria. Moreover, BHPF induced reactive oxygen species accumulation and early apoptosis. Oocyte quality was also impaired by BHPF exposure through altering histone modifications evidenced by increased H3K9me3 and H3K27me3 levels. Collectively, our results indicated that BHPF exposure disrupted mouse oocyte maturation and reduced oocyte quality through affecting cytoskeleton architecture, mitochondrial function, oxidative stress, apoptosis, and histone modifications. Environ. Mol. Mutagen. 2018. © 2018 Wiley Periodicals, Inc.
    Keywords:  ATP; fluorene-9-bisphenol; mitochondria; mouse oocyte; oxidative stress; spindle assembly
    DOI:  https://doi.org/10.1002/em.22258
  16. Front Pharmacol. 2018 ;9 1297
    N-myristoylation of Antimicrobial Peptide CM4 Enhances Its Anticancer Activity by Interacting With Cell Membrane and Targeting Mitochondria in Breast Cancer Cells.
    Caiyun Li, Hongyan Liu, Yunqing Yang, Xixi Xu, Tongtong Lv, Huidan Zhang, Kehang Liu, Shuangquan Zhang, Yuqing Chen.
      Development of antimicrobial peptides (AMPs) as highly effective and selective anticancer agents would represent great progress in cancer treatment. Here we show that myristoyl-CM4, a new synthetic analog generated by N-myristoylation of AMPs CM4, had anticancer activity against MCF-7, MDA-MB-231, MX-1 breast cancer cells (IC50 of 3-6 μM) and MDA-MB-231 xenograft tumors. The improved activity was attributed to the effect of myristoyl on the cell membrane. Flow cytometry and confocal laser scanning microscopy results showed that N-myristoylation significantly increased the membrane affinity toward breast cancer cells and also effectively mediated cellular entry. Despite increasing cytotoxicity against HEK293 and NIH3T3 cells and erythrocytes associated with its anticancer activity, myristoyl-CM4 maintained a certain selectivity toward breast cancer cells. Accordingly, the membrane affinity toward breast cancer cells was two to threefold higher than that of normal cells. Glycosylation analysis showed that sialic acid-containing oligosaccharides (including O-mucin and gangliosides) were important targets for myristoyl-CM4 binding to breast cancer cells. After internalization, co-localization analysis revealed that myristoyl-CM4 targeted mitochondria and induced mitochondrial dysfunction, including alterations in mitochondrial transmembrane potential, reactive oxygen species (ROS) generation and cytochrome c release. Activation of caspase 9, caspase 3 and cleavage of PARP were observed in MX-1, MCF-7, and MDA-MB-231 cells after myristoyl-CM4 treatment. The current work indicates that increasing hydrophobicity by myristoylation to modulate peptide-membrane interactions and then target mitochondria is a good strategy to develop AMPs as anticancer agents in the future.
    Keywords:  antimicrobial peptides CM4; breast cancer; membrane; mitochondria; myristoylation; xenograft tumor
    DOI:  https://doi.org/10.3389/fphar.2018.01297
  17. Chemosphere. 2018 Nov 17. pii: S0045-6535(18)32116-7. [Epub ahead of print]218 438-448
    Microcystin-LR induces angiodysplasia and vascular dysfunction through promoting cell apoptosis by the mitochondrial signaling pathway.
    Qilong Wang, Yuanli Liu, Jingsong Guo, Song Lin, Yeqi Wang, Tieying Yin, Hans Gregersen, Tingzhang Hu, Guixue Wang.
      The harmful algal blooms are becoming increasingly problematic in the regions that drinking water production depends on surface waters. With a global occurrence, microcystins are toxic peptides produced by multiple cyanobacterial genera in the harmful algal blooms. In this study, we examined the effects of microcystin-LR (MC-LR), a representative toxin of the microcystin family, on vascular development in zebrafish and the apoptosis of human umbilical vein endothelial cells (HUVECs). In zebrafish larvae, MC-LR induced angiodysplasia, damaged vascular structures and reduced lumen size at 0.1 μM and 1 μM, leading to the decrease of the blood flow area in the blood vessels and brain hemorrhage, which showed that MC-LR could dose-dependently inhibit vascular development and cause vascular dysfunction. In MC-LR treated HUVECs, the proportion of early apoptosis and late apoptosis cells increased in a concentration-dependent manner. Different concentrations of MC-LR could also activate caspase 3/9 in HUVECs, increase the level of mitochondrial ROS and reduce mitochondrial membrane potential. Additionally, MC-LR could promote the expression of p53 and inhibit the expression of PCNA. The findings showed that MC-LR could promote apoptosis of HUVECs through the mitochondrial signaling pathway. Combined with these results, MC-LR may promote vascular endothelial cell apoptosis through mitochondrial signaling pathway, leading to angiodysplasia and vascular dysfunction.
    Keywords:  Angiodysplasia; Blood vessel; Cell apoptosis; Microcystin-LR; Zebrafish
    DOI:  https://doi.org/10.1016/j.chemosphere.2018.11.019
  18. Oncol Rep. 2018 Nov 27.
    Levistolide A synergistically enhances doxorubicin‑induced apoptosis of k562/dox cells by decreasing MDR1 expression through the ubiquitin pathway.
    Yuanyuan Ding, Weibo Niu, Tao Zhang, Jue Wang, Jiao Cao, He Chen, Ruiqi Wang, Hongli An.
      Multidrug resistance (MDR) is one of the main reasons underlying failure of cancer chemotherapy. Certain natural compounds may help prevent MDR, and may be used in combination with chemotherapeutic agents to enhance their efficacy. Levistolide A is a natural product that is extracted from the rhizome of Angelicae sinensis (Oliv.), which has been used as an essential component of antitumor formulas since ancient times in China. The present study conducted the following experiments: MTT assay, apoptosis analysis, cellular doxorubicin accumulation assay, immunoblotting and reverse transcription‑quantitative polymerase chain reaction, to investigate whether levistolide A enhance doxorubicin‑induced apoptosis of k562/dox cells and to determine the molecular mechanisms involved. When combined with doxorubicin, levistolide A exhibited a synergistic effect and induced cytotoxicity in k562/dox cells. Drug accumulation studies revealed that levistolide A increased the intracellular concentration of doxorubicin in a dose‑dependent manner. Cell apoptosis experiments indicated that levistolide A increased the sensitivity of k562/dox cells to doxorubicin. Furthermore, detection of reactive oxygen species (ROS) revealed that levistolide A enhanced doxorubicin‑induced cell death by increasing the levels of ROS. Mitochondrial potential detection with JC‑1 staining also indicated that levistolide A synergistically enhanced doxorubicin‑induced cell death. Immunoblotting demonstrated that levistolide A enhanced doxorubicin‑induced cell death by decreasing the expression levels of B‑cell lymphoma 2 and increasing caspase 3 expression. Furthermore, multidrug resistance protein 1 (MDR1) expression in k562/dox cells was downregulated by levistolide A in a dose‑dependent manner, thus suggesting that levistolide A may modulate MDR1 during cancer therapy. Therefore, the combination of levistolide A with doxorubicin could result in more effective and less toxic anticancer regimens.
    DOI:  https://doi.org/10.3892/or.2018.6889
  19. Med Sci Monit. 2018 Nov 24. 24 8489-8499
    Suppression of Apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) by Klotho Protein is Associated with Reduced Endoplasmic Reticulum Oxidative Stress and Activation of the PI3K/AKT Pathway.
    Wei Cui, Bin Leng, Wei Liu, GaoPin Wang.
      BACKGROUND Klotho protein has been shown to act as a hormone on the cardiovascular system, and to have specific protective effects on vascular endothelial cells. The aim of this study was to investigate the mechanisms of the anti-oxidative and anti-apoptotic effects of klotho protein on hydrogen peroxide (H₂O₂)-induced apoptosis and endoplasmic reticulum oxidative stress in human umbilical vein endothelial cells (HUVECs). MATERIAL AND METHODS HUVECs were cultured in vitro and treated with H₂O₂. The MTT assay evaluated cell viability of H₂O₂-treated HUVECs, and flow cytometry measured cell apoptosis. An enzyme-linked immunosorbent assay (ELISA) measured the levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6. Western blot was used to detect the expression of the proteins, 78 kD glucose-regulated protein (GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), caspase-3, caspase-9, caspase-12, and AKT. The effects of LY294002, a pharmacological inhibitor of PI3K, were evaluated. RESULTS Klotho protein increased the viability of H2O2-treated HUVECs and reduced the expression of NO, TNF-α, and IL-6. Klotho protein reduced the rate of apoptosis of H₂O₂-treated HUVECs and downregulated the expression of proteins associated with endoplasmic reticulum oxidative stress, GRP78 and CHOP, and the expression of the apoptotic proteins, caspase-3, caspase-9, and caspase-12, and activated the phosphorylation of AKT. The addition of LY294002 inhibited klotho protein downregulation of GRP78, CHOP, caspase-3, caspase-9, and caspase-12 expression. CONCLUSIONS In HUVECs, klotho protein suppressed apoptosis mediated by endoplasmic reticulum oxidative stress by activation of the PI3K/AKT pathway.
    DOI:  https://doi.org/10.12659/MSM.911202
  20. Xenobiotica. 2018 Nov 25. 1-19
    The effects of Para-phenylenediamine (PPD) on the skin fibroblast cells.
    Enayatollah Seydi, Mohsen Fatahi, Parvaneh Naserzadeh, Jalal Pourahmad.
      1. Para-phenylenediamine (PPD) is the commonest and most well-known component of hair dyes. PPD is found in more than 1000 hair dye formulations and is the most frequently used permanent hair dye component in Europe, North America, and East Asia. PPD containing hair dyes have been associated with cancer and mutagenicity. Apart from that, PPD has potential toxicity which includes acute toxicity such as allergic contact dermatitis and subacute toxicity. 2. In this study, we examined the effects of the PPD composition on the skin-isolated fibroblast cells. Fibroblast cells were isolated from the skin and cell viability, reactive oxygen species (ROS) production, the collapse of mitochondrial membrane potential (MMP), lipid peroxidation, damage to the lysosome and finally release of cytochrome c were examined following the exposure to various concentrations of PPD. 3. Our results showed that exposure to PPD increased reactive oxygen species (ROS) generation, lipid peroxidation (LPO), the collapse of mitochondrial membrane potential (MMP), and cytochrome c release. Our results suggest that PPD can induce damage to the lysosomal membrane. 4. These results showed that PPD composition has a selective toxicity on skin fibroblasts cell and mitochondria are considered one of the goals of its toxicity.
    Keywords:  Fibroblast; Lysosome; Mitochondria; Para-phenylenediamine; Reactive Oxygen Species
    DOI:  https://doi.org/10.1080/00498254.2018.1541264
  21. Cell Biol Int. 2018 Nov 29.
    Silencing Astrocyte Elevated Gene-1 Attenuates Lipopolysaccharide-induced Inflammation and Mucosal Barrier Injury in NCM460 Cells by Suppressing the Activation of NLRP3 Inflammasome.
    Yang Peng, Hongyan Li, Dandan Chen.
      The effect of oncogene astrocyte-elevated gene-1 (AEG-1) on noncancerous colonic epithelial cell disease is rarely studied. We aim to investigate the role of AEG-1 in lipopolysaccharide (LPS)-induced inflammation and mucosal barrier injury, and their potential mechanisms. NCM460 cells were stimulated by different concentrations of LPS at 12 h or 24 h. Cell viability and the expression of AEG-1 was determined by CCK-8, qRT-PCR and western blotting. Silencing AEG-1 was successfully established. Reactive oxygen species (ROS) level and apoptosis were measured by flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was performed to detect IL-1β and IL-18 level. qRT-PCR and western blot were performed to assess the mRNA and protein level of tight junction (TJ) -associated genes, NLRP3 inflammasome activation-related factors.. Silencing AEG-1 decreased ROS production, cell apoptosis and IL-1β, IL-18 release, compared to those treated by LPS. Up-regulation of ZO-1 and Occludin showed that siAEG-1 could protect mucosal barrier from LPS injured. Silencing AEG-1 could significantly inhibit NLRP3 and cleaved caspase-1 expression in LPS stimulation environment. Silencing AEG-1 inhibited NLRP3 activation, while the activation of caspase-1 reduced the secretion of proinflammatory cytokines IL-1β and IL-18. However, over-expressing AEG-1 aggravated LPS-triggered injury and activation of NLRP3 inflammasome.
    Keywords:  LPS; NLRP3 inflammasome; inflammation; mucosal barrier; siAEG-1
    DOI:  https://doi.org/10.1002/cbin.11078
  22. J Neuroimmune Pharmacol. 2018 Nov 27.
    Melatonin Rescue Oxidative Stress-Mediated Neuroinflammation/ Neurodegeneration and Memory Impairment in Scopolamine-Induced Amnesia Mice Model.
    Tahir Muhammad, Tahir Ali, Muhammad Ikram, Amjad Khan, Sayed Ibrar Alam, Myeong Ok Kim.
      Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of melatonin, we here explored the possible underlying mechanisms of the protective effect of melatonin against scopolamine-induced oxidative stress-mediated c-Jun N-terminal kinase (JNK) activation, which ultimately results in synaptic dysfunction, neuroinflammation, and neurodegeneration. According to our findings, scopolamine administration resulted in LPO and ROS generation and decreased the protein levels of antioxidant proteins such as Nrf2 and HO-1; however, melatonin co-treatment mitigated the generation of oxidant factors while improving antioxidant protein levels. Similarly, melatonin ameliorated oxidative stress-mediated JNK activation, enhanced Akt/ERK/CREB signaling, promoted cell survival and proliferation, and promoted memory processes. Immunofluorescence and western blot analysis indicated that melatonin reduced activated gliosis via attenuation of Iba-1 and GFAP. We also found that scopolamine promoted neuronal loss by inducing Bax, Pro-Caspase-3, and Caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, melatonin significantly decreased the levels of apoptotic markers and increased neuronal survival. We further found that scopolamine disrupted synaptic integrity and, conversely, that melatonin enhanced synaptic integrity as indicated by Syntaxin, PSD-95, and SNAP-23 expression levels. Furthermore, melatonin ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. On the whole, our findings revealed that melatonin attenuated scopolamine-induced synaptic dysfunction and memory impairments by ameliorating oxidative brain damage, stress kinase expression, neuroinflammation, and neurodegeneration. Graphical Abstract The proposed schematic diagram showing the neuroprotective effect of melatonin against scopolamine-induced oxidative stress-mediated synaptic dysfunction, memory impairment neuroinflammation and neurodegeneration.
    Keywords:  Amnesia; Brain-derived neurotrophic factor (BDNF); Cyclic AMP response element-binding protein (CREB); Melatonin; Reactive oxygen species (ROS); Scopolamine
    DOI:  https://doi.org/10.1007/s11481-018-9824-3
  23. Zhonghua Shao Shang Za Zhi. 2018 Nov 20. 34(11): 809-814
    [Effects of endotoxin/lipopolysaccharide on early apoptosis of human neutrophil through PIM3].
    M M Song, P Li, X Y Jin, J D Su, B W Sun.
      Objective: To explore the effects of endotoxin/lipopolysaccharide (LPS) on early apoptosis of human neutrophil through PIM3. Methods: Venous blood samples were collected from a healthy adult volunteer to isolate neutrophils. The neutrophils were divided into control group, LPS group, and LPS+ PIM447 group according to the random number table. No treatment was given to the cells in control group. The cells in LPS group underwent LPS stimulation (1 μL, 1 μg/mL). The cells in LPS+ PIM447 group underwent PIM447 (1 μL, final amount-of-substance concentration of 5 μmol/L) intervention 30 min before having the same LPS stimulation as that in LPS group. After conventional culture for 1 h, the early cell apoptosis rate was determined with flow cytometer; the generation level of reactive oxygen species (ROS) was assessed with dihydrogenrhodamine 123 fluorescent probe staining method; and the level of PIM3 was detected by Western blotting. After conventional culture for 2 h, the cell chemotaxis distance was measured by agarose chemotaxis cell model. The sample numbers of each group in the 4 experiments were all 5. Data were processed with one-way analysis of variance and Student-Newman-Keuls test. Results: (1) The early apoptosis rate of cells in LPS group [(0.891±0.012)%] was close to that in control group [(1.351±0.183)%, P>0.05)]. The early apoptosis rate of cells in LPS+ PIM447 group [(82.057±0.121)%] was higher than that in LPS group (P<0.01). (2) The cell chemotaxis distance of cells in LPS group [(984±5) μm] was significantly shorter than that in control group [(2 241±7) μm, P<0.01]. The cell chemotaxis distance of cells in LPS+ PIM447 group [(1 785±11) μm]was significantly longer than that in LPS group (P<0.05). (3) The generation level of ROS in cells of LPS group was significantly higher than that in control group (P<0.05). The generation level of ROS in cells of LPS+ PIM447 group was significantly lower than that in LPS group (P<0.05). (4) The expression level of PIM3 in cells of LPS group (1.297±0.015) was significantly higher than that in control group (0.789±0.021, P<0.05). The expression level of PIM3 in cells of LPS+ PIM447 group (0.731±0.011) was significantly lower than that in LPS group (P<0.05). Conclusions: LPS stimulation can reduce the early apoptosis of human neutrophils. Pre-intervention with PIM447 can significantly increase the early apoptosis of neutrophils after LPS stimulation, recover the chemotaxis, and inhibit the production of ROS. The mechanism may be related to LPS promoting the expression of PIM3.
    Keywords:  Apoptosis; Lipopolysaccharides; Neutrophils; PIM3; Sepsis
    DOI:  https://doi.org/10.3760/cma.j.issn.1009-2587.2018.11.017
  24. Asian Pac J Cancer Prev. 2018 Nov 29. 19(11): 3175-3178
    Oxidants-Antioxidants Profile in the Breast Cancer Cell Line MCF-7
    Isnaini Isnaini, Nur Permatasari, Karyono Mintaroem, Bunga Prihardina, M Aris Widodo.
      Reactive oxygen species (ROS) have various biological effects and they are non-linear in characteristic. In high oxidative stress, they may cause cytotoxicity, inhibit cell proliferation, and induce cell death in the form of apoptosis/necrosis; while in low or medium oxidative stress, ROS may cause DNA damage, cell mutation, inflammation, cell proliferation, and eventually they may induce carcinogenesis. Antioxidants are compounds with the ability to reduce ROS. Cell line MCF-7 is one of the breast cancer cell lines that is known to have small amount of antioxidant MnSOD compared to the other cell lines. Low antioxidant MnSOD level in breast cancer cell line MCF-7 leads to low concentration of hydrogen peroxide, because antioxidant MnSOD will convert radical superoxide to hydrogen peroxide. The aim of this research was to analyze oxidants and antioxidants profile in breast cancer cell line MCF-7 and their relationship with cell number. Observations were conducted for 5 days. The cell number was counted with tryphan blue method and haematometer. The concentration of radical superoxide was measured with DHE staining using LSCM tipe Olympus Fluoview FV 1000-Ver 1.7. MnSOD activity, hydrogen peroxide concentration, and catalase activity were measured with ELISA. The results showed that the longer of observation, the greater concentration of oxidants and MnSOD activity, but there was no change in catalase activity. Conclusion the increase in cancer cells number is influenced by radical superoxide.
    Keywords:  Oxidant; antioxidant; MCF-7; breast cancer
  25. Biochemistry (Mosc). 2018 Oct;83(10): 1263-1278
    Does Oxidation of Mitochondrial Cardiolipin Trigger a Chain of Antiapoptotic Reactions?
    A Y Mulkidjanian, D N Shalaeva, K G Lyamzaev, B V Chernyak.
      Oxidative stress causes selective oxidation of cardiolipin (CL), a four-tail lipid specific for the inner mitochondrial membrane. Interaction with oxidized CL transforms cytochrome c into peroxidase capable of oxidizing even more CL molecules. Ultimately, this chain of events leads to the pore formation in the outer mitochondrial membrane and release of mitochondrial proteins, including cytochrome c, into the cytoplasm. In the cytoplasm, cytochrome c promotes apoptosome assembly that triggers apoptosis (programmed cell death). Because of this amplification cascade, even an occasional oxidation of a single CL molecule by endogenously formed reactive oxygen species (ROS) might cause cell death, unless the same CL oxidation triggers a separate chain of antiapoptotic reactions that would prevent the CL-mediated apoptotic cascade. Here, we argue that the key function of CL in mitochondria and other coupling membranes is to prevent proton leak along the interface of interacting membrane proteins. Therefore, CL oxidation should increase proton permeability through the CL-rich clusters of membrane proteins (CL islands) and cause a drop in the mitochondrial membrane potential (MMP). On one hand, the MMP drop should hinder ROS generation and further CL oxidation in the entire mitochondrion. On the other hand, it is known to cause rapid fission of the mitochondrial network and formation of many small mitochondria, only some of which would contain oxidized CL islands. The fission of mitochondrial network would hinder apoptosome formation by preventing cytochrome c release from healthy mitochondria, so that slowly working protein quality control mechanisms would have enough time to eliminate mitochondria with the oxidized CL. Because of these two oppositely directed regulatory pathways, both triggered by CL oxidation, the fate of the cell appears to be determined by the balance between the CL-mediated proapoptotic and antiapoptotic reactions. Since this balance depends on the extent of CL oxidation, mitochondria-targeted antioxidants might be able to ensure cell survival in many pathologies by preventing CL oxidation.
    DOI:  https://doi.org/10.1134/S0006297918100115
  26. Anticancer Agents Med Chem. 2018 Nov 26.
    Synthesis of 3-Arylaminopropenone Linked 2-Arylbenzo[d]imidazo[2,1-b]thiazole Conjugates as Anticancer and Apoptotic Inducing Agents.
    Ahmed Kamal, Siddiq Pasha Shaik, T Srinivasa Reddy, Satish Sunkari, A V Subba Rao, Korrapati Suresh Babu.
      A new series of 3-arylaminopropenone linked 2-arylbenzo[d]imidazo[2,1-b]thiazole conjugates (4a-z) were synthesized and screened for cytotoxic activity against four human cancer cell lines. These conjugates showed moderate to good antiproliferative activity in the range of 1.6 - 48.5 µM. Some conjugates like 4e, 4f, 4g, 4k, 4m, 4r and 4t exhibited good antiproliferative activity and the insights of structure activity relationships were developed. Among them, conjugate 4e showed significant potential particularly against HeLa cell line with IC50 value 1.6 µM. Flow cytometry analysis indicates that conjugate 4e induce cell cycle arrest at G1 phase. In addition, the mechanism of cell growth inhibition and apoptotic induction by this conjugate was investigated in HeLa cancer cells using cell-based assays, including wound healing assay and Hoechst staining. Moreover, conjugate 4e led to collapse of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS) were noted.
    Keywords:  1-b]thiazole; Benzo[d]imidazo[2; ROS. ; apoptosis; cytotoxicity; mitochondrial membrane depolarization
    DOI:  https://doi.org/10.2174/1871520619666181127112621
  27. Biol Trace Elem Res. 2018 Nov 28.
    Ethanol Exacerbates Manganese-Induced Neurobehavioral Deficits, Striatal Oxidative Stress, and Apoptosis Via Regulation of p53, Caspase-3, and Bax/Bcl-2 Ratio-Dependent Pathway.
    Kpobari W Nkpaa, Ifeoluwa O Awogbindin, Benjamin A Amadi, Amos O Abolaji, Isaac A Adedara, Matthew O Wegwu, Ebenezer O Farombi.
      This study investigated the effects of ethanol (EtOH) on manganese (Mn)-induced striatal toxicity in rat by evaluating the neurobehavioral changes, biochemical and molecular events in rats exposed to Mn alone at 30 mg/kg, or their combination with EtOH at 1.25- and 5-g/kg body weight for 35 consecutive days. Locomotive and exploratory profiles were assessed using a video tracking software (ANY-Maze software) during a 5-min trial in a novel environment. Subsequently, acetylcholinesterase (AChE) activity, oxidative stress markers, histological morphology, and expression of apoptotic proteins (p53 and Bax and caspase-3) and anti-apoptotic protein (Bcl-2) were assessed in the striatum. Results showed that Mn, EtOH, and their combination induced locomotor and motor deficits. Track plot analysis indicated that EtOH exacerbated the Mn-induced reduction in exploratory profiles of exposed rats. Similarly, exposure of rats to Mn, EtOH, or combination of Mn and EtOH resulted in decreased activities of anti-oxidant enzymes, diminished level of reduced glutathione, downregulated Bcl-2 expression, increased AChE activity, enhanced hydrogen peroxide and lipid peroxidation levels, and upregulated expressions of p53, Bax, and caspase-3. Moreover, potentiation of Mn-induced striatal toxicity by EtOH co-exposure was dose dependent. Taken together, it seems that EtOH exacerbates Mn-induced neurobehavioral deficits, oxidative stress, and apoptosis induction via the regulation of p53, caspase-3, and Bax/Bcl-2 ratio-dependent pathway in rat striatum.
    Keywords:  Apoptosis; Ethanol; Manganese; Neurobehavioral deficits; Oxidative stress; Striatum
    DOI:  https://doi.org/10.1007/s12011-018-1587-4
  28. Immunopharmacol Immunotoxicol. 2018 Nov 29. 1-7
    Protective effect of sesamin in lipopolysaccharide-induced mouse model of acute kidney injury via attenuation of oxidative stress, inflammation, and apoptosis.
    Ali-Mohammad Rousta, Seyed-Mohamad-Sadegh Mirahmadi, Alireza Shahmohammadi, Davood Nourabadi, Mohammad-Reza Khajevand-Khazaei, Tourandokht Baluchnejadmojarad, Mehrdad Roghani.
       CONTEXT: Acute kidney injury (AKI) is considered a major public health concern in today's world. Sepsis-induced AKI is large as a result of exposure to lipopolysaccharide (LPS) that is the major outer membrane component of Gram-negative bacteria. Sesamin is the main lignan of sesame seeds with multiple protective effects.
    OBJECTIVE: In this research, we tried to demonstrate the protective effect of sesamin pretreatment in LPS-induced mouse model of AKI.
    METHODS: LPS was injected at a single dose of 10 mg/kg (i.p.) and sesamin was given p.o. at doses of 25, 50, or 100 mg/kg, one hour prior to LPS.
    RESULTS: Treatment of LPS-challenged mice with sesamin reduced serum level of creatinine and blood urea nitrogen (BUN) and returned back renal oxidative stress-related parameters including glutathione (GSH), malondialdehyde (MDA), and activity of catalase and superoxide dismutase (SOD). Moreover, sesamin alleviated inappropriate changes of renal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα), interleukin-6, DNA fragmentation (an apoptotic index), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, sesamin diminished magnitude of kidney tissue damage due to LPS.
    CONCLUSION: In summary, sesamin could dose-dependently abrogate LPS-induced AKI via attenuation of renal oxidative stress, inflammation, and apoptosis.
    Keywords:  Sesamin; acute kidney injury; apoptosis; inflammation; lipopolysaccharide; oxidative stress
    DOI:  https://doi.org/10.1080/08923973.2018.1523926
  29. Cell Physiol Biochem. 2018 Nov 27. 51(3): 1354-1363
    Galangin Alleviates Liver Ischemia-Reperfusion Injury in a Rat Model by Mediating the PI3K/AKT Pathway.
    Yang Li, Liquan Tong, Jingyan Zhang, Yafeng Zhang, Feng Zhang.
       BACKGROUND/AIMS: Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. There are numerous causes of liver I/R injury, but the mechanism is unknown. Galangin (GA) is a flavonoid, a polyphenolic compound widely distributed in medicinal herbs that has anti-inflammatory, antioxidant, and antitumor activity. This study evaluated the protective effect of GA on hepatic I/R injury.
    METHODS: An I/R model was created in male Wistar rats by clamping the hepatoportal vein, hepatic artery and hepatic duct for 30 min followed by reperfusion for 2 h. A hypoxia/restoration (H/R) model was established in buffalo rat liver (BRL) cells by hypoxia for 4 h followed by normoxic conditions for 10 h. The extent of liver injury was assayed by serum ALT/AST, hepatic histology, and MPO activity. Oxidative stress was assayed by serum superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA). Expression of apoptosis-related proteins in BRL cells was assayed in western blots. Expression of AKT and p-AKT proteins in vivo and vitro were assayed in western blots.
    RESULTS: GA significantly decreased ALT/AST expression, reversed changes in oxidative stress markers induced by I/R, and mediated caspase-3 activity expression of apoptosis-related proteins in vivo and in vitro. Methylthiazol tetrazolium (MTT) assay, flow cytometry, and Hoechst 33258 staining confirmed that GA inhibited apoptosis of BRL cells. GA also increased the expression of phosphorylated AKT after H/R.
    CONCLUSION: GA reduced liver I/R injury both in vivo and vitro and inhibited BRL cell apoptosis. PI3K/AKT signaling have been involved. GA may protect against liver I/R and be a potential therapeutic candidate.
    Keywords:  Cell apoptosis; Galangin; Liver ischemia-reperfusion injury; PI3K/AKT
    DOI:  https://doi.org/10.1159/000495553
  30. Bioorg Med Chem Lett. 2018 Nov 22. pii: S0960-894X(18)30920-X. [Epub ahead of print]
    Sanguiin H-11 from Sanguisorbae radix protects HT22 murine hippocampal cells against glutamate-induced death.
    Ji Hoon Song, Song-Yi Kim, Gwi Seo Hwang, Youn-Sub Kim, Hyun Young Kim, Ki Sung Kang.
      Excessive glutamate level induces neuronal death in acute brain injuries and chronic neurodegenerative diseases. Natural compounds from medicinal and food plants have been attracting interest as a treatment for neurological disorders. Sanguiin H-11 (SH-11), a hydrolysable ellagitannin, inhibits neutrophil movement and nitric oxide -production. However, its neuroprotective effect has not been studied. Therefore, the present study examined the protective effect of SH-11 from Sanguisorbae radix and its mechanism against glutamate-induced death in HT22 cells. Our results showed that SH-11 possessed a strong antioxidant activity and prevented glutamate-induced death in HT22 cells. As a strong antioxidant, SH-11 significantly reduced glutamate-induced increases in intracellular reactive oxygen species accumulation and calcium ion influx. Western blotting analysis showed that glutamate-induced phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-related kinases 1/2, c-Jun N-terminal kinase, and p38, was significantly decreased by SH-11. Furthermore, SH-11 significantly decreased the number of annexin V-positive HT22 cells, which is indicating apoptotic cell death. In conclusion, our results suggested that SH-11 exerted a potent neuroprotective activity against glutamate-mediated apoptotic cell death by inhibiting oxidative stress-mediated MAPK activation.
    Keywords:  Glutamate; HT22 cells; Mitogen-activated protein kinase; Oxidative stress; Sanguiin H-11 (SH-11)
    DOI:  https://doi.org/10.1016/j.bmcl.2018.11.042
  31. Nanoscale. 2018 Nov 30.
    Integrating in situ formation of nanozymes with three-dimensional dendritic mesoporous silica nanospheres for hypoxia-overcoming photodynamic therapy.
    Xiaoli Cai, Yanan Luo, Yang Song, Dong Liu, Hongye Yan, He Li, Dan Du, Chengzhou Zhu, Yuehe Lin.
      Despite great progress in photodynamic therapy (PDT), the therapeutic effect is still limited by some points, such as tumor hypoxia, the short lifetime and the limited action region of 1O2. Herein, a special kind of three-dimensional dendritic mesoporous silica nanosphere (3D-dendritic MSN) was synthesized and used as a robust nanocarrier to deliver abundant hydrophobic photosensitizer chlorin e6 (Ce6) to the A549 lung cancer cells. To address the tumor hypoxia issue, the nanozyme Pt nanoparticles (Pt NPs) were immobilized onto the channels of 3D-dendritic MSNs to catalyze the conversion of intracellular H2O2 to oxygen. Moreover, due to the in situ reduction process, the uniform Pt NPs distributed well on the surface of 3D-dendritic MSNs with high homogeneous dispersity. Additionally, a mitochondria-targeting ligand, triphenylphosphine (TPP), was conjugated to the Pt-decorated 3D-dendritic MSN composites to form a mitochondria targeted system for the PDT. In a combination of the peroxidase-like Pt NPs with mitochondria-targeting ability of TPP, a reactive oxygen species (ROS) burst in the mitochondria was achieved and resulted in the cell apoptosis. This well-designed system shows an enhanced PDT effect of killing A549 cells, and promotes a new H2O2-activatable strategy to overcome hypoxia for tumor PDT.
    DOI:  https://doi.org/10.1039/c8nr07679k
  32. Phytother Res. 2018 Nov 28.
    The chemical composition and events related to the cytotoxic effects of propolis on osteosarcoma cells: A comparative assessment of Colombian samples.
    Dolly Patricia Pardo Mora, Karina Basso Santiago, Bruno José Conti, Eliza de Oliveira Cardoso, Fernanda Lopes Conte, Lucas Pires Garcia Oliveira, Marjorie de Assis Golim, Jaime Fabian Cruz Uribe, Rafael María Gutiérrez, Mauricio Rey Buitrago, Milena Popova, Boryana Trusheva, Vassya Bankova, Orlando Torres García, José Maurício Sforcin.
      Osteosarcoma (OSA) is a type of bone cancer showing an aggressive biological behavior with metastatic progression. Because propolis potential for the development of new antitumoral drugs has been indicated, we evaluated the chemical composition of Colombian propolis samples and the mechanisms involved in their cytotoxic effects on OSA cells. The chemical composition was analyzed by GC-MS and the DPPH free radical scavenging activity was measured. Cluster and principal components analysis were used to establish an association with their inhibitory concentration 50% (IC50 ). Cell viability was analyzed by MTT assay; apoptosis was determined by flow cytometry; mitochondrial membrane permeability and reactive oxygen species were evaluated by rhodamine 123 and DCFH-DA. Transwell assay was used to evaluate the invasiveness of propolis-treated cells. Samples were grouped: Cluster 1 contained diterpenes and benzophenones and showed the highest antiradical activity; Cluster 2 was characterized by triterpenes, fatty acid, and diterpenes. Usm contained diterpenes and triterpenes different of the other samples and Sil contained triterpenes and flavonoids. Apoptosis, mitochondrial membrane alteration, and suppression of cell invasion were the main mechanisms involved in the inhibition of OSA cells in vitro, suggesting the potential of Colombian propolis to discover new antitumor drugs.
    Keywords:  apoptosis; chemical composition; cytotoxicity; mitochondrial membrane potential; osteosarcoma; propolis
    DOI:  https://doi.org/10.1002/ptr.6246
  33. Exp Eye Res. 2018 Nov 21. pii: S0014-4835(18)30355-5. [Epub ahead of print]
    Thermosensitive chitosan-gelatin-based hydrogel containing curcumin-loaded nanoparticles and latanoprost as a dual-drug delivery system for glaucoma treatment.
    Yung-Hsin Cheng, Yu-Chieh Ko, Yu-Fan Chang, Shu-Huei Huang, Catherine Jui-Ling Liu.
      Elevated intraocular pressure (IOP) in glaucoma is due to impairment of aqueous humor drainage via the uveoscleral or trabecular outflow pathway. Latanoprost reduces IOP by increasing the uveoscleral outflow. Despite its potency, long-term daily application of it may cause undesirable side effects and many require more than one medication for IOP control. Recent studies have suggested that oxidative stress in the trabecular meshwork (TM) play an important role in the pathogenesis of impaired trabecular outflow facility. Curcumin, a natural phenolic compound, possesses anti-oxidant and anti-inflammation properties. In this study, we developed a thermosensitive hydrogel containing latanoprost and curcumin-loaded nanoparticles (CUR-NPs), and evaluated its possible therapeutic effects with cultured human TM cells under oxidative stress. The results demonstrated that 20 μM of CUR-NPs might be the optimal concentration to treat TM cells without causing cytotoxicity. Using the newly developed system, both latanoprost and CUR-NPs displayed a sustained-release profile. Treatment with this hydrogel containing CUR-NPs effectively decreased the oxidative stress-mediated damage in TM cells via decreasing inflammation-related gene expression, mitochondrial reactive oxygen stress (ROS) production and apoptosis level. The in vivo biocompatibility revealed no signs of inflammation or damage after topical application of developed hydrogel in rabbits. These results suggest that this dual-drug delivery system might enhance both trabecular and uveoscleral outflow and is promising to develop into a novel treatment for glaucoma.
    Keywords:  Curcumin; Glaucoma; Latanoprost; Oxidative stress; Sustained release
    DOI:  https://doi.org/10.1016/j.exer.2018.11.017
  34. J Vet Sci. 2018 Nov 26.
    Iodixanol supplementation during sperm cryopreservation improves protamine level and reduces reactive oxygen species of canine sperm.
    Dimas Arya Abdillah, Setyawan Emn, Min Jung Kim, Hyun Ju Oh, Seok Hee Lee, Kihae Ra, Byeong Chun Lee.
      The objectives of this study were to analyze the protective effects of OptiprepTM (iodixanol) on dog spermatozoa during cryopreservation. The optimal concentration of OptiprepTM, 2.5%, was determined using fresh spermatozoa, and applied for the following experiment. The 2.5% OptiprepTM group showed significantly increased sperm motility than the control (P < 0.05). Lower mitochondrial ROS modulator (ROMO1) and pro-apoptotic gene (BAX), together with higher expression of protamine-2 (PRM2), protamine-3 (PRM3), anti-apoptotic gene (BCL2) and sperm acrosome associated-3 (SPACA3), were expressed in the iodixanol treated group. In addition, decreased protamine deficiency and cryocapacitation was observed in the treatment group. Our findings show that supplementation of 2.5% OptiprepTM is ideal for reducing production of ROS and preventing detrimental effects during cryopreservation process of canine sperm, manifested as increased motility and reduced cryocapacitation in the frozen-thawed spermatozoa.
    Keywords:  cryocapacitation; cryopreservation; dog; protamine; reactive oxygen species
  35. J Cell Biochem. 2018 Nov 28.
    Resveratrol improves ex vivo expansion of CB-CD34+ cells via downregulating intracellular reactive oxygen species level.
    Chaochun Tang, Weiwei Zhang, Haibo Cai, Zhaoyang Ye, Xu Zhang, Wensong Tan.
      Intracellular reactive oxygen species (ROS) play important roles in the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). In this study, the effects of resveratrol (RES), on the ex vivo expansion of HSPCs were investigated by analyzing CD34+ cells expansion and biological functions, with the objective to optimize ex vivo culture conditions for CD34 + cells. Among the five tested doses (0, 0.1, 1, 10, 20, and 50 μM), 10 μM RES was demonstrated to be the most favorable for ex vivo CD34 + cells expansion. In the primary cultures, 10 μM RES favored higher expansion folds of CD34 + cells, CD34 + CD38 - cells, and colony-forming units (CFUs) ( P < 0.05). It was found that the percentages of primitive HSPCs (CD34 + CD38 - CD45R - CD49f + CD90 + cells) in 10 μM RES cultures were higher than those without RES. Further, in the secondary cultures, expanded CD34 + cells derived from primary cultures with 10 μM RES exhibited significantly higher total cells and CD34 + cells expansion ( P < 0.05). In the semisolid cultures, the frequency of CFU-GM and total CFUs of 10 μM RES group were both higher than those of without RES group, demonstrating that CD34 + cells expanded with 10 μM RES possessed better biological function. Furthermore, the addition of 10 μM RES downregulated the intracellular ROS level via strengthening the scavenging capability of ROS, and meanwhile reducing the percentages of apoptotic cells in cultures. Collectively, RES could stimulate the ex vivo expansion of CD34 + cells, preserved more primitive HSPCs and maintain better biological function by alleviating intracellular ROS level and cell apoptosis in cultures.
    Keywords:  CD34+ cells; ex vivo expansion; reactive oxygen species; resveratrol
    DOI:  https://doi.org/10.1002/jcb.28052
  36. Environ Sci Pollut Res Int. 2018 Nov 26.
    Long-term exposure to low level of fluoride induces apoptosis via p53 pathway in lymphocytes of aluminum smelter workers.
    Pingjing Wen, Xiaomin Wei, Guiqiang Liang, Yanfei Wang, Yiping Yang, Lilin Qin, Weiyi Pang, Guangqiu Qin, Hai Li, Yueming Jiang, Qijun Wu.
      Long-term occupational exposure to low level of fluoride can induce oxidative stress and apoptosis in many cells, including lymphocyte. However, the underlying mechanism remains unclear. Hence, this study was designed to explore the potential oxidative stress and apoptosis of long-term occupational exposure to low level of fluoride in aluminum smelter workers. A total of 120 aluminum smelter workers were recruited in control, low-, middle-, and high-fluoride exposure groups with 30 workers for each group. The peripheral blood samples were collected, centrifuged, and isolated to obtain serum and lymphocyte suspensions. The air and serum fluoride concentrations were detected by fluoride ion-selective electrode method. The lymphocytic apoptosis rate, DNA damage, oxidative stress, and mRNA levels of p53, Bcl-2, and Bax were assessed by Annexin V/PI staining, comet assay, attenuated total reflectance Fourier transform infrared spectroscopy and real-time polymerase chain reaction, respectively. Results showed that the air and serum fluoride concentrations of fluoride-exposed groups were higher than those of the control group (p < 0.05). Fluoride exposure might induce apoptosis, DNA damage and oxidative stress in a dose-dependent manner in lymphocytes (p < 0.05). The expression levels of p53 and Bax were increased with fluoride exposure in lymphocytes (p < 0.05), whereas the Bcl-2 expression was decreased but not significantly. Taken together, these observations indicate that long-term occupational exposure to low level of fluoride may lead to oxidative stress and induce apoptosis through the p53-dependent pathway in peripheral blood lymphocytes of aluminum smelter workers. Serum fluoride level may be the potential biomarker of fluoride exposure.
    Keywords:  Apoptosis; DNA damage; Fluoride; Oxidative stress; p53-dependent pathway
    DOI:  https://doi.org/10.1007/s11356-018-3726-z
  37. Mol Cell Biochem. 2018 Nov 26.
    Effects of long-term dehydration on oxidative stress, apoptotic markers and neuropeptides in the gastric mucosa of the dromedary camel.
    Mahmoud A Ali, Hassan Abu Damir, Naheed Amir, E A Adeghate, Salim Bastaki, David Murphy, Abdu Adem.
      We investigated the effects of 20 days of dehydration and 20 days of dehydration followed by 72 h of rehydration on the gastric mucosa of the one-humped dromedary camel. The parameters addressed include biomarkers of oxidative stress, apoptosis, gastric epithelial histology, gastric neuropeptides, and their receptors. Nineteen clinically healthy, 4-5 year-old male dromedary camels were divided into three groups (five control camels, eight dehydrated for 20 days, six dehydrated for 20 days and then rehydrated for 72 h). Dehydration affected the oxidative stress biomarkers causing a significant increase in malondialdehyde, glutathione, nitric oxide, and catalase values compared with controls. Also the results revealed that dehydration caused different size cellular vacuoles and focal necrosis in the gastric mucosa. Rehydration for 72 h resulted in improvement in some parameters but was not enough to fully abolish the effect of dehydration. Dehydration caused significant increase in apoptotic markers; tumor necrosis factor α, caspases 8 and 3, BcL-x1 and TGFβ whereas caspase 9, p53, Beclin 1, and PARP1 showed no significant change between the three groups indicating that apoptosis was initiated by the extrinsic pathway. Also there were significant increases in prostaglandin E2 receptors and somatostatin in plasma and gastric epithelium homogenate, and a significant decrease in cholecystokinin-8 receptors. A significant decrease of hydrogen potassium ATPase enzyme activity was also observed. Pepsinogen C was not affected by dehydration. It is concluded that long-term dehydration induces oxidative stress and apoptosis in camel gastric mucosa and that camels adjust gastric functions during dehydration towards water economy. More than 72 h are needed before all the effects of dehydration are reversed by rehydration.
    Keywords:  Apoptotic markers; Dehydration/rehydration; Dromedary camels; Gastric mucosa vacuoles; Gastric peptides; Oxidative stress biomarkers; Prostaglandin E2
    DOI:  https://doi.org/10.1007/s11010-018-3474-x
  38. Biomed Pharmacother. 2018 Nov 23. pii: S0753-3322(18)35650-6. [Epub ahead of print]110 213-223
    Cytokine augments the sorafenib-induced apoptosis in Huh7 liver cancer cell by inducing mitochondrial fragmentation and activating MAPK-JNK signalling pathway.
    Lijuan Zhang, Shuping Li, Rong Wang, Changyuan Chen, Wen Ma, Hongyi Cai.
      Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer.
    Keywords:  IL-2; Liver cancer; MAPK-JNK signliang pathway; Mitochondrial fragmentation; Sorafenib; TAZ
    DOI:  https://doi.org/10.1016/j.biopha.2018.11.037
  39. Eur J Pharmacol. 2018 Nov 22. pii: S0014-2999(18)30670-8. [Epub ahead of print]
    Hydralazine protects against renal ischemia-reperfusion injury in rats.
    Yong Li, Daorong Hou, Xuguan Chen, Jingfeng Zhu, Ruyi Zhang, Wei Sun, Peng Li, Yunfan Tian, Xiangqing Kong.
      In this study, we investigated whether hydralazine could reduce renal ischemia and reperfusion (I/R) injury in rats. Renal I/R was induced by a 70-min occlusion of the bilateral renal arteries and a 24-h reperfusion, which was confirmed by the increased the mortality, the levels of blood urea nitrogen (BUN), blood creatinine (Cr), renal tissue NO and the visible histological damage of the kidneys. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, the serum levels of malonaldehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were significantly elevated in renal I/R group, while the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) levels were suppressed. However, intragastric pretreatment with hydralazine at doses of 7.5 to 30mg/kg before renal I/R significantly limited the increase in mortality, BUN, Cr, oxidative stress, inflammatory factors, histological damage and apoptosis in the kidneys. In addition, hydralazine also increased p-AKT, Bcl-2 expression and decreased iNOS, Bax, cleaved caspase-3 expression in the kidneys. In conclusion, hydralazine reduced renal I/R injury probably via inhibiting NO production by iNOS/NO pathway, inhibiting oxidative stress, inflammatory response and apoptosis by a mitochondrial-dependent pathway.
    Keywords:  acute kidney injury; apoptosis; hydralazine; inflammatory cytokines; oxidative stress; renal ischemia and reperfusion
    DOI:  https://doi.org/10.1016/j.ejphar.2018.11.015
  40. Am J Physiol Cell Physiol. 2018 Nov 28.
    ROS-induced autophagy regulates porcine trophectoderm cell apoptosis, proliferation and differentiation.
    Zhen Luo, Xue Xu, Takami Sho, Jing Zhang, Weina Xu, Jianbo Yao, Jianxiong Xu.
      Significant embryo loss remains a serious problem in pig production. Reactive oxygen species (ROS) play a critical role in embryonic implantation and placentation. However, the potential mechanism of ROS on porcine trophectoderm (pTr) cell fate during peri-implantation period has not been investigated. This study aimed to elucidate the effects of ROS on pTr cell phenotypes and the regulatory role in cell attachment and differentiation. Herein, results showed that exogenous H2O2 inhibited pTr cell viability, arrested cell cycle at S and G2/M phase, increased cell apoptosis and autophagy protein light chain 3B (LC3B) and Beclin-1, while these effects were reversed by different concentrations of N-acety-l-cysteine (NAC) post-treatment. In addition, NAC abolished H2O2-induced autophagic flux, inhibited intracellular and mitochondrial ROS, and restored expression of genes important for mitochondrial DNA and biogenesis, cell attachment and differentiation. NAC reversed H2O2-activated MAPK and Akt/mTOR pathways in dose-dependent manners. Furthermore, analyses with pharmacological and RNA interference approaches suggested that autophagy regulated cell apoptosis and gene expression of caudal-related homeobox 2 (Cdx2) and IL1β. Collectively, these results provide new insights into the role of the ROS-induced autophagy in pTr cell apoptosis, attachment and differentiation, indicating a promising target for decreasing porcine conceptus loss during the peri-implantation period.
    Keywords:  Autophagy; ROS; differentiation; pTr cells; proliferation;
    DOI:  https://doi.org/10.1152/ajpcell.00256.2018
  41. Food Chem Toxicol. 2018 Nov 26. pii: S0278-6915(18)30857-3. [Epub ahead of print]
    Taurine ameliorates oxidative stress induced inflammation and ER stress mediated testicular damage in STZ-induced diabetic Wistar rats.
    Sumit Ghosh, Sayantani Chowdhury, Abhishek Kumar Das, Parames C Sil.
      One of the major consequences of diabetes is reproductive dysfunction but the fundamental mechanisms are still poorly known. The objective of the present study was to explore the beneficial role of taurine against streptozotocin induced testicular dysfunctions in diabetic male Wister rats and understanding the underlying intricate molecular mechanisms. Exposure to streptozotocin (50 mg kg-1 body weight, i.p., once) elevated blood glucose level, induced testicular histological alterations and reduced testis-to-body weight ratio, serum testosterone, testicular markers and activity of antioxidant enzymes. Generation of ER stress (increased expression of calpain-1, caspase-12 and upregulation of CHOP, GRP78 via eIF2α signaling), translocation of NF κB in the nucleus (leading to the upregulation in the levels of inflammatory cytokines), activation of mitochondria dependent apoptotic pathway and DNA fragmentation were revealed from this study. However, administration of taurine at a dose of 100 mg kg-1 body weight for 6 weeks post diabetic induction, successfully ameliorated all these adverse effects. Thus, taurine, as a potential therapeutic agent, may hold promise in preventing oxidative and ER stress mediated diabetic testicular complications in rats.
    Keywords:  Apoptosis; ER stress; Inflammation; Oxidative stress; Taurine; Testis
    DOI:  https://doi.org/10.1016/j.fct.2018.11.055
  42. Cell Death Dis. 2018 Nov 26. 9(12): 1163
    Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy.
    You Chul Chung, Ji Hee Lim, Hyun Mi Oh, Hyung Wook Kim, Min Young Kim, Eun Nim Kim, Yaeni Kim, Yoon Sik Chang, Hye Won Kim, Cheol Whee Park.
      Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKβ and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca++ ([Ca++]i) levels, and CaMKKβ-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca++]i levels and subsequent activation of CaMKKβ-LKB-1-AMPK-eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy.
    DOI:  https://doi.org/10.1038/s41419-018-1192-7
  43. Int J Mol Med. 2018 Nov 19.
    Rosiglitazone attenuates cell apoptosis through antioxidative and anti-apoptotic pathways in the hippocampi of spontaneously hypertensive rats.
    Yali Li, Guanghu Yu, Lijuan Liu, Jun Long, Shujie Su, Ting Zhao, Wenjin Liu, Shunji Shen, Xiaolin Niu.
      Oxidative stress serves an important role in hypertensive brain damage. Peroxisome proliferator‑activated receptor γ (PPAR‑γ) agonists possess antioxidative and anti‑apoptotic effects. The present study verified the possibility that rosiglitazone serves a neuroprotective role by alleviating oxidative stress and cell apoptosis in the hippocampi of spontaneously hypertensive rats (SHRs). SHRs and age‑matched Wistar‑Kyoto (WKY; both 56 weeks old) rats received gavage administration of vehicle or rosiglitazone (5 mg/kg/day) for eight weeks. Systolic blood pressure (SBP) was measured by the indirect tail‑cuff method. The expression ratio of activated astrocytes was analyzed by glial fibrillary acidic protein immunohistochemistry. PPAR‑γ, inducible nitric oxide synthase (iNOS), gp47phox, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and caspase‑3 expression were investigated by quantitative polymerase chain reaction and western blot analysis. The number of apoptotic cells in the hippocampus of four groups was detected using the terminal deoxynucleotidyl transferase‑mediated dUTP end‑labeling (TUNEL) method. Compared with the WKY group, the SHR group exhibited decreased Bcl‑2 and PPAR‑γ expression, increased SBP, increased ratio of activated astrocytes and TUNEL‑positive cells, increased expression of iNOS, gp47phox, caspase‑3 and Bax. Rosiglitazone administration increased Bcl‑2 and PPAR‑γ expression, decreased the ratio of activated astrocytes and TUNEL‑positive cells, decreased iNOS, gp47phox, caspase‑3 and Bax expression in the hippocampi of SHRs. However, rosiglitazone did not significantly decreased SBP in the SHR group. Therefore, rosiglitazone exerts neuroprotective effect through antioxidative and anti‑apoptotic pathways, which was independent of blood pressure control.
    DOI:  https://doi.org/10.3892/ijmm.2018.3991
  44. Neurotoxicology. 2018 Nov 22. pii: S0161-813X(18)30318-8. [Epub ahead of print]
    Soluble epoxide hydrolase inhibitor, APAU, protects dopaminergic neurons against rotenone induced neurotoxicity: Implications for Parkinson's disease.
    Navya Lakkappa, Praveen T Krishnamurthy, M D Pandareesh, Bruce D Hammock, Sung Hee Hwang.
      Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inflammation and apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel strategy for neuroprotection. In the present study, sEH inhibitors APAU was screened in silico and further evaluated for their antiparkinson activity against rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and Drosophila melanogaster model of Parkinson disease (PD). In the in vitro study cell viability (MTT and LDH release assay), oxidative stress parameters (total intracellular ROS, hydroperoxides, protein oxidation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, glutathione, total antioxidant status, mitochondrial complex-1activity and mitochondrial membrane potential), inflammatory markers (IL-6, COX-1 and COX-2), and apoptotic markers (JNK, phospho-JNK, c-jun, phospho-c-jun, pro and active caspase-3) were assessed to study the neuroprotective effects. In vivo activity of APAU was assessed in Drosophila melanogaster by measuring survival rate, negative geotaxis, oxidative stress parameters (total intracellular ROS, hydroperoxides, glutathione levels) were measured. Dopamine and its metabolites were estimated by LC-MS/MS analysis. In the in silico study the molecule, APAU showed good binding interaction at the active site of sEH (PDB: 1VJ5). In the in vitro study, APAU significantly attenuated ROT induced changes in oxidative, pro-inflammatory and apoptotic parameters. In the in vivo study, APAU significantly attenuates ROT induced changes in survival rate, negative geotaxis, oxidative stress, dopamine and its metabolites levels (p < 0.05). Our study, therefore, concludes that the molecule APAU, has significant neuroprotection benefits against rotenone induced Parkinsonism.
    Keywords:  APAU; Parkinson; apoptosis; epoxyeicosatrienoic acids; inflammation; neuroprotection; oxidative stress; soluble epoxide hydrolase
    DOI:  https://doi.org/10.1016/j.neuro.2018.11.010
  45. Biomol Ther (Seoul). 2018 Nov 27.
    7,8-Dihydroxyflavone Protects High Glucose-Damaged Neuronal Cells against Oxidative Stress.
    Suk Ju Cho, Kyoung Ah Kang, Mei Jing Piao, Yea Seong Ryu, Pincha Devage Sameera Madushan Fernando, Ao Xuan Zhen, Yu Jae Hyun, Mee Jung Ahn, Hee Kyoung Kang, Jin Won Hyun.
      Oxidative stress is considered a major contributor in the pathogenesis of diabetic neuropathy and in diabetes complications, such as nephropathy and cardiovascular diseases. Diabetic neuropathy, which is the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. This study aimed to investigate whether 7,8-dihydroxyflavone (7,8-DHF) protects SH-SY5Y neuronal cells against high glucose-induced toxicity. In the current study, we found that diabetic patients exhibited higher lipid peroxidation caused by oxidative stress than healthy subjects. 7,8-DHF exhibits superoxide anion and hydroxyl radical scavenging activities. High glucose-induced toxicity severely damaged SH-SY5Y neuronal cells, causing mitochondrial depolarization; however, 7,8-DHF recovered mitochondrial polarization. Furthermore, 7,8-DHF effectively modulated the expression of pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) under high glucose, thus inhibiting the activation of caspase signaling pathways. These results indicate that 7,8-DHF has antioxidant effects and protects cells from apoptotic cell death induced by high glucose. Thus, 7,8-DHF may be developed into a promising candidate for the treatment of diabetic neuropathy.
    Keywords:  Diabetic neuropathy; High glucose; Oxidative stress
    DOI:  https://doi.org/10.4062/biomolther.2018.202
  46. Biochemistry (Mosc). 2018 Oct;83(10): 1245-1254
    SkQ1 Controls CASP3 Gene Expression and Caspase-3-Like Activity in the Brain of Rats under Oxidative Stress.
    S B Panina, O I Gutsenko, N P Milyutina, I V Kornienko, A A Ananyan, D Yu Gvaldin, A A Plotnikov, V V Vnukov.
      Here, we studied the effect of the mitochondria-targeted antioxidant SkQ1 (plastoquinone cationic derivative) on the CASP3 gene expression and caspase-3 activity in rat cerebral cortex and brain mitochondria under normal conditions and in oxidative stress induced by hyperbaric oxygenation (HBO). Under physiological conditions, SkQ1 administration (50 nmol/kg, 5 days) did not affect the CASP3 gene expression and caspase-3-like activity in the cortical cells, as well as caspase-3-like activity in brain mitochondria, but caused a moderate decrease in the content of primary products of lipid peroxidation (LPO) and an increase in the reduced glutathione (GSH) level. HBO-induced oxidative stress (0.5 MPa, 90 min) was accompanied by significant upregulation of CASP3 mRNA and caspase-3-like activity in the cerebral cortex, activation of the mitochondrial enzyme with simultaneous decrease in the GSH content, increase in the glutathione reductase activity, and stimulation of LPO. Administration of SkQ1 before the HBO session maintained the basal levels of the CASP3 gene expression and enzyme activity in the cerebral cortex cells and led to the normalization of caspase-3-like activity and redox parameters in brain mitochondria. We hypothesize that SkQ1 protects brain cells from the HBO-induced oxidative stress due to its antioxidant activity and stimulation of antiapoptotic mechanisms.
    DOI:  https://doi.org/10.1134/S0006297918100097
  47. Curr Med Chem. 2018 Nov 26.
    The role of mitochondria in systemic lupus erythematosus: A glimpse of various pathogenetic mechanisms.
    Shi-Kun Yang, Hao-Ran Zhang, Shu-Peng Shi, Ying-Qiu Zhu, Na Song, Qing Dai, Wei Zhang, Ming Gui, Hao Zhang.
       BACKGROUND: Systemic lupus erythematosus (SLE) is a polysystem autoimmune disease that adversely affects human health. Various organ can be affected, including the kidney or brain. Traditional treatment methods for SLE primarily rely on glucocorticoids and immunosuppressors. Unfortunately, these therapeutic agents cannot prevent a high recurrence rate after SLE remission. Therefore, novel therapeutic targets are urgently required.
    METHODS: A systematic search of the published literature regarding the abnormal structure and function of mitochondria in SLE and therapies targeting mitochondria was performed in several databases.
    RESULTS: Accumulating evidence indicates that mitochondrial dysfunction plays important roles in the pathogenesis of SLE, including influencing mitochondrial DNA damage, mitochondrial dynamics change, abnormal mitochondrial biogenesis and energy metabolism, mitophagy, oxidative stress, inflammatory reactions, apoptosis and NETosis. Further investigation of mitochondrial pathophysiological roles will result in further clarification of SLE. Specific lupus-induced organ damage also exhibits characteristic mitochondrial changes.
    CONCLUSION: This review aimed to summarize the current research on the role of mitochondrial dysfunction in SLE, which will necessarily provide potential novel therapeutic targets for SLE.
    Keywords:  ROS; apoptosis; mitochondria; systemic lupus erythematosus
    DOI:  https://doi.org/10.2174/0929867326666181126165139
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