bims-aporos Biomed news
on Apoptosis and reactive oxygen species
Issue of 2018‒11‒18
37 papers selected by
Gavin McStay
Staffordshire University


  1. J Transl Med. 2018 Nov 16. 16(1): 313
    Zhang Q, Liu X, Li N, Zhang J, Yang J, Bu P.
      BACKGROUND: Sirtuin 3 (Sirt3) is a key regulator of energy metabolism and oxidative stress. To investigate the role of Sirt3 in contrast-induced acute kidney injury (CIAKI), we established the model both in vivo and in vitro to explore the potential mechanisms.METHODS: In vivo, we established CIAKI models in wild-type (WT) and Sirt3-knockout (Sirt3-KO) mice. Blood urea nitrogen (BUN) and serum creatinine (Scr) were detected by enzyme-linked immunosorbent assay, Glomerular Filtration Rate (GFR) and creatinine clearance were also investigated. We detected the production of reactive oxygen species (ROS) via 2'7'-dichlorodihydro-fluorescein diacetate. The expressions of Sirt3, oxidative stress and apoptosis related markers (MnSOD, Catalase, Acetyl-MnSOD K68, Nox4, Bax, Bcl-2 and Caspase3) were measured and analyzed. In addition, we observed the effect of nicotinamide riboside (NR) on CIAKI in WT and Sirt3-KO mice. In vitro, Sirt3 was knocked out by siRNA transfection method in HK-2 cells. Sirt3, ROS, oxidative stress and apoptosis markers in HK-2 cells were also measured.
    RESULTS: Our data demonstrated that the levels of Scr and BUN in Sirt3-KO mice were increased while the levels of the GFR and creatinine clearance were decreased in CIAKI mice. In Sirt3-KO or siRNA groups, the activities of MnSOD and Catalase were markedly down-regulated. Also, the expression of Caspase3 were markedly increased and the ratio of Bcl-2/Bax was decreased, while the ROS level was increased in Sirt3 deficiency groups. NR ameliorated CIAKI in WT mice but not in Sirt3-KO mice.
    CONCLUSION: Our results suggest that Sirt3 deficiency aggravates contrast-induced acute kidney injury. Sirt3 is critical in NR-mediated renoprotection in CIAKI.
    Keywords:  Apoptosis; Contrast-induced acute kidney injury; Reactive oxygen species; Sirt3
    DOI:  https://doi.org/10.1186/s12967-018-1690-5
  2. Int J Mol Med. 2018 Nov 08.
    Zhao S, Li W, Cheng F, Rao T, Yu W, Ruan Y, Yuan R, Yao X, Ning J.
      The primary aim of the present study was to investigate the potential effect of high‑pressure carbon dioxide (CO2) pneumoperitoneum on kidneys with severe hydronephrosis and to investigate the possible underlying mechanism. A total of 18 rabbits underwent a surgical procedure inducing severe hydronephrosis. Rabbits were then divided at random into three groups (n=6 each) and subjected to intraabdominal pressure of 0, 8 or 18 mmHg, respectively. CO2 inflation lasted for 90 min in the pneumoperitoneum groups. Oxidative stress was assessed by measurements of reactive oxygen species (ROS). Activation of apoptosis was analyzed by western blot analysis of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated x protein (Bax), cytochrome c (Cyt c), caspase‑3 and caspase‑9 levels. In addition, TUNEL assay, hematoxylin and eosin (H&E) staining, measurement of mitochondrial membrane potential (MMP) and detection of changes to kidney ultramicrostructure were performed. In the 0 and 8 mmHg groups, all results were normal and similar. However, in the 18 mmHg group, the kidneys suffered oxidative damage and mitochondrial injuries, and increased ROS levels, lower MMP and mitochondrial vacuolization were observed. Furthermore, the mitochondrial/caspase‑dependent pathway of apoptosis was activated, as indicated by the apoptotic index, and the expression levels and translocation of Bax, Bcl‑2, Cyt c, caspase‑3 and caspase‑9. Therefore, it is concluded that high‑pressure CO2 pneumoperitoneum induces oxidative damage and apoptosis in rabbit kidneys with severe hydronephrosis, which is associated with the mitochondrial apoptotic pathway.
    DOI:  https://doi.org/10.3892/ijmm.2018.3986
  3. Mol Med Rep. 2018 Nov 15.
    Zhou Y, Yang J, Zhang Q, Xu Q, Lu L, Wang J, Xia W.
      Colon cancer is the second most lethal malignancy worldwide. A better understanding of colon cancer at the molecular level may increase overall survival rates. Previous studies have indicated that prolyl 4‑hydroxylase, β polypeptide (P4HB) is associated with tumorigenesis in colon cancer; however, its role and molecular mechanisms in colon cancer remain unclear. In the present study, the cellular responses to P4HB in human colon cancer cell lines were investigated by proliferation and apoptosis assays, western blotting, and immunohistochemistry. The results showed that expression of P4HB was higher in colon cancer tissues compared within adjacent normal tissues. P4HB knockdown increased the apoptosis of human HT29 cells. Furthermore, P4HB knockdown reduced the activation of signal transducer and activator of transcription 3 (STAT3) and promoted accumulation of reactive oxygen species (ROS). Inhibiting the accumulation of ROS abrogated the increased cell apoptosis induced by P4HB knockdown. Notably, decreased ROS levels effectively antagonized the effects of P4HB on STAT3 inactivation. In conclusion, these findings suggested that P4HB knockdown may induce HT29 human colon cancer cell apoptosis through the generation of ROS and inactivation of the STAT3 signaling pathway.
    DOI:  https://doi.org/10.3892/mmr.2018.9660
  4. Oncol Rep. 2018 Nov 12.
    Chen X, Song L, Hou Y, Li F.
      Increased production of reactive oxygen species (ROS) is a distinct feature of various types of cancer. ROS drive tumor progression and render cancer cells vulnerable to additional oxidative insult. The various natural herb compounds have been shown to induce additional production of ROS in cancer cells, although the physiological implications of ROS under these conditions are not fully determined. In the present study, icaritin, a natural compound derived from the medicinal plants Epimedium, was demonstrated to potently suppresses the proliferation of human HeLa and SiHa cervical cancer cells, without similar affects on non-cancerous CCD‑1095Sk fibroblasts and 293 cells, as measured by MTT and colony formation assays. Icaritin treatment caused a rapid increase in ROS in HeLa and SiHa cells, which was followed by a prominent increase in the number of DNA strand breaks. Consequently, the levels of the pro‑apoptotic protein Bax and activated caspase 3 and 9 enzymes were increased, while the levels of the anti‑apoptotic proteins Bcl‑2 and XIAP were downregulated. These protein expression changes were accompanied by marked induction of apoptosis in icaritin‑treated cancer cells. The results suggested that the icaritin‑induced ROS overload promoted cancer cell death via induction of extensive oxidative DNA damage, which subsequently resulted in large numbers of DNA strand breaks and the activation of the intrinsic apoptotic pathway.
    DOI:  https://doi.org/10.3892/or.2018.6864
  5. Int J Mol Med. 2018 Nov 05.
    Han H, Xu B, Amin A, Li H, Yu X, Gong M, Zhang L.
      Quercetin‑3‑O‑α‑L‑rhamnopyranoside (QI) is derived from the leaves of Lindera aggregata (Sims) Kosterm. And exhibits multiple biological activities, including an antioxidant activity. However, the detailed molecular mechanism of its antioxidant activity remains unknown. The aim of the present study was to investigate the antioxidant activity of QI and the underlying molecular mechanism in human umbilical vein endothelial cells (HUVECs). An oxidative stress model was established in HUVECs using H2O2, and cells were then treated with different concentrations of QI. The results revealed that the exposure of HUVECs to QI protected these cells from H2O2‑induced damage. QI treatment also increased the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione (GSH) in the cell culture medium. In addition, QI inhibited H2O2‑induced apoptosis by decreasing the expression levels of cleaved Caspase‑9 and poly(ADP‑ribose) polymerase. QI also inhibited the production of DNA fragments and reactive oxygen species induced by H2O2. Furthermore, QI decreased the oxidative stress by promoting the nuclear transfer of nuclear factor erythroid 2‑related factor 2 (Nrf2) and heme oxygenase‑1 by activating autophagy, and inhibited the competition of Bach1 from Nrf2. Finally, QI significantly improved the activities of T‑SOD and GSH, and decreased the content of malondialdehyde in the serum and heart tissue of aging rats. These data support the use of QI as a health supplement to alleviate oxidative stress or further development of this compound as an antioxidant drug.
    DOI:  https://doi.org/10.3892/ijmm.2018.3976
  6. Neurotox Res. 2018 Nov 13.
    Manigandan V, Nataraj J, Karthik R, Manivasagam T, Saravanan R, Thenmozhi AJ, Essa MM, Guillemin GJ.
      The present investigation was an attempt to study the effect of low molecular weight sulfated chitosan (LMWSC) on in vitro rotenone model of Parkinson's disease (PD) by evaluating cell viability, oxidative stress, mitochondrial membrane potential, DNA fragmentation, and apoptosis. Incubation of SH-SY5Y cells with 100 nm rotenone resulted in neuronal cell death, redox imbalanced mitochondrial dysfunction, DNA fragmentation, condensation, and apoptotic cellular morphology. Rotenone exposure enhanced the expression of preapoptotic (cytochrome C (cyto c), caspase-3, -8, -9, and Bax) and down-regulated the expression of anti-apoptotic (Bcl-2) markers. Reduction of the intracellular reactive oxygen species (ROS) levels ensued due to pretreatment of LMWSC along with consequent normalization of antioxidant enzymes, mitigation of rotenone induced mitochondrial dysfunction and apoptosis. Our current findings suggested that LMWSC exhibit the pronounced neuroprotective effects, which could be due to its antioxidant, mitochondrial protection, and anti-apoptotic properties. We thus conclude that LMWSC could be developed as a novel therapeutic molecule for the benefit of reducing the consequences of PD. However, further extensive preclinical and clinical studies are warranted.
    Keywords:  Apoptosis; Mitochondrial dysfunction; Neuronal damage; Oxidative stress; Rotenone; Sulfated chitosan
    DOI:  https://doi.org/10.1007/s12640-018-9978-z
  7. Life Sci. 2018 Nov 11. pii: S0024-3205(18)30727-6. [Epub ahead of print]
    Chen J, Liu GZ, Sun Q, Zhang F, Liu CY, Yuan L, Zhao XQ, Wang YJ, Jia YS.
      This work aims to evaluate the effect of ginsenoside Rg3 on the apoptosis, proliferation, extracellular matrix (ECM) metabolism and oxidative stress-induced damage of human nucleus pulposus cells (NPCs) induced by TNF-α. The human NPCs were divided into Control, TNF-α, TNF-α + low Rg3, TNF-α + medium Rg3 and TNF-α + high Rg3 groups. Annexin V-FITC/PI, CCK-8 and flow cytometry were used to detect the apoptosis, proliferation, and cell cycle of NPCs, respectively. The expressions of ECM-related molecules were determined by qRT-PCR, ELISA and Western blotting. NF-κB p65 pathway and apoptosis-related proteins were evaluated by Western blotting, and the production of reactive oxygen species (ROS) was detected by DCFH-DA assay. Compared with Control group, NPCs in the TNF-α group had elevated proportion of apoptotic cells with up-regulation of Bax and Caspase-3 and down-regulation of Bcl-2. Besides, TNF-α inhibited proliferation and arrested cell cycle at G1 of NPCs. Moreover, human NPCs induced by TNF-α presented the increase in the expressions of ECM degrading genes (MMP3 and ADAMTS5), the content of ROS and malondialdehyde (MDA), and the expression of NF-κB/p65 in nucleus, but showed the decrease in the expression of ECM synthesis genes (Aggrecan and COL2A1) and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). However, NPCs treated by both TNF-α and Rg3 demonstrated a certain degree of reversal in the above indexes, which became increasingly evident with the up-regulation of Rg3 concentration. Ginsenoside Rg3 may exert the effect of attenuating TNF-α-induced NPCs impairment via blocking the NF-κB signaling pathway.
    Keywords:  NF-κB; Nucleus pulposus cells; Rg3; TNF-α
    DOI:  https://doi.org/10.1016/j.lfs.2018.11.022
  8. Innate Immun. 2018 Nov 14. 1753425918809860
    Li T, Huang X, Yuan Z, Wang L, Chen M, Su F, Ling X, Piao Z.
      Pseudomonas aeruginosa-derived pigment pyocyanin (PCN) has been proved to induce cell apoptosis mediated by the generation of reactive oxygen species (ROS), which has been studied mainly in epithelial cells and neutrophils. However, we previously found that the PCN-producing strain PA14 induces cell apoptosis in human NK cell line NK92 more effectively than in PCN-deficient strain PA14-phZ1/2 via a yet undetermined mechanism. In the current study, we found that PCN-induced NK92 cell apoptosis occurs through mitochondrial damage despite inhibiting intracellular ROS generation. Intracellular Ca2+ ([Ca2+]i) and Bcl-2 family proteins act as important "priming signals" for apoptosis. PCN treatment increased [Ca2+]i in NK92 cells more than twofold after 2 h stimulation, whereas the Ca2+-chelating agent ethylene glycol tetra-acetic acid (EGTA) inhibited apoptosis. PCN triggered the activation of Bim, Bid, Bik, Bak, and phospho-Bad in NK92 cells in a concentration-dependent manner, but these pro-apoptotic Bcl-2 family proteins were not inhibited by EGTA. In this study, we describe the function of PCN in NK92 cells and identify mitochondrial damage as the mechanism underlying the apoptosis. [Ca2+]i and pro-apoptotic Bcl-2 family proteins are novel targets for PCN-induced apoptosis. Clarification of the cytotoxic diversity of PCN provides a new therapeutic target for defense from P. aeruginosa-induced immune cell damage.
    Keywords:  NK cell; Pyocyanin; intracellular calcium; mitochondrial damage
    DOI:  https://doi.org/10.1177/1753425918809860
  9. Cell Commun Signal. 2018 Nov 15. 16(1): 81
    Liu H, Feng Y, Xu M, Yang J, Wang Z, Di G.
      BACKGROUND: Four-octyl itaconate (OI), the itaconate's cell-permeable derivative, can activate Nrf2 signaling via alkylation of Keap1 at its cysteine residues. The current study tested the potential neuroprotective function of OI in hydrogen peroxide (H2O2)-treated neuronal cells.METHODS: SH-SY5Y neuronal cells and epigenetically de-repressed (by TSA treatment) primary murine neurons were treated with OI and/or H2O2. Nrf2 pathway genes were examined by Western blotting assay and real-time quantitative PCR analysis. Neuronal cell death was tested by the LDH and trypan blue staining assays. Apoptosis was tested by TUNEL and Annexin V assays.
    RESULTS: In SH-SY5Y neuronal cells and primary murine neurons, OI activated Nrf2 signaling, causing Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation, as well as expression of Nrf2-regulated genes (HO1, NQO1 and GCLC) and ninjurin2 (Ninj2). Functional studies showed that OI attenuated H2O2-induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage as well as neuronal cell death and apoptosis. shRNA-mediated knockdown, or CRISPR/Cas9-induced knockout of Nrf2 almost abolished OI-induced neuroprotection against H2O2. Keap1 is the primary target of OI. Keap1 knockout by CRISPR/Cas9 method mimicked and abolished OI-induced actions in SH-SY5Y cells. Introduction of a Cys151S mutant Keap1 in SH-SY5Y cells reversed OI-induced Nrf2 activation and anti-H2O2 neuroprotection.
    CONCLUSIONS: OI activates Keap1-Nrf2 signaling to protect SH-SY5Y cells and epigenetically de-repressed primary neurons from H2O2 in vitro.
    Keywords:  Four-octyl itaconate; Keap1-Nrf2 signaling; Neuronal cells; Oxidative stress
    DOI:  https://doi.org/10.1186/s12964-018-0294-2
  10. Redox Rep. 2018 Dec;23(1): 206-212
    Kim HY, Noh JR, Moon SJ, Choi DH, Kim YH, Kim KS, Yook HS, An JP, Oh WK, Hwang JH, Lee CH.
      OBJECTIVE: We aimed to investigate the effect of Sicyos angulatus (SA) ethanolic extracts as antioxidants and potential treatments for liver disease.METHODS: To establish a mouse model of liver injury, C57BL/6 male mice were injected via the caudal vein with a single dose of concanavalin A (Con A, 15 mg kg-1). SA extracts were administered once by oral gavage 30 min before Con A injection.
    RESULTS: In vitro studies showed that SA decreased tert-butyl hydroperoxide (t-BHP)-induced reactive oxygen species (ROS) production. SA administration reduced plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as hepatic ROS levels, in a dose-dependent manner. Moreover, SA increased the activities of the hepatic antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in a dose-dependent manner. Furthermore, SA treatment reduced pro-apoptotic protein levels. Con A-mediated cytosolic release of Smac/DIABLO and apoptosis-inducing factor (AIF), which are markers of necrosis, were dramatically decreased in HepG2 cells treated with SA.
    CONCLUSION: SA ameliorated liver injury and might be a good strategy for the treatment of liver injury.
    Keywords:  Antioxidants; apoptosis; enzyme; extracts; injury; liver; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1080/13510002.2018.1546986
  11. Biology (Basel). 2018 Nov 15. pii: E48. [Epub ahead of print]7(4):
    Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I.
      Ischemia⁻reperfusion injury contributes to the pathogenesis of many diseases, with acute kidney injury included. Hibernating mammals survive prolonged bouts of deep torpor with a dramatic drop in blood pressure, heart, and breathing rates, interspersed with short periods of arousal and, consequently, ischemia⁻reperfusion injury. Clarifying the differences under warm anoxia or reoxygenation between human cells and cells from a native hibernator may reveal interventions for rendering human cells resistant to ischemia⁻reperfusion injury. Human and hamster renal proximal tubular epithelial cells (RPTECs) were cultured under warm anoxia or reoxygenation. Mouse RPTECs were used as a phylogenetic control for hamster cells. Cell death was assessed by both cell imaging and lactate dehydrogenase (LDH) release assay, apoptosis by cleaved caspase-3, autophagy by microtubule-associated protein 1-light chain 3 B II (LC3B-II) to LC3B-I ratio, necroptosis by phosphorylated mixed-lineage kinase domain-like pseudokinase, reactive oxygen species (ROS) fluorometrically, and lipid peroxidation, the end-point of ferroptosis, by malondialdehyde. Human cells died after short periods of warm anoxia or reoxygenation, whereas hamster cells were extremely resistant. In human cells, apoptosis contributed to cell death under both anoxia and reoxygenation. Although under reoxygenation, ROS increased in both human and hamster RPTECs, lipid peroxidation-induced cell death was detected only in human cells. Autophagy was observed only in human cells under both conditions. Necroptosis was not detected in any of the evaluated cells. Clarifying the ways that are responsible for hamster RPTECs escaping from apoptosis and lipid peroxidation-induced cell death may reveal interventions for preventing ischemia⁻reperfusion-induced acute kidney injury in humans.
    Keywords:  apoptosis; autophagy; ferroptosis; hibernation; ischemia–reperfusion; lipid peroxidation; necroptosis
    DOI:  https://doi.org/10.3390/biology7040048
  12. J Reprod Dev. 2018 Nov 15.
    Ullah O, Li Z, Ali I, Xu L, Liu H, Shah SZA, Fang N.
      Pterostilbene (PTS) in blueberries is a phytoalexin with antioxidant properties. PTS exerts strong cytoprotective effects on various cells via Nuclear Factor Erythroid 2 like 2 (NFE2L2) pathway. We evaluated the antioxidant PTS treatment in mouse preimplantation embryos. In vitro culture media were supplemented with different concentrations of PTS. Treatment of zygotes with 0.25 μM PTS improved the development of day 4 blastocysts (P < 0.05). Moreover, H2O2 treatment significantly increased the reactive oxygen species level and reduced the glutathione level in mouse blastocyst, whereas PTS treatment counteracted these effects. The fluorescence intensity of apoptotic positive cell was higher in the H2O2 group than in the PTS group. Furthermore, PTS-treated embryos significantly increased the protein expression of NFE2L2 in the nucleus and decreased Kelch-like ECH-associated protein1 (KEAP1). PTS treatment significantly increased the expression of downstream target genes involved in the NFE2L2 pathway, such as catalase (CAT), heme oxygenase1 (HMOX1), glutathione peroxidase (GPX), and superoxide dismutase (SOD); these genes confer cellular protection. In addition, PTS treatment significantly increased the expression of anti-apoptotic B-cell lymphoma 2 (BCL2), with a concomitant reduction in the apoptotic Bcl-2-associated X protein (BAX) and Caspase-3 genes in the embryo. PTS treatment also increased the protein expression of BCL2 and reduced the protein expression of BAX in the mouse embryo. In conclusion, PTS activated NFE2L2 signaling pathway in the development of mouse embryos by altering downstream expression of genes involved in the antioxidant mechanisms and apoptosis.
    Keywords:  In vitro culture medium; Mouse embryo; Nuclear Factor Erythroid 2 like 2 (NFE2L2); Oxidative stress; Pterostilbene
    DOI:  https://doi.org/10.1262/jrd.2018-089
  13. J Biochem Mol Toxicol. 2018 Nov 15. e22245
    Zhai J, Qu X, Zhang Y, Gao H, Tao L, Song Y, Zhang S.
      Salvianolic acid (SA) is known for improving blood circulation, scavenging hydroxyl radicals, and preventing platelet aggregation. The research explored whether SA can protect against cardiovascular disease induced by high glucose conditions. Our results indicate that SA significantly increases cells viability and nitric oxide levels while decreasing reactive oxygen species generation. SA upregulated the expression levels of Bcl-2 and decreased the levels of Bax, cleaved caspase-3, and cleaved caspase-9. Furthermore, the expression levels of Sirtuin 1 (Sirt1) and p-endothelial nitric oxide synthase (eNOS) were markedly increased in response to SA treatment. Moreover, exposure of human umbilical vein endothelial cells to Ex527 resulted in reducing expression of p-eNOS. However, the beneficial effects of SA were abolished partially when Ex527 was added. These findings suggest that SA can be used as a potential therapeutic to protect against high glucose-induced endothelial injury by modulating Sirt1-eNOS pathway.
    Keywords:  Sirtuin 1 (Sirt1); cardiovascular disease (CVD); high glucose; salvianolic acid (SA)
    DOI:  https://doi.org/10.1002/jbt.22245
  14. Cancer Lett. 2018 Nov 12. pii: S0304-3835(18)30669-4. [Epub ahead of print]
    Li K, Zhao G, Ao J, Gong D, Zhang J, Chen Y, Li J, Huang L, Xiang R, Hu J, Lin P, Wei Y.
      Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The molecular mechanism by which hepatocellular carcinoma (HCC) cells resist anoikis remains not fully understood. Here, we report that ZNF32 expression is markedly upregulated in HCC cells upon detachment. Enforced ZNF32 expression significantly promotes the anchorage-independent growth capability of HepG2 and Huh7 cells, whereas knockdown of ZNF32 results in increased apoptosis of HCC cells after detachment. Mechanistically, we demonstrate that ZNF32 overexpression suppresses the reactive oxygen species (ROS) accumulation and maintains mitochondrial membrane potential, leading to ATP, GSH and NADPH elevation and promoting HCC cell survival in response to suspension. Moreover, ZNF32 enhances the phosphorylation and activation of Src/FAK signaling. Src and FAK inhibitors effectively reverse ZNF32-induced anoikis resistance in HCC cells. Collectively, our findings not only reveal a novel and important mechanism by which ZNF32 contributes to anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling, but also suggest the potential therapeutic value of ZNF32 in HCC patients.
    Keywords:  Anoikis; Hepatocellular carcinoma; Redox homeostasis; Src/FAK signaling; ZNF32
    DOI:  https://doi.org/10.1016/j.canlet.2018.09.033
  15. Redox Biol. 2018 Nov 03. pii: S2213-2317(18)30738-9. [Epub ahead of print]20 451-457
    Tai Y, Cao F, Li M, Li P, Xu T, Wang X, Yu Y, Gu B, Yu X, Cai X, Ao F, Ge P, Xiang L, Yang B, Jiang Y, Li Y.
      Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease.
    Keywords:  Colon cancer; Glycolysis; Interferon-γ; Mitochondrial pyruvate carriers; Redox
    DOI:  https://doi.org/10.1016/j.redox.2018.10.024
  16. Int J Biol Macromol. 2018 Nov 13. pii: S0141-8130(18)35103-1. [Epub ahead of print]
    Vasantharaja R, Stanley Abraham L, Gopinath V, Hariharan D, Smita KM.
      In this present study, isolation, characterization and protective effect of sulfated polysaccharide (SP) isolated from the brown algae Padina gymnospora was investigated. SP was isolated and characterized through FT-IR, 1H NMR, TGA, GC-MS and CHN analysis. The molecular weight of SP was found to be 16 kDa. The isolated SP contains 29.4 ± 0.35% of sulfate, 27 ± 0.11% of fucose, 0.05 ± 0.12% of protein, respectively. Furthermore, SP exhibits its excellent radical scavenging effects were evaluated by DPPH, ABTS radical scavenging and reducing power assays. Moreover, pretreatment with SP significantly mitigates H2O2 induced cytotoxicity in L-929 cells in a dose dependent manner. Furthermore, SP pretreatment ameliorates oxidative stress induced apoptosis and DNA damage, alleviates the generation of intracellular reactive oxygen species (ROS) and restores mitochondrial membrane potential (MMP) in L-929 cells through its antioxidant potential. Together, these results suggest that SP can be exploited as a natural antioxidant in the food and pharmaceutical industries.
    Keywords:  Antioxidants; Oxidative stress; Padina gymnospora; Reactive oxygen species; Sulfated polysaccharide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2018.11.104
  17. J Cell Mol Med. 2018 Nov 12.
    Wang W, Wang Y, Liu M, Zhang Y, Yang T, Li D, Huang Y, Li Q, Bai G, Shi L.
      Hepatocellular carcinoma (HCC) is a high incidence and mortality malignant tumour globally. Betulinic acid (BA) is a pentacyclic triterpenoid with potential pro-apoptotic activities which widely found in many plants. In this study, we determined the effects of BA on proliferation, apoptosis, invasion, and metastasis in HCC cell lines and on tumour growth and pulmonary metastasis in mice. The results suggested that BA could inhibit cell viability and proliferation of HCC cell lines including HepG2, LM3, and MHCC97H. In addition, BA induced apoptosis of HepG2 cells characterised condensed nuclei and nuclear fragmentation. Moreover, western blot analysis showed that BA-induced apoptosis associated with increasing of pro-apoptotic protein Bax and cleaved caspase-3 and decreasing of anti-apoptotic protein Bcl-2. Meanwhile, BA also reduced the reactive oxygen species (ROS) level. Furthermore, BA also significantly inhibited HCC growth in vivo and blocked pulmonary metastasis of HCC by regulating the metastasis-related proteins including MMP-2, MMP-9, and TIMP2 without obvious toxicity. In all, the present study suggested that BA might be a promising anti-HCC drug candidate by inhibiting proliferation, inducing apoptosis, and blocking metastasis.
    Keywords:  apoptosis; betulinic acid; hepatocellular carcinoma; metastasis
    DOI:  https://doi.org/10.1111/jcmm.13964
  18. Anticancer Drugs. 2018 Nov 08.
    Paul T, Banerjee A, Reddy SVB, Mahato SK, Biswas N.
      The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of cytokine superfamily, induces apoptosis in a number of tumor cells through the activation of extrinsic apoptotic pathway but shows little or no cytotoxicity toward normal cells. However some tumor cells are inherently resistant to TRAIL-mediated apoptosis, which needs to be addressed to establish TRAIL as a potential chemotherapeutic drug. In this study, our aim was to manipulate TRAIL-apoptosis pathway by hydroxychavicol (HCH), a polyphenol from Piper betel leaf, for the induction of apoptosis in TRAIL resistant chronic myeloid leukemia cell. When imatinib-resistant K562 cells were treated with HCH, it made these K562 cells sensitive to TRAIL. It was observed that HCH downregulated antiapoptotic proteins XIAP and FLIP, whereas the expression of TRAIL receptors, DR4 and DR5, remains unchanged. Moreover, we observed that reactive oxygen species or ROS played a crucial role in the downregulation of FLIP and XIAP because ROS scavenger significantly reversed the decrease of XIAP, and FLIP. Ubiquitin-proteasome pathway was observed to play a crucial role in the downregulation of XIAP and FLIP, as proteasomal inhibitor MG132 significantly reversed the downregulation of XIAP and FLIP. In conclusion, this study demonstrates the combinatorial treatment of TRAIL and HCH as promising alternative therapeutic approach to treat the imatinib-resistant leukemia, which are also resistant to TRAIL.
    DOI:  https://doi.org/10.1097/CAD.0000000000000710
  19. PLoS One. 2018 ;13(11): e0206443
    Niewiarowska-Sendo A, Kozik A, Guevara-Lora I.
      Endothelial dysfunction is a hallmark of a wide range of cardiovascular diseases and is often linked to oxidative stress and inflammation. Our earlier study reported the formation of a functional heterodimer between bradykinin receptor 2 (B2R) and dopamine receptor 2 (D2R) that may modulate cell responses, dependent on intracellular signaling. Here, for the first time, we showed a cooperative effect of these receptors on the modulation of processes involved in oxidative stress, inflammation, and apoptosis in endothelial cells. Sumanirole, a specific D2R agonist, was shown to diminish the excessive production of reactive oxygen species induced by bradykinin, a proinflammatory B2R-activating peptide. This effect was accompanied by modified activities of antioxidant enzymes and increased phosphorylation of endothelial nitric oxide synthase, leading to enhance NO production. In turn, endothelial cell co-stimulation with B2R and D2R agonists inhibited the release of interleukin-6 and endothelin-1 and modulated the expression of apoptosis markers, such as Bcl-2, Bcl-xL, Bax, and caspase 3/7 activity. All these observations argue that the D2R agonist counteracts the pro-oxidative, pro-inflammatory, and pro-apoptotic effects induced through B2R, finally markedly improving endothelial functions.
    DOI:  https://doi.org/10.1371/journal.pone.0206443
  20. Biomol Ther (Seoul). 2018 Nov 12.
    Zhen AX, Piao MJ, Hyun YJ, Kang KA, Ryu YS, Cho SJ, Kang HK, Koh YS, Ahn MJ, Kim TH, Hyun JW.
      Purpurogallin, a natural phenol obtained from oak nutgalls, has been shown to possess antioxidant, anticancer, and anti-inflammatory effects. Recently, in addition to ultraviolet B (UVB) radiation that induces cell apoptosis via oxidative stress, particulate matter 2.5 (PM2.5) was shown to trigger excessive production of reactive oxygen species. In this study, we observed that UVB radiation and PM2.5 severely damaged human HaCaT keratinocytes, disrupting cellular DNA, lipids, and proteins and causing mitochondrial depolarization. Purpurogallin protected HaCaT cells from apoptosis induced by UVB radiation and/or PM2.5. Furthermore, purpurogallin effectively modulates the pro-apoptotic and anti-apoptotic proteins under UVB irradiation via caspase signaling pathways. Additionally, purpurogallin reduced apoptosis via MAPK signaling pathways, as demonstrated using MAPK-p38, ERK, and JNK inhibitors. These results indicate that purpurogallin possesses antioxidant effects and protects cells from damage and apoptosis induced by UVB radiation and PM2.5.
    Keywords:  Human HaCaT keratinocytes; Oxidative stress; Particulate matter 2.5; Purpurogallin; Ultraviolet B radiation
    DOI:  https://doi.org/10.4062/biomolther.2018.151
  21. Int J Nanomedicine. 2018 ;13 6735-6750
    Dhupal M, Oh JM, Tripathy DR, Kim SK, Koh SB, Park KS.
      Background: Titanium dioxide nanoparticles (TiO2 NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO2 NPs with components of innate immune system remains elusive.Aim: This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO2 NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling.
    Materials and methods: In this study, chemically synthesized BSA-functionalized TiO2 NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells.
    Results: We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (Δψm) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control.
    Conclusion: Collectively, this study shows that the molecular nature of TiO2 SA20(-) NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen-associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO2 SA20(-) NP-induced immunotoxicity.
    Keywords:  MAPK pathways; apoptosis; nanoparticles; oxidative stress; titanium dioxide; toll-like receptors
    DOI:  https://doi.org/10.2147/IJN.S176087
  22. Pharmaceutics. 2018 Nov 13. pii: E228. [Epub ahead of print]10(4):
    Badea MA, Prodana M, Dinischiotu A, Crihana C, Ionita D, Balas M.
      In this paper we developed a method for multiwalled carbon nanotubes (MWCNTs) use as carriers for a drug based on platinum in breast cancer therapy. The method of functionalization involves the carboxyl functionalization of nanotubes and encapsulation of cisplatin (CDDP) into MWCNTs. The biological properties of MWCNTs loaded with CDDP (MWCNT-COOH-CDDP) and of individual components MWCNT-COOH and free CDDP were evaluated on MDA-MB-231 cells. Various concentrations of CDDP (0.316⁻2.52 µg/mL) and MWCNTs (0.5⁻4 µg/mL) were applied on cells for 24 and 48 h. Only at high doses of CDDP (1.26 and 2.52 µg/mL) and MWCNT-COOH-CDDP (2 and 4 µg/mL) cell morphological changes were observed. The cellular viability decreased only with approx. 40% after 48 h of exposure to 2.52 µg/mL CDDP and 4 µg/mL MWCNT-COOH-CDDP despite the high reactive oxygen species (ROS) production induced by MWCNTs starting with 24 h. After 48 h, ROS level dropped as a result of the antioxidant defence activation. We also found a significant decrease of caspase-3 and p53 expression after 48 h, accompanied by a down-regulation of NF-κB in cells exposed to MWCNT-COOH-CDDP system which promotes apoptosis escape and thus failing to overcome the triple negative breast cancer (TNBC) cells resistance.
    Keywords:  MDA-MB-231 cells; Nrf2; carbon nanotubes; cisplatin; reactive oxygen species
    DOI:  https://doi.org/10.3390/pharmaceutics10040228
  23. Theranostics. 2018 ;8(18): 5059-5071
    Liang H, Zhou Z, Luo R, Sang M, Liu B, Sun M, Qu W, Feng F, Liu W.
      Photodynamic therapy relies on photosensitizers to generate cytotoxic reactive oxygen species (ROS) resulting in the apoptois of tumor cells. However, there is an antioxidant system that impedes the elevation of oxidation levels in tumor cells. Thus, photodynamic therapy may exhibit insufficient curative effects due to ungenerous reactive oxygen species levels. Herein, we describe tumor-specific activated photodynamic therapy using an oxidation-regulating strategy. Methods: We first synthesised a reactive oxygen species-sensitive amphipathic prodrug of gambogic acid-grafted hyaluronic acid (HA-GA). The hydrophobic photosensitizer chlorin e6 (Ce6) was then loaded into HA-GA by hydrophobic interactions between GA and Ce6, forming amphipathic nanomicelles (HA-GA@Ce6). The ROS-responsive behavior, cytotoxicity, cell uptake, tumor cell killing, in vivo biodistribution and in vivo anti-tumor efficacy of HA-GA@Ce6 were investigated. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model. Results: We validated that the micelles of HA-GA@Ce6 showed stronger cell uptake in 4T1 tumor cells and lower cytotoxicity in normal cells compared with free Ce6 and GA, which exhibited the benefits of nanomicelles on enhancing the tumor cell acumulation and reducing the side effects on normal cells synchronously. Additionally, the cytotoxic free radicals of photodynamic therapy were generated after irradiation and the high oxidation levels activated the ROS-sensitive GA prodrug efficiently, which killed the tumor cells and depleted intracellular glutathione (GSH), thereby impairing antioxidant levels and enhancing photodynamic therapy. Conclusion: With the successfully eradicated tumor growth in vivo. Our work represents a new photodynamic therapy concept, achieving superior anti-tumor efficacy by reducing intracellular antioxidant levels.
    Keywords:  GSH depletion; ROS-sensitive; chlorin e6; gambogic acid; photodynamic therapy
    DOI:  https://doi.org/10.7150/thno.28344
  24. Eur J Pharmacol. 2018 Nov 13. pii: S0014-2999(18)30671-X. [Epub ahead of print]
    Tian M, Xie Y, Meng Y, Ma W, Tong Z, Yang X, Lai S, Zhou Y, He M, Liao Z.
      Our previous studies showed that the effect of resveratrol preventing mitochondrial permeability transition pore (mPTP) opening in myocardial ischemia/reperfusion injury was achieved by regulating voltage-dependent anion channel 1 (VDAC1). However, the underlying mechanism remains unclear. Previous studies demonstrated that the activity and function of VDAC1 are highly regulated by post-translational modification. In present study, we investigated whether resveratrol modulates VDAC1 phosphorylation to achieve cardioprotection and explored the signaling pathways involved. Our findings demonstrated that anoxia/reoxygenation (A/R) treatment, an ischemia/reperfusion model in vitro, enhanced VDAC1 phosphorylation in cardiomyocytes. Moreover, we found phosphorylated VDAC1 showed increased affinity to Bax, whereas interaction with hexokinase 2 (HK2) was reduced. Accordingly, the generation of reactive oxygen species increased, the mitochondrial membrane potential collapsed, mPTP opening increased and cytochrome c released into cytoplasm, thereby leading to increased apoptosis. Moreover, our data showed that pretreatment with resveratrol prior to A/R injury inhibited VDAC1 phosphorylation. Dephosphorylated VDAC1 using pretreated resveratrol promoted dissociation with Bax and binding to HK2, which subsequently protected cardiomyocytes against A/R injury. In addition, Akt and its downstream glycogen synthase kinase 3 β (GSK3β) were phosphorylated by the action of resveratrol. Akt inhibitor IV abrogated Akt-GSK3β phosphorylation and thereby abolished the dephosphorylation activity of resveratrol on VDAC1. Moreover, all resveratrol-mediated protective effects on A/R injured cardiomyocytes were abolished by Akt inhibitor IV. Taken together, our data indicated that A/R injury enhanced VDAC1 phosphorylation in cardiomyocytes, whereas pretreatment with resveratrol dephosphorylated VDAC1 through the Akt-GSK3β pathway, thereby protecting cardiomyocytes against A/R injury.
    Keywords:  Akt-GSK3β pathway; anoxia/reoxygenation; cardiomyocyte; phosphorylation; resveratrol; voltage-dependent anion channel 1
    DOI:  https://doi.org/10.1016/j.ejphar.2018.11.016
  25. Int J Biol Macromol. 2018 Nov 08. pii: S0141-8130(18)33665-1. [Epub ahead of print]123 81-90
    Wang Y, Wang S, Song R, Cai J, Xu J, Tang X, Li N.
      In this study, ginger polysaccharide (GP) was obtained from ginger by enzymatic method, its chemical properties and antitumor activity were investigated. The results indicated that the composition and proportion of GP were l‑rhamnose, d‑arabinose, d‑mannose, d‑glucose and d‑galactose in a molar ratio of 3.64:5.37:3.04:61.03:26.91, GP had the characteristic absorption peak of polysaccharide. Congo red experiment showed that GP had a triple helix structure, which could have anti-tumor effect. Furthermore, MTT assay, cell morphology observation, nuclear morphology observation and reactive oxygen species observation demonstrated that GP had significant antitumor effect. Flow cytometry suggested that GP could promote apoptosis and arrest cells in G0-G1 phase. Real-time fluorescence quantification and Western blot revealed that GP could up-regulate the expression of Bax, Fas, FasL, caspase-3, p21 and p53, and down-regulate the expression of Bcl-2. These studies suggested that GP would be used as an antitumor drug in foods to promote the development of functional foods.
    Keywords:  Apoptosis; Cell cycle arrest; Ginger polysaccharide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2018.10.169
  26. Chin Med J (Engl). 2018 Nov 20. 131(22): 2666-2675
    Song CC, Hong Q, Geng XD, Wang X, Wang SQ, Cui SY, Guo MD, Li O, Cai GY, Chen XM, Wu D.
      Background: Focal segmental glomerulosclerosis (FSGS) is a kidney disease that is commonly associated with proteinuria and the progressive loss of renal function, which is characterized by podocyte injury and the depletion and collapse of glomerular capillary segments. The pathogenesis of FSGS has not been completely elucidated; however, recent advances in molecular genetics have provided increasing evidence that podocyte structural and functional disruption is central to FSGS pathogenesis. Here, we identified a patient with FSGS and aimed to characterize the pathogenic gene and verify its mechanism.Methods: Using next-generation sequencing and Sanger sequencing, we screened the causative gene that was linked to FSGS in this study. The patient's total blood RNA was extracted to validate the messenger RNA (mRNA) expression of coenzyme Q10 monooxygenase 6 (COQ6) and validated it by immunohistochemistry. COQ6 knockdown in podocytes was performed in vitro with small interfering RNA, and then, F-actin was determined using immunofluorescence staining. Cell apoptosis was evaluated by flow cytometry, the expression of active caspase-3 was determined by Western blot, and mitochondrial function was detected by MitoSOX.
    Results: Using whole-exome sequencing and Sanger sequencing, we screened a new causative gene, COQ6, NM_182480: exon1: c.G41A: p.W14X. The mRNA expression of COQ6 in the proband showed decreased. Moreover, the expression of COQ6, which was validated by immunohistochemistry, also had the same change in the proband. Finally, we focused on the COQ6 gene to clarify the mechanism of podocyte injury. Flow cytometry showed significantly increased in apoptotic podocytes, and Western blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile, reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group.
    Conclusions: This study reported a possible mechanism for FSGS and suggested that a new mutation in COQ6, which could cause respiratory chain defect, increase the generation of ROS, destroy the podocyte cytoskeleton, and induce apoptosis. It provides basic theoretical basis for the screening of FSGS in the future.
    Keywords:  Apoptosis; Coenzyme Q10; Focal Segmental Glomerulosclerosis; Monooxygenase 6 Mutation; Podocyte
    DOI:  https://doi.org/10.4103/0366-6999.245158
  27. Physiol Res. 2018 Oct 23.
    Miao H, Xu J, Xu D, Ma X, Zhao X, Liu L.
      Paclitaxel is used for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. In this study we examined the engagement of antioxidative signal pathway of the dorsal root ganglion (DRG) in mechanical and thermal hypersensitivity evoked by paclitaxel. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-antioxidant response element (ARE) and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our results show that paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals. Paclitaxel also impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress, namely 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine. Systemic administration of SOD mimetic using tempol, antioxidant vitamin C or blocking oxidative pathway using NADPH oxidase inhibitor (GKT137831) attenuated mechanical and thermal hypersensitivity induced by paclitaxel. This inhibitory effect was accompanied with decreases of proinflammatory cytokines (PICs) such as IL-1beta, IL-6 and TNF-alpha in the DRG. In conclusion, the data revealed impairment of Nrf2-ARE and heightened oxidative and PIC signals in the DRG of paclitaxel rats, leading to neuropathic pain. Balancing of reactive oxygen species by supplying antioxidants and/or inhibiting NADPH oxidase appears significant to yield beneficial effects in neuropathic pain conditions after chemotherapeutic paclitaxel.
  28. J Biomed Sci. 2018 Nov 15. 25(1): 81
    Hsieh Li SM, Liu ST, Chang YL, Ho CL, Huang SM.
      BACKGROUND: Metformin is the most commonly used first-line medicine for type II diabetes mellitus. Acting via AMP-activated protein kinase, it has been used for more than 60 years and has an outstanding safety record. Metformin also offers protection against cancer, but its precise mechanisms remain unclear.METHODS: We first examined the cytotoxic effects of metformin in the HeLa human cervical carcinoma and ZR-75-1 breast cancer cell lines using assays of cell viability, cleaved poly-ADP-ribose polymerase, and Annexin V-fluorescein isothiocyanate apoptosis, as well as flow cytometric analyses of the cell cycle profile and reactive oxygen species (ROS). We later clarified the effect of metformin on p53 protein stability using transient transfection and cycloheximide chase analyses.
    RESULTS: We observed that metformin represses cell cycle progression, thereby inducing subG1 populations, and had induced apoptosis through downregulation of p53 protein and a target gene, differentiated embryo chondrocyte 1 (DEC1). In addition, metformin increased intracellular ROS levels, but N-acetyl cysteine, a ROS scavenger, failed to suppress metformin-induced apoptosis. Further results showed that metformin disrupted the electron transport chain and collapsed the mitochondrial membrane potential, which may be the cause of the elevated ROS levels. Examination of the mechanisms underlying metformin-induced HeLa cell death revealed that reduced stability of p53 in metformin-treated cells leads to decreases in DEC1 and induction of apoptosis.
    CONCLUSION: The involvement of DEC1 provides new insight into the positive or negative functional roles of p53 in the metformin-induced cytotoxicity in tumor cells.
    Keywords:  Apoptosis; DEC1; Metformin; Reactive oxygen species; p53
    DOI:  https://doi.org/10.1186/s12929-018-0478-5
  29. J Microencapsul. 2018 Nov 16. 1-27
    Moghimipour E, Rezaei M, Kouchak M, Ramezani Z, Amini M, Ahmadi Angali K, Saremy S, Dorkoosh FA, Handali S.
      This study was performed to prepare 5FU containing targeted liposomes for the safety and efficacy enhancement. Liposomes were prepared using thin layer method and transferrin (Tf) was employed as the targeting ligand. Morphology of 5FU loaded liposomes was assessed by transmission electron microscopy (TEM). The in vitro cytotoxicity was investigated via MTT assay on HT-29, CT26 and fibroblast cells. Mitochondrial membrane and cell death evaluations were also investigated. Resulted showed that the encapsulation efficiency (EE%) and particle size of the liposomes were 40.12% and 130 nm, respectively. TEM image implied that liposomes were spherical in shape. In cancer cells, targeted liposomes triggered the mitochondrial apoptotic pathway by lower production of reactive oxygen species (ROS) (63.58 vs 84.95 fluorescence intensity), reduced mitochondrial membrane potential and releasing of cytochrome c (68.66 vs 51.13 ng/mL). The results of this study indicated that Tf targeted 5FU liposomes can be employed as promising nano-carrier for the delivery of drugs to cancer cells.
    Keywords:  5-Fluorouracil; Apoptosis; Cancer; Liposome; Transferrin
    DOI:  https://doi.org/10.1080/02652048.2018.1547325
  30. Antioxidants (Basel). 2018 Nov 11. pii: E161. [Epub ahead of print]7(11):
    Kang SW, Lee S, Lee JHS.
      Cancer cells are abnormal cells that do not comply with tissue homeostasis but undergo uncontrolled proliferation. Such abnormality is driven mostly by somatic mutations on oncogenes and tumor suppressors. Cancerous mutations show intra-tumoral heterogeneity across cancer types and eventually converge into the self-activation of proliferative signaling. While transient production of intracellular reactive oxygen species (ROS) is essential for cell signaling, its persistent production is cytotoxic. Thus, cancer cells require increased levels of intracellular ROS for continuous proliferation, but overexpress cellular peroxidase enzymes, such as 2-Cys peroxiredoxins, to maintain ROS homeostasis. However, suppression of 2-Cys peroxiredoxins has also been reported in some metastatic cancers. Hence, the cancer-associated functions of 2-Cys peroxiredoxins must be illuminated in the cellular context. In this review, we describe the distinctive signaling roles of 2-Cys peroxiredoxins beyond their intrinsic ROS-scavenging role in relation to cancer cell death and survival.
    Keywords:  apoptosis; autophagy; cancer; chemical inhibitor; peroxiredoxin
    DOI:  https://doi.org/10.3390/antiox7110161
  31. Int J Mol Sci. 2018 Nov 12. pii: E3568. [Epub ahead of print]19(11):
    Chirumbolo S, Bjørklund G, Lysiuk R, Vella A, Lenchyk L, Upyr T.
      The role of phytochemicals as potential prodrugs or therapeutic substances against tumors has come in the spotlight in the very recent years, thanks to the huge mass of encouraging and promising results of the in vitro activity of many phenolic compounds from plant raw extracts against many cancer cell lines. Little but important evidence can be retrieved from the clinical and nutritional scientific literature, where flavonoids are investigated as major pro-apoptotic and anti-metastatic compounds. However, the actual role of these compounds in cancer is still far to be fully elucidated. Many of these phytochemicals act in a pleiotropic and poorly specific manner, but, more importantly, they are able to tune the reactive oxygen species (ROS) signaling to activate a survival or a pro-autophagic and pro-apoptosis mechanism, depending on the oxidative stress-responsive endowment of the targeted cell. This review will try to focus on this issue.
    Keywords:  apoptosis; cancer; flavonoids; mitochondria; phytochemicals
    DOI:  https://doi.org/10.3390/ijms19113568
  32. J Med Chem. 2018 Nov 16.
    Morsy A, Trippier PC.
      Alzheimer's Disease (AD) is the most common dementia. No cure exists and current treatment only manages early symptoms. Mitochondrial dysfunction is a hallmark of amyloid-beta (Aβ) neurotoxicity, the pathogenic protein implicated in AD. This is due in part to the interaction between Aβ and amyloid-binding alcohol dehydrogenase (ABAD). This mitochondrial protein is a vital energy regulator, that following Aβ binding, activates signaling cascades that lead to neuronal death. One of the most significant roles of ABAD is to maintain the balance of estradiol/estrone in neurons. However, the Aβ-ABAD interaction disrupts this balance and leads to a reduction in levels of estradiol, thus leading to an increase in reactive oxygen species levels, and apoptosis. Two additional proteins; peroxiredoxin-2 and endophilin-1 are implicated in Aβ-ABAD complex-mediated toxicity. Targeting the Aβ-ABAD interaction has emerged as a novel therapeutic strategy for AD. Herein, we review the chemistry and pharmacology of reported ABAD inhibitors.
    DOI:  https://doi.org/10.1021/acs.jmedchem.8b01530
  33. Sci Rep. 2018 Nov 15. 8(1): 16837
    Tabe Y, Saitoh K, Yang H, Sekihara K, Yamatani K, Ruvolo V, Taka H, Kaga N, Kikkawa M, Arai H, Miida T, Andreeff M, Spagnuolo PA, Konopleva M.
      Adipocytes are the prevalent stromal cell type in adult bone marrow (BM), and leukemia cells continuously adapt to deficiency of nutrients acquiring chemoresistant profiles in the BM microenvironment. We have previously shown that fatty acid metabolism is a key energy pathway for survival of acute myeloid leukemia (AML) cells in the adipocyte-abundant BM microenvironment. The novel fatty acid β-oxidation (FAO) inhibitor avocatin B, an odd-numbered carbon lipid derived from the avocado fruit, induced apoptosis and growth inhibition in mono-cultured AML cells. In AML cells co-cultured with BM adipocytes, FAO inhibition with avocatin B caused adaptive stimulation of free fatty acid (FFA) uptake through upregulation of FABP4 mRNA, enhanced glucose uptake and switch to glycolysis. These changes reflect the compensatory response to a shortage of FFA supply to the mitochondria, and facilitate the protection of AML cells from avocatin B-induced apoptosis in the presence of BM adipocytes. However, the combination treatment of avocatin B and conventional anti-AML therapeutic agent cytarabine (AraC) increased reactive oxygen species and demonstrated highly synergistic effects on AML cells under BM adipocyte co-culture condition. These findings highlight the potential for combination regimens of AraC and FAO inhibitors that target bone marrow-resident chemoresistant AML cells.
    DOI:  https://doi.org/10.1038/s41598-018-35198-6
  34. Life Sci. 2018 Nov 09. pii: S0024-3205(18)30726-4. [Epub ahead of print]
    Enayati A, Yassa N, Mazaheri Z, Rajaei M, Pourabouk M, Ghorghanlu S, Basiri S, Khori V.
      BACKGROUND: Previous studies have shown that proanthocyanidins have cardioprotective effects which are mediated via the release of nitric oxide (NO) ultimately resulting in increasing the antioxidant activity. We have investigated to show whether 1) the total extract and ethyl acetate fraction (Et) of Potentilla reptans root have an ischemic preconditioning (IPC) effect, 2) P. reptans has antioxidant and cardioprotective effects mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and scavenging of reactive oxygen species (ROS), 3) NO, caspase-3 and Bcl-2/Bax are involved in the IPC effect of P. reptans.METHODS: Male Wistar rats were divided into 10 groups. The isolated hearts were subjected to 30 min of ischemia and 100 min of reperfusion. The P. reptans was applied before the main ischemia. The infarct size was estimated by triphenyl-tetrazolium chloride staining. The hemodynamic parameters and ventricular arrhythmias were calculated during the reperfusion. Antioxidant markers and immunohistochemistry assays were determined at the end of the protocol.
    RESULTS: The Et significantly decreased the infarct size, arrhythmia scores, ventricular fibrillation incidence, and enhanced the hemodynamic parameters in a concentration-dependent manner against the ischemia/reperfusion group. SOD and CAT activity were increased and MDA level was decreased in response to the Et. Meanwhile, Et attenuated the suppression of Nrf2 expression and reduced the apoptotic indexes. The cardioprotective effect of P. reptans was abrogated by L-NAME.
    CONCLUSIONS: P. reptans demonstrated that the cardioprotective preconditioning effects via NO release, Nrf2 pathway, and antioxidant activity lead to a decrease in the apoptotic index.
    Keywords:  Anti-apoptotic; Antioxidant; Ischemia/reperfusion; Ischemic preconditioning; Potentilla reptans root
    DOI:  https://doi.org/10.1016/j.lfs.2018.11.021
  35. Medchemcomm. 2018 Oct 01. 9(10): 1663-1672
    Hu K, Liu C, Li J, Liang F.
      Three copper(ii) complexes, [Cu(L1)(NO3)2] (C1), [Cu(L2)Cl2] (C2) and [Cu(L2)SO4]2·H2O (C3), were designed and synthesized by the reaction of Cu(NO3)2·3H2O, CuCl2·2H2O and CuSO4·5H2O with a quinoline-derived Schiff base ligand, L1 or L2, prepared by the condensation of quinoline-8-carbaldehyde with 4-aminobenzoic acid methyl ester or 4-aminobenzoic acid ethyl ester (benzocaine). The efficient bindings of the C1-C3 complexes with human serum albumin (HSA) and calf thymus DNA (CT-DNA) were analyzed by spectroscopy and molecular docking. These complexes could significantly quench the fluorescence of HSA through the static quenching process, and hydrophobic interactions with HSA through the sub-domain IIA and IIIA cavities. The complexes bind to DNA via the intercalative mode and they fit well into the curved contour of the DNA target in the minor groove region. Furthermore, the interaction abilities of the Cu(ii) complexes with HSA/DNA were greater as compared to their corresponding ligands. Interestingly, C1-C3, particularly C3, exhibited more cytotoxicity toward HeLa cells compared to normal HL-7702 cells and three other tumor cell lines (Hep-G2, NCI-H460, and MGC80-3). Their cytotoxicity toward the HeLa cell lines was 1.9-3.5-fold more potent than cisplatin. Further studies indicated that these complexes arrested the cell cycle in the G0/G1 phase and promoted tumor cell apoptosis via a reactive oxygen species (ROS)-mediated mitochondrial pathway.
    DOI:  https://doi.org/10.1039/c8md00223a
  36. Eur Heart J Acute Cardiovasc Care. 2018 Nov 13. 2048872618812148
    van der Weg K, Prinzen FW, Gorgels AP.
      Reperfusion does not only salvage ischaemic myocardium but can also cause additional cell death which is called lethal reperfusion injury. The time of reperfusion is often accompanied by ventricular arrhythmias, i.e. reperfusion arrhythmias. While both conditions are seen as separate processes, recent research has shown that reperfusion arrhythmias are related to larger infarct size. The pathophysiology of fatal reperfusion injury revolves around intracellular calcium overload and reactive oxidative species inducing apoptosis by opening of the mitochondrial protein transition pore. The pathophysiological basis for reperfusion arrhythmias is the same intracellular calcium overload as that causing fatal reperfusion injury. Therefore both conditions should not be seen as separate entities but as one and the same process resulting in two different visible effects. Reperfusion arrhythmias could therefore be seen as a potential marker for fatal reperfusion injury.
    Keywords:  Myocardial infarction; arrhythmias; myocardial reperfusion injury; pathophysiology
    DOI:  https://doi.org/10.1177/2048872618812148
  37. Food Chem Toxicol. 2018 Nov 10. pii: S0278-6915(18)30816-0. [Epub ahead of print]
    Sivalingam K, Amirthalingam V, Ganasan K, Huang CY, Viswanadha VP.
      Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The aim of this study was to evaluate the anti-cancer effect of neferine against diethylnitrosamine (DEN)-induced lung carcinogenesis in Wistar rats and to explore the underlying molecular mechanism. DEN-administration induced oxidative stress as indicated by alterations in the levels of pulmonary reactive-oxygen species, lipid peroxidation, protein carbonyl content and antioxidant status whereas treatment with neferine restored cellular normalcy, highlighting the antioxidant potential of neferine in mitigating the oxidative stress-mediated damage produced during DEN-induced lung carcinogenesis. Histopathological analysis showed disorganized alveolar structure, thickened alveolar wall, infiltration of inflammatory cells in DEN-induced rats, the damage was significantly reduced upon neferine treatment. DEN-induced rats exhibited increased expression of NF-κB, COX-2, CYP2E1, VEGF, Bcl-2, PI3K/AKT/mTOR genes and significantly decreased the expression of p53, Bax, caspase-9 and caspase-3 genes. Neferine treatment restored the DEN induced alteration in the expression of these genes. Further, blotting analysis revealed increased expression of NF-κB, COX-2, Bcl-2 and decreased expression of Bax, caspase-9 and caspase-3 proteins in DEN-induced rats. Neferine treatment restored the expression of these proteins in DEN induced lung carcinogenesis.
    Keywords:  Apoptosis; Diethylnitrosamine; Inflammation; Lung cancer; Neferine
    DOI:  https://doi.org/10.1016/j.fct.2018.11.014