bims-aporos Biomed News
on Apoptosis and reactive oxygen species
Issue of 2019‒06‒09
sixty-three papers selected by
Gavin McStay
Staffordshire University
  1. Anagliptin protects neuronal cells against endogenous amyloid β (Aβ)-induced cytotoxicity and apoptosis.
  2. Di-(2-ethylhexyl) phthalate (DEHP) inhibits steroidogenesis and induces mitochondria-ROS mediated apoptosis in rat ovarian granulosa cells.
  3. Acetamiprid, a neonicotinoid insecticide, induced cytotoxicity and genotoxicity in PC12 cells.
  4. Ethyl acetate extract of Nepenthes adrianii x clipeata induces antiproliferation, apoptosis, and DNA damage against oral cancer cells through oxidative stress.
  5. Effects of transcription factor EB on oxidative stress and apoptosis induced by high glucose in podocytes.
  6. Attenuation of Palmitic Acid-Induced Lipotoxicity by Chlorogenic Acid Through Activation of SIRT1 in Hepatocytes.
  7. Neochamaejasmin A extracted from Stellera chamaejasme L. induces apoptosis involving mitochondrial dysfunction and oxidative stress in Sf9 cells.
  8. Severe Periodontitis May Influence Cementum and Dental Pulp Through Inflammation, Oxidative Stress and Apoptosis.
  9. Tetramethylpyrazine protects retinal ganglion cells against H2O2‑induced damage via the microRNA‑182/mitochondrial pathway.
  10. S-allyl-L-cysteine (SAC) protects hepatocytes from alcohol-induced apoptosis.
  11. N-acetyl cysteine, inulin and the two as a combined therapy ameliorate cognitive decline in testosterone-deprived rats.
  12. Ethyl Acetate Extract of Nepenthes ventricosa x maxima Exerts Preferential Killing to Oral Cancer Cells.
  13. Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis.
  14. Protective effects of cynaroside on oxidative stress in retinal pigment epithelial cells.
  15. l-arginine Alleviates Doxorubicin-Induced Endothelium-Dependent Dysfunction by Promoting Nitric Oxide Generation and Inhibiting Apoptosis.
  16. Astragalus polysaccharide alleviates H2O2-triggered oxidative injury in human umbilical vein endothelial cells via promoting KLF2.
  17. Hydroxysafflor Yellow A mitigated myocardial ischemia/reperfusion injury by inhibiting the activation of the JAK2/STAT1 pathway.
  18. Multi-generational effects and variations of stress response by hexabromocyclododecane (HBCD) exposure in the nematode Caenorhabditis elegans.
  19. Notoginsenoside R1 protects human renal proximal tubular epithelial cells from lipopolysaccharide-stimulated inflammatory damage by up-regulation of miR-26a.
  20. Lipid storage droplet protein 5 reduces sodium palmitate‑induced lipotoxicity in human normal liver cells by regulating lipid metabolism‑related factors.
  21. Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway.
  22. Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells.
  23. Triptolide Induces Glioma Cell Autophagy and Apoptosis via Upregulating the ROS/JNK and Downregulating the Akt/mTOR Signaling Pathways.
  24. METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway.
  25. Tetramethylpyrazine guards against cisplatin-induced nephrotoxicity in rats through inhibiting HMGB1/TLR4/NF-κB and activating Nrf2 and PPAR-γ signaling pathways.
  26. Role of TXNIP/NLRP3 in sepsis-induced myocardial dysfunction.
  27. Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress.
  28. Hepatotoxicity of tricyclazole in zebrafish (Danio rerio).
  29. Dexmedetomidine alleviates LPS-induced apoptosis and inflammation in macrophages by eliminating damaged mitochondria via PINK1 mediated mitophagy.
  30. Oxidative stress and Parkinson's disease: conflict of oxidant-antioxidant systems.
  31. The synthesis and anticancer activity of 2-styrylquinoline derivatives. A p53 independent mechanism of action.
  32. Gamma-Irradiated Chrysin Improves Anticancer Activity in HT-29 Colon Cancer Cells Through Mitochondria-Related Pathway.
  33. Curcumin‑loaded PEG‑PDLLA nanoparticles for attenuating palmitate‑induced oxidative stress and cardiomyocyte apoptosis through AMPK pathway.
  34. Myricetin prevents thapsigargin-induced CDK5-P66Shc signalosome mediated pancreatic β-cell dysfunction.
  35. Garlic and allopurinol attenuate hepatic apoptosis induced by fipronil in male albino rats.
  36. Protective effects of zingerone on cisplatin-induced nephrotoxicity in female rats.
  37. Are platinum nanoparticles safe to human health?
  38. Contribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells.
  39. Centaurea cyanus extracted 13-O-acetylsolstitialin A decrease Bax/Bcl-2 ratio and expression of cyclin D1/Cdk-4 to induce apoptosis and cell cycle arrest in MCF-7 and MDA-MB-231 breast cancer cell lines.
  40. Autophagy protects nucleus pulposus cells from cyclic mechanical tension‑induced apoptosis.
  41. p53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma.
  42. 3,4-dimethoxybenzyl isothiocyanate enhances doxorubicin efficacy in LoVoDX doxorubicin-resistant colon cancer and attenuates its toxicity in vivo.
  43. Mitochondria as playmakers of apoptosis, autophagy and senescence.
  44. Cadmium stress effects indicating marine pollution in different species of sea urchin employed as environmental bioindicators.
  45. DUSP26 regulates podocyte oxidative stress and fibrosis in a mouse model with diabetic nephropathy through the mediation of ROS.
  46. Melatonin attenuates inflammation-related venous endothelial cells apoptosis through modulating the MST1-MIEF1 pathway.
  47. Mechanistic assessment of cadmium toxicity in association with the functions of estrogen receptors in the Langerhans islets.
  48. Neurodevelopmental toxicity assessments of alkyl phenanthrene and Dechlorane Plus co-exposure in zebrafish.
  49. Embryonic Stem Cell-Derived Exosomes Inhibit Doxorubicin Induced TLR4-NLRP3 Mediated Cell Death - Pyroptosis.
  50. Empagliflozin alleviates renal inflammation and oxidative stress in streptozotocin-induced diabetic rats partly by repressing HMGB1-TLR4 receptor axis.
  51. Modulatory effects of swimming exercise against malathion induced neurotoxicity in male and female rats.
  52. Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring.
  53. Cyanidin-3-o-glucoside inhibits UVA-induced human dermal fibroblast injury by upregulating autophagy.
  54. Protective effects of salvianolic acid B against hydrogen peroxide‑induced apoptosis of human umbilical vein endothelial cells and underlying mechanisms.
  55. Muscular apoptosis but not oxidative stress increases with old age in a long-lived diver, the Weddell seal.
  56. A Nutraceutical Strategy to Slowing Down the Progression of Cone Death in an Animal Model of Retinitis Pigmentosa.
  57. TIGAR suppresses seizures induced by kainic acid through inhibiting oxidative stress and neuronal apoptosis.
  58. An integrated PKD1-dependent signaling network amplifies IRE1 pro-survival signaling.
  59. Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis.
  60. Long-term treatment with 3,4-methylenedioxymethamphetamine caused retina damage in C57BL/6 mice.
  61. Acupuncture attenuates cognitive impairment, oxidative stress and NF-κB activation in cerebral multi-infarct rats.
  62. The Beneficial Roles of Metformin on the Brain with Cerebral Ischaemia/Reperfusion Injury.
  63. Small-Molecule-Targeting Hairpin Loop of hTERT Promoter G-Quadruplex Induces Cancer Cell Death.
  1. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1): 2213-2220
    Anagliptin protects neuronal cells against endogenous amyloid β (Aβ)-induced cytotoxicity and apoptosis.
    Zhenbo Chen, Shanwei Tao, Xiaohui Li, Xudong Zeng, Mirong Zhang, Qinghe Yao.
      Excessive generation and accumulation of amyloid-β (Aβ) fragments by familial mutations of amyloid precursor protein (APP) and presenilin 1 (PS1) play a key role in causing oxidative stress, mitochondrial abnormalities and neuronal apoptosis in Alzheimer's disease (AD). Anagliptin, a novel DPP-4 inhibitor, is a clinical drug for the management of type II diabetes approved for use in 2012. Little on the pharmacological function of anagliptin against Aβ-induced cytotoxicity in neuronal cells is known. Here, we examined the protective capacities of anagliptin against cytotoxicity in N2a neuronal cells overexpressing APP Swedish mutant and PS1 exon 9 deletion mutant (N2a/Swe.D9). Our results demonstrate that anagliptin reduced the production of ROS and the expression of NADPH oxidase 4 (NOX-4) in N2a/Swe.D9 cells. We also reported that anagliptin activates the antioxidant system by increasing the level of reduced glutathione (GSH) and glutathione peroxidase (GPx) activity. Notably, anagliptin is able to improve mitochondrial function by elevating mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) production. Additionally, our results demonstrate that anagliptin decreased the vulnerability of cells to hydrogen peroxide (H2O2)-induced secondary insult by increasing cell viability and reducing the secretion of lactate dehydrogenase (LDH) and high mobility group box 1 protein (HMGB-1). Importantly, we found that treatment with anagliptin suppressed the mitochondrial-dependent apoptosis pathway by preventing the translocation of cytochrome C, reducing cleavage of caspase-3, and the inhibiting expression of Bax. These results implicate that anagliptin may have potential as a therapeutic agent for AD treatment.
    Keywords:  Alzheimer’s disease; amyloid-β; apoptosis; mitochondria; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1080/21691401.2019.1609979
  2. Toxicol Res (Camb). 2019 May 01. 8(3): 381-394
    Di-(2-ethylhexyl) phthalate (DEHP) inhibits steroidogenesis and induces mitochondria-ROS mediated apoptosis in rat ovarian granulosa cells.
    Anima Tripathi, Vivek Pandey, Alakh N Sahu, Alok Singh, Pawan K Dubey.
      Increased oxidative stress (OS) due to ubiquitous exposure to di-(2-ethylhexyl) phthalate (DEHP) can affect the quality of oocytes by inducing apoptosis and hampering granulosa cell mediated steroidogenesis. This study was carried out to investigate whether DEHP induced OS affects steroidogenesis and induces apoptosis in rat ovarian granulosa cells. OS was induced by exposing granulosa cells to various concentrations of DEHP (0.0, 100, 200, 400 and 800 μM) for 72 h in vitro. Intracellular reactive oxygen species (ROS), oxidative stress (OS), mitochondrial membrane potential, cellular senescence, apoptosis, steroid hormones (estradiol & progesterone) and gene expression were analyzed. The results showed that an effective dose of DEHP (400 μg) significantly increased OS by elevating the ROS level, mitochondrial membrane potential, and β-galactosidase activity with higher mRNA expression levels of apoptotic genes (Bax, cytochrome-c and caspase3) and a lower level of an anti-apoptotic gene (Bcl2) as compared to the control. Further, DEHP significantly (P > 0.05) decreased the level of steroid hormones (estradiol and progesterone) in a conditioned medium and this effect was reciprocated with a lower expression (P > 0.05) of steroidogenic responsive genes (Cyp11a1, Cyp19A1, Star, ERβ1) in treated granulosa cells. Furthermore, co-treatment with N-Acetyl-Cysteine (NAC) rescues the effects of DEHP on OS, ROS, β-galactosidase levels and gene expression activities. Altogether, these results suggest that DEHP induces oxidative stress via ROS generation and inhibits steroid synthesis via modulating steroidogenic responsive genes, which leads to the induction of apoptosis through the activation of Bax/Bcl-2-cytochrome-c and the caspase-3-mediated mitochondrial apoptotic pathway in rat granulosa cells.
    DOI:  https://doi.org/10.1039/c8tx00263k
  3. Toxicol Mech Methods. 2019 Jun 07. 1-24
    Acetamiprid, a neonicotinoid insecticide, induced cytotoxicity and genotoxicity in PC12 cells.
    Emna Annabi, Intidhar Ben Salem, Salwa Abid-Essefi.
      Neonicotinoids are a group of pesticides widely used in agriculture and home. Among those pesticides, Acetamiprid (ACM) is a broad-spectrum insecticide used for the protection of vegetables and fruits from pest. The extensive use of this pesticide had led to contamination of environment including soil, water, as well as food products. However, there are few information's regarding the molecular mechanism by which ACM exerts its cytotoxic and genotoxic effects. The aim of the present study was to investigate the toxic effects of ACM in PC12 cells. We demonstrated that ACM significantly decreased cell viability as assessed by the MTT assay. We also shown that ACM induced reactive oxygen species (ROS) generation followed by lipid peroxidation as evidenced by an increase in the MDA levels. The increase in cell death was accompanied by a reduction in the mitochondrial membrane potential. Besides, pretreatment with Z-VAD-FMK, a general caspases inhibitor, decreased significantly the ACM-induced cell death. Our results also indicate that ACM induced a concentration-dependent increase in DNA damage as evident by the comet assay. These data indicate that ACM produces cytotoxicity and DNA damage in mammalian cells. Highlights ACM is cytotoxic towards rat pheochromocytoma adrenal medulla cells (PC12) ACM induces ROS generation, lipid peroxidation and DNA fragmentation ACM induces caspase-dependent apoptosis in PC12 cells.
    Keywords:  Acetamiprid; DNA fragmentation; PC12; oxidative stress
    DOI:  https://doi.org/10.1080/15376516.2019.1624907
  4. Environ Toxicol. 2019 Jun 03.
    Ethyl acetate extract of Nepenthes adrianii x clipeata induces antiproliferation, apoptosis, and DNA damage against oral cancer cells through oxidative stress.
    Jen-Yang Tang, Sheng-Yao Peng, Yuan-Bin Cheng, Chun-Lin Wang, Ammad Ahmad Farooqi, Tzu-Jung Yu, Ming-Feng Hou, Sheng-Chieh Wang, Chia-Hung Yen, Leong-Perng Chan, Fu Ou-Yang, Hsueh-Wei Chang.
      Nepenthes plants are regarded as a kind of Traditional Chinese Medicine for several diseases but its anticancer activity remain unclear. The subject of this study is to evaluate the antiproliferation effects on oral cancer cells by Nepenthes plants using ethyl acetate extract of Nepenthes adrianii x clipeata (EANA). Cell viability was detected using MTS assay. Its detailed mechanisms including cell cycle, apoptosis, oxidative stress, and DNA damage were explored by flow cytometry or western blotting. For 24 hours EANA treatment, five kinds of oral cancer cells (CAL 27, Ca9-22, OECM-1, HSC-3, and SCC9) show IC50 values of cell viability ranging from 8 to 17 μg/mL but the viability of normal oral cells (HGF-1) remains over 80%. Subsequently, CAL 27 and Ca9-22 cells with high sensitivity to EANA were chosen to investigate the detailed mechanism. EANA displays the time course and concentration effects for inducing apoptosis based on flow cytometry (subG1 and annexin V analyses) and western blotting [cleaved poly (ADP-ribose) polymerase (c-PARP)]. Oxidative stress and DNA damage were induced by EANA treatments in oral cancer cells through reactive oxygen species (ROS), mitochondrial membrane potential disruption, mitochondrial superoxide, and γH2AX. All these changes of EANA treatments in oral cancer cells were reverted by the ROS scavenger N-acetylcysteine pretreatment. Therefore, EANA induces preferential killing, apoptosis, and DNA damage against oral cancer cells through oxidative stress.
    Keywords:  DNA damage; Nepenthes plants; apoptosis; ethyl acetate extract; oxidative stress
    DOI:  https://doi.org/10.1002/tox.22748
  5. Int J Mol Med. 2019 May 24.
    Effects of transcription factor EB on oxidative stress and apoptosis induced by high glucose in podocytes.
    Yingli Kang, Ying Li, Tao Zhang, Yanqing Chi, Maodong Liu.
      The aim of the present study was to investigate the effects of transcription factor EB (TFEB) overexpression on oxidative stress, mitochondrial function and apoptosis in podocytes induced with high glucose. High glucose‑induced time‑dependent changes in TFEB expression were identified and nuclear translocation of TFEB was observed in podocytes. Overexpression of TFEB markedly reduced high glucose‑induced oxidative stress in podocytes, and increased the expression of superoxide dismutase 2 and heme oxygenase 1 antioxidant enzymes. It was further observed that TFEB overexpression could partially restore the expression of peroxisome proliferator‑activated receptor‑γ coactivator‑1α, transcription factor A, mitochondrial, and cytochrome c oxidase subunit 4, thereby enhancing mitochondrial biosynthesis. Furthermore, overexpression of TFEB reduced mitochondrial swelling and fragmentation, restored mitochondrial membrane potential, and contributed to the restoration of mitochondrial function. By overexpressing TFEB, it was revealed that TFEB increased the ratios of phosphorylated (p)‑Akt/Akt and p‑Bad/Bad, and the expression of downstream Bcl‑xl, and reduced the ratio of Bax/Bcl‑2 and the expression of cleaved‑caspase‑3 compared with high glucose‑treatment. Furthermore, when the Akt phosphorylation inhibitor Ly294002 was added, the improvement by TFEB to high glucose‑induced apoptosis was significantly reduced. These findings suggest that overexpressing TFEB could reduce the production of reactive oxygen species in podocytes in a high glucose environment, relieve oxidative stress, promote mitochondrial biogenesis and renewal functions, and reduce high glucose‑induced podocyte apoptosis by activating the Akt/Bad pathway.
    DOI:  https://doi.org/10.3892/ijmm.2019.4209
  6. Mol Nutr Food Res. 2019 Jun 05. e1801432
    Attenuation of Palmitic Acid-Induced Lipotoxicity by Chlorogenic Acid Through Activation of SIRT1 in Hepatocytes.
    Lele Yang, Jinchao Wei, Feiya Sheng, Peng Li.
      SCOPE: Saturated free fatty acids (FFAs) induce hepatocyte lipotoxicity, wherein oxidative stress-associated mitochondrial dysfunction is mechanistically involved. Chlorogenic acid (CGA), a potent antioxidant and anti-inflammatory compound, protects against high-fat diet-induced oxidative stress and mitochondrial dysfunction in liver. This study investigated whether CGA protected against FFAs-induced hepatocyte lipotoxicity via regulation of mitochondrial fission/fusion and elucidated its underlying mechanisms.METHODS AND RESULTS: AML12 cell, a non-transformed hepatocyte cell line, was treated with palmitate. Here, we showed that CGA prevented palmitate-induced lipotoxicity by activation of SIRT1 regulated mitochondrial morphology. CGA treatment mitigated oxidative stress and mitochondrial dysfunction, as evidenced by a decrease in reactive oxygen species (ROS) production, an increase in mitochondrial mass and mitochondrial membrane potential. CGA also significantly decreased Bax expression and thereby reduced mitochondria-mediated caspase-dependent apoptosis. Mechanistically, CGA attenuated ROS induced mitochondrial fragmentation by inhibiting Drp1 and enhancing Mfn2 expression. In contrast, the inhibitory effects of CGA on the generation of mitochondrial ROS and Drp1 were blocked by siRNA knockdown of SIRT1.
    CONCLUSION: Collectively, these findings show that supplementation with CGA protected hepatocytes from FFAs-induced lipotoxicity through activation of SIRT1, which reversed the oxidative stress and dysfunction of mitochondrial biogenesis directly. This article is protected by copyright. All rights reserved.
    Keywords:  Chlorogenic acid; lipotoxicity; mitochondrial dysfunction; mitochondrial fission/fusion; saturated free fatty acids
    DOI:  https://doi.org/10.1002/mnfr.201801432
  7. Pestic Biochem Physiol. 2019 Jun;pii: S0048-3575(18)30630-8. [Epub ahead of print]157 169-177
    Neochamaejasmin A extracted from Stellera chamaejasme L. induces apoptosis involving mitochondrial dysfunction and oxidative stress in Sf9 cells.
    Yuanhang Ren, Yangping Mu, Ying Yue, Hong Jin, Ke Tao, Taiping Hou.
      To explore the toxicity mechanisms of neochamaejasmin A (NCA), extracted from Stellera chamaejasme L., we first evaluated its cytotoxicity on the Spodoptera frugiperda (Sf9) cell line. The results confirmed that NCA inhibited Sf9 cell survival in both a dose- and time-dependent manner. Then, intracellular biochemical assays showed that NCA induced apoptosis in Sf9 cells. Evidence of apoptosis was confirmed by morphological changes and the activation of caspases-3/9. We also observed that NCA induced apoptosis via mitochondrial-dependent intrinsic apoptotic pathway by upregulating cytochrome c and proapoptotic protein (Bax) and downregulating the mitochondrial membrane potential (MMP) and antiapoptotic protein (Bcl-2). Moreover, we found a dose-dependent increase in reactive oxygen species (ROS), accumulation of lipid peroxidation product and an inactivation of the antioxidant enzymes in treated cells. Additionally, the cleavage of PARP and G2/M arrest were also detected in Sf9 cells exposed to NCA. These findings provide critical information that NCA effectively induced apoptosis in Sf9 cells through mitochondrial pathways.
    Keywords:  Apoptosis; Mitochondrial dysfunction; Neochamaejasmin A; Oxidative stress; Sf9 cells; Stellera chamaejasme L.
    DOI:  https://doi.org/10.1016/j.pestbp.2019.03.025
  8. J Periodontol. 2019 Jun 04.
    Severe Periodontitis May Influence Cementum and Dental Pulp Through Inflammation, Oxidative Stress and Apoptosis.
    Xiangchun Li, Liang Hu, Linsha Ma, Shimin Chang, Weili Wang, Yuanyong Feng, Yipu Xu, Jinchao Hu, Chunmei Zhang, Songlin Wang.
      BACKGROUND: The relationship between chronic periodontitis and pulpal/cemental changes is seldom reported. This study aimed to report on the microstructural changes of cementum and histopathological features of the dental pulp in teeth with severe chronic periodontitis.METHODS: Eighty molar teeth with severe chronic periodontitis, and 50 extracted third molars (as normal controls) were collected. The microstructure of cementum was evaluated by scanning electron microscopy, and the pulp was stained with hematoxylin and eosin. Interleukin (IL)-17 and IL-1β levels were examined by immunohistochemistry (IHC)/western blotting. Reactive oxygen species (ROS) and superoxide dismutase (SOD1) levels were also checked. Caspase 3 expression and terminal-deoxynucleoitidyl transferase mediated nick end labeling staining were used as apoptotic indices, and LC3B and P62 were detected to demonstrate the level of autophagy.
    RESULTS: The surface of cementum showed rhagades; the dental pulp was inflamed and under oxidative stress. IL-17 and IL-1β levels were increased in the pulp of teeth with periodontitis. ROS and apoptosis levels were higher than in normal dental pulp, while SOD 1 level was reduced. Intriguingly, autophagy markers LC3B and P62 were up-regulated in the pulp obtained from teeth with periodontitis.
    CONCLUSION: Severe chronic periodontitis influenced the microstructure of both cementum and dental pulp. The dental pulp collected from teeth with periodontitis was inflamed, under oxidative stress, and presented increased levels of apoptosis and autophagy relative to normal dental pulp. This article is protected by copyright. All rights reserved.
    Keywords:  apoptosis; cementum; dental pulp; inflammation; oxidative stress; periodontitis
    DOI:  https://doi.org/10.1002/JPER.18-0604
  9. Int J Mol Med. 2019 May 29.
    Tetramethylpyrazine protects retinal ganglion cells against H2O2‑induced damage via the microRNA‑182/mitochondrial pathway.
    Xinmin Li, Qiuli Wang, Yanfan Ren, Xiaomin Wang, Huaxu Cheng, Hua Yang, Baojun Wang.
      Glaucoma is the leading cause of irreversible blindness worldwide; the apoptosis of the retinal ganglion cells (RGCs) is a hallmark of glaucoma. Tetramethylpyrazine (TMP) is the main active component of Ligusticum wallichii Franchat, and has been demonstrated to improve a variety of injuries through its antioxidative and antiapoptotic properties. However, these effects of TMP on glaucoma have not been studied. The present study aimed to investigate the potential role of TMP in glaucoma and to elucidate its possible mechanisms responsible for these effects. An in vitro model was generated, in which primary RGCs (PRGCs) were treated with H2O2. Our study revealed that TMP protected against H2O2‑induced injury to PRGCs, as evidenced by enhanced cell viability, reduced caspase 3 activity and decreased cell apoptosis. We also reported that TMP treatment inhibited reactive oxygen species (ROS) production and malondialdehyde levels, but upregulated the antioxidative enzyme superoxide dismutase. In particular, TMP significantly increased the expression of microRNA‑182‑5p (miR‑182) in H2O2‑treated PRGCs, which was selected as the target miRNA for further research. In addition, our findings suggested that the protective effects of TMP on H2O2‑induced injury were attenuated by knockdown of miR‑182. The results of a luciferase reporter assay demonstrated that Bcl‑2 interacting protein 3 (BNIP3), an effector of mitochondria‑mediated apoptosis, was a direct target of miR‑182. In addition, TMP treatment significantly decreased the expression of BNIP3, Bax, cleaved‑caspase‑3 and cleaved‑poly(ADP‑ribose)polymerase, but increased that of Bcl‑2. Also, TMP treatment decreased the release of cytochrome c from mitochondria and improved mitochondrial membrane potential in H2O2‑treated RGCs. Of note, the inhibitory effects of TMP on the mitochondrial apoptotic pathway were suggested to be reversed by knockdown of miR‑182. Collectively, our findings provide novel evidence that TMP protects PRGCs against H2O2‑induced damage through suppressing apoptosis and oxidative stress via the miR‑182/mitochondrial apoptotic pathway.
    DOI:  https://doi.org/10.3892/ijmm.2019.4214
  10. FEBS Open Bio. 2019 Jun 03.
    S-allyl-L-cysteine (SAC) protects hepatocytes from alcohol-induced apoptosis.
    Peng Chen, Mingdao Hu, Feng Liu, Henghai Yu, Chen Chen.
      Hepatocyte apoptosis is frequently observed in alcohol-related liver disease (ARLD), which ranks among the 30 leading causes of death worldwide. In the current study, we explored the impact of S-allyl-L-cysteine (SAC), an organosulfur component of garlic, on hepatocyte apoptosis induced by alcohol. Rat liver (BRL-3A) cells were challenged by ethanol with or without SAC treatment. Cell death/viability, reactive oxygen species (ROS) generation, mitochondrial Cytochrome C release and Caspase 3 activity were then examined. We found that ethanol remarkably induced apoptosis of hepatocytes, while SAC treatment rescued ethanol-induced hepatocyte injury, as demonstrated by Cell Counting Kit-8 (CCK8) assay, TUNEL assay and annexin V/PI staining assay. Ethanol evoked ROS generation in BRL-3A cells, and this was abated by SAC pretreatment, as indicated by 2',7'-dichlorofluorescin diacetate (DCFDA) staining assay. Moreover, ethanol suppressed cellular anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) expression, increased pro-apoptotic protein Bcl-2-associated X protein (Bax) expression, induced mitochondrial Cytochrome C release, and activated the Caspase 3-dependent apoptosis pathway in BRL-3A cells. SAC was sufficient to abolish all these changes induced by ethanol, thereby revealing the molecular mechanisms underlying its protective effects. In conclusion, SAC protects hepatocytes from ethanol-induced apoptosis, and may be suitable for use as a novel anti-apoptotic agent for treating ARLD.
    Keywords:  S-allyl-L-cysteine; alcohol; apoptosis; hepatocyte; oxidative stress
    DOI:  https://doi.org/10.1002/2211-5463.12684
  11. Aging (Albany NY). 2019 Jun 03.
    N-acetyl cysteine, inulin and the two as a combined therapy ameliorate cognitive decline in testosterone-deprived rats.
    Titikorn Chunchai, Puntarik Keawtep, Apiwan Arinno, Napatsorn Saiyasit, Dillon Prus, Nattayaporn Apaijai, Wasana Pratchayasakul, Nipon Chattipakorn, Siriporn C Chattipakorn.
      Our previous studies reported that testosterone-deprived rats developed cognitive decline as a result of increased brain oxidative stress, microglia hyperactivity, and hippocampal dysplasticity. In addition, gut dysbiosis occurred in these rats. Previous studies demonstrated that n-acetyl cysteine (NAC) and a prebiotic (inulin) improved cognition in several pathological conditions. However, its effects on cognition in the testosterone-deprived condition have never been investigated. This study hypothesized that the administration of NAC, inulin, and a combined therapy improved cognition in castrated rats. Here we report that metabolic disturbance was not observed in the ORX rats, but gut dysbiosis was found in these rats. ORX rats developed blood-brain-barrier (BBB) breakdown, and increased brain oxidative stress as indicated by increased hippocampal production of reactive oxygen species (ROS) and an increase in brain malondialdehyde level. ORX rats also demonstrated glia hyperactivation, resulting in hippocampal apoptosis, hippocampal dysplasticity, and cognitive decline. All treatments equally ameliorated cognitive decline by improving gut dysbiosis, alleviating BBB dysfunction, decreasing hippocampal ROS production, decreasing hippocampal apoptosis, and reducing microglia and astrocyte activity. These findings suggest that NAC, inulin, and the combined therapy ameliorated the deleterious effects on the brain in castrated male rats similar to those treated with testosterone.
    Keywords:  apoptosis; cognition; glia; gut dysbiosis; hippocampal plasticity; testosterone deprivation
    DOI:  https://doi.org/10.18632/aging.101989
  12. DNA Cell Biol. 2019 Jun 06.
    Ethyl Acetate Extract of Nepenthes ventricosa x maxima Exerts Preferential Killing to Oral Cancer Cells.
    Jen-Yang Tang, Li-Jie Li, Fu Ou-Yang, Chun-Lin Wang, Chih-Wen Shu, Kuang-Han Wu, Hui-Ru Wang, Chia-Hung Yen, Yuan-Bin Cheng, Hsueh-Wei Chang.
      Nepenthes plants are a folk medicine in many Southeast Asia countries for curing diseases but its anticancer effect is rarely investigated. The objectives of this study were to investigate the antioral cancer ability of ethyl acetate extract of Nepenthes ventricosa x maxima (EANV). The preferential killing ability of EANV was determined by MTS-based cell viability assays. The bioactive effects were further screened by flow cytometry for apoptosis, oxidative stress, and DNA damage. At 24 h treatment, EANV dose dependently decreased six types of oral cancer cells, but the normal oral cells (HGF-1) kept a 90% viability. EANV also showed chronic antiproliferative effects and inhibited 3D sphere formation ability of oral cancer cells. Ca9-22 and CAL 27 oral cancer cells with high response to EANV increased subG1 populations and enhanced Annexin V- and pancaspase-detected apoptosis in these cells. EANV also induced the generation of reactive oxygen species (ROS) and mitochondrial superoxide and the dysfunction of mitochondrial membrane potential. Moreover, the oxidative DNA damage level such as 8-oxo-2'deoxyguanosine was increased in EANV-treated oral cancer cells. Taken together, EANV has a preferential killing effect against oral cancer cells associated with oxidative stress, apoptosis, and DNA damage, suggesting EANV as a potential antioral cancer agent.
    Keywords:  ; apoptosis; ethyl acetate; oxidative stress; preferential killing
    DOI:  https://doi.org/10.1089/dna.2018.4436
  13. Chem Biol Interact. 2019 May 30. pii: S0009-2797(19)30281-9. [Epub ahead of print]
    Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis.
    Xinliang Chen, Wei Wei, Yazhen Li, Jingbo Huang, Xinxin Ci.
      Although cisplatin is an effective anticancer drug, its clinical application is limited due to various side effects, especially nephrotoxicity. In this study, we investigated the protective effects and possible mechanisms of hesperetin on cisplatin-induced kidney damage. In vitro, hesperetin significantly attenuated oxidative stress-induced apoptosis by reducing ROS levels in cisplatin-treated HK-2 cells. Simultaneously, hesperetin activated the Nrf2 signaling pathway and regulated its downstream genes, including NQO1 and HO-1. In vivo, hesperetin could significantly attenuate cisplatin-induced nephrotoxicity, blood urea nitrogen (BUN) and serum creatinine (SCr). Furthermore, hesperetin clarifies cisplatin-induced oxidative stress by reducing MDA/MPO levels and increasing SOD/GSH levels. In addition, from the histopathological analysis of the kidney, hesperetin significantly reduced the nephrotoxicity caused by cisplatin compared with the cisplatin group. Moreover, western blotting of renal tissue revealed that hesperetin activates Nrf2 in a dose-dependent manner, attenuates the MAPK signaling pathway against inflammation, and inhibits the expression of apoptotic proteins to protect kidneys from AKI caused by cisplatin. Altogether, these findings suggest that hesperetin may be a potential protectant against cisplatin-induced nephrotoxicity.
    Keywords:  Acute kidney injury; Apoptosis; Cisplatin; Hesperetin; Inflammation; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cbi.2019.05.040
  14. J Biochem Mol Toxicol. 2019 Jun 03. e22352
    Protective effects of cynaroside on oxidative stress in retinal pigment epithelial cells.
    Haoli Yu, Junyan Li, Xiaolong Hu, Jiahao Feng, Hao Wang, Fei Xiong.
      Cynaroside is a flavonoid compound proved to possess antioxidant activity, but its protective effect on age-related macular degeneration still remains unclear. In this study, the protective effects of cynaroside on oxidative stress and apoptosis in retinal pigment epithelial (RPE) cells induced by hydrogen peroxide (H2 O2 ) were investigated. Results showed that cynaroside effectively attenuated the decrease of cell activity induced by H2 O2 . The total reactive oxygen species can be remitted by decreasing malondialdehyde level, as well as increasing glutathione level, and superoxide dismutase and catalase activities. In addition, Western blot analysis indicated that cynaroside protected ARPE-19 cells from apoptosis through downregulation of caspase-3 protein activation which was controlled by the upstream proteins Bcl-2 and Bax. It was finally proved that cynaroside could enhance the antioxidant and antiapoptotic ability in ARPE-19 cells by promoting the expression of p-Akt.
    Keywords:  age-related macular degeneration; cynaroside; oxidative stress; p-Akt; retinal pigment epithelial cells
    DOI:  https://doi.org/10.1002/jbt.22352
  15. Toxicology. 2019 May 31. pii: S0300-483X(19)30166-0. [Epub ahead of print]
    l-arginine Alleviates Doxorubicin-Induced Endothelium-Dependent Dysfunction by Promoting Nitric Oxide Generation and Inhibiting Apoptosis.
    Xunan Li, Jie Gu, Yunlong Zhang, Siting Feng, Xin Huang, Yinong Jiang, Yunlong Xia, Yang Liu, Xiaolei Yang.
      BACKGROUND/AIMS: Patients with doxorubicin (Dox) treatment have a high risk of developing vascular toxicity with an unknown mechanism. l-arginine is a substrate for nitric oxide (NO). The decreased level of arginine-NO metabolite in Dox-treated cancer patients was associated with increased level of vascular damage, which promoted us to investigate the mechanism of Dox-induced vascular dysfunction and verify whether l-arginine supplement could alleviate this vasculotoxic effect.METHOD: Within a mouse model of Dox injection (5 mg/kg i.p., 2 or 4 weeks), we measured vascular relaxation, blood pressure, vascular NO generation, apoptosis, and oxidative stress. We tested the efficacy of l-arginine (1.5 mg/g/day, 4 weeks) on Dox-induced vascular relaxation, blood pressure, vascular NO generation, apoptosis, as well as oxidative stress.
    RESULTS: Dox induced endothelium-dependent vascular dysfunction, which was associated with increased reactive oxidative stress (ROS) production and reduced NO generation in the vessel. ROS was required for Dox-induced apoptosis of both smooth muscle cells and endothelial cells. Dox treatment in mice increased blood pressure, but had no effect on vascular inflammation and fibrosis. L-aringine restored Dox-induced vascular dysfunction via enhancing vascular NO production and alleviating ROS-mediated apoptosis.
    CONCLUSION: We for the first time demonstrated l-arginine was effectively in suppressing Dox-induced vascular dysfunction, by attenuating vascular NO release and apoptosis. Our results provide a therapeutic target or a circulating marker for assessing vascular dysfunction which response to Dox treatment, and advance our understanding of the mechanisms of Dox-induced vascular dysfunction.
    Keywords:  Doxorubicin; apoptosis; l-arginine; reactive oxygen species; vascular toxicity
    DOI:  https://doi.org/10.1016/j.tox.2019.05.016
  16. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1): 2188-2195
    Astragalus polysaccharide alleviates H2O2-triggered oxidative injury in human umbilical vein endothelial cells via promoting KLF2.
    Dongtao Li, Yan Liu, Rong Xu, Xin Jia, Xing Li, Cong Huo, Xiaoming Wang.
      The damage of vascular endothelial cells has become an indispensable factor in the occurrence and advancement of cardiovascular diseases. In the current study, we investigated the effect of Astragalus Polysacharin (APS) on H2O2-evoked oxidative injury in HUVECs. HUVECs cells were treated by H2O2 to induce oxidative damage. Cells viability, apoptosis and reactive oxygen species (ROS) level were detected through CCK8 assay and flow cytometry. The cell growth-related proteins and heme oxygenase-1(HO-1) and KLF2 expression were evaluated via Western blot assay. The functions of KLF2 in APS and H2O2 co-disposed HUVECs were explored after si-KLF2 transfection. MEK/ERK pathway was finally measured through Western blot. We found that H2O2 stimulation-evoked HUVECs oxidative damage meanwhile impeded HO-1 expression. APS treatment effectively suppressed H2O2-induced oxidative injury in HUVECs. KLF2 and Nrf2 expression were elevated by APS and KLF2 repression abolished the protective action of APS in H2O2-triggered cell injury. MEK/ERK pathway was activated by APS treatment. Furthermore, the MEK/ERK pathway inhibitor weakened the promoting effect of APS on the expression of KLF2. In conclusion, our study reveals that APS alleviates H2O2-triggered oxidative injury in HUVECs via elevating the expression of KLF2 via the MEK/ERK pathway.
    Keywords:  Astragalus polysaccharide; HO; KLF2; MEK/ERK; vascular dysfunction
    DOI:  https://doi.org/10.1080/21691401.2019.1621886
  17. Int J Mol Med. 2019 Jun 05.
    Hydroxysafflor Yellow A mitigated myocardial ischemia/reperfusion injury by inhibiting the activation of the JAK2/STAT1 pathway.
    Donglai Zhou, Tingting Ding, Bin Ni, Yunyan Jing, Shanxin Liu.
      Hydroxysafflor Yellow A (HSYA) may reduce ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms remain unclear. The present study explored the effect and the mechanisms of HSYA on myocardial injury in vivo and in vitro. Myocardial infarct size was assessed by Evans blue/2,3,5‑triphenyltetrazoliumchloride staining. Levels of cardiac troponin I (cTnI), interleukin‑6 (IL‑6), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured using commercial kits. Alteration of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation was determined by fluorescent signals. Apoptosis was detected by terminal deoxynucleotidyl‑transferase‑mediated dUTP nick‑end labeling staining, flow cytometry assay and caspase‑3 activity. Expression levels of the apoptosis‑associated proteins were detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. In vivo, animals treated with HSYA presented less severe myocardial injury and decreased janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) activity, improved antioxidant capacity and decreased apoptosis. In vitro, compared with the hypoxia (H)/reoxygenation (R) + HSYA group, AG490 and S1491 treatment decreased the releases of cTnI, IL‑6 and LDH and enhanced the resistance to oxidative stress by maintaining MMP and decreasing ROS generation. In addition, AG490 and S1491 were also identified to alleviate the H/R‑induced apoptosis by inhibiting caspase 3 activity and modulating the expression levels of cleaved caspase‑3, tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein. These data suggested that inactivation of the JAK2/STAT1 pathway strengthened the HSYA‑induced protective effect in H/R‑induced myocardial injury. In conclusion, the treatment of HSYA was effective in decreasing IR‑induced myocardial injury, and this may be largely dependent on the JAK2/STAT1 pathway. Therefore, the present study provided a potential strategy to prevent myocardial I/R injury.
    DOI:  https://doi.org/10.3892/ijmm.2019.4230
  18. J Environ Manage. 2019 May 30. pii: S0301-4797(19)30731-5. [Epub ahead of print]245 216-222
    Multi-generational effects and variations of stress response by hexabromocyclododecane (HBCD) exposure in the nematode Caenorhabditis elegans.
    Haibo Chen, Shu Guo, Hui Li, Dong Zhou, Xue Cao, Chen Wang, Yongdi Liu, Mingdeng Xiang, Liangzhong Li, Yunjiang Yu.
      In order to understand multi-generational effects and changes of stress response by hexabromocyclododecane (HBCD) exposure, the animal model Caenorhabditis elegans was chosen for toxicity study. Multiple endpoints, including the physiological levels (growth, reproduction, and locomotion behaviors), stress-related gene expressions, reactive oxygen species (ROS) production and degree of cell apoptosis, were evaluated on exposed nematodes and their progeny. Prolonged exposure to HBCD at concentrations of 2 nM-200 nM caused adverse physiological effects in the parental generation (F0), and these effects were also observed in the offspring under HBCD-free conditions (F1). HBCD-induced toxicities could be transferred from parent to offspring. The integrated gene expressions profiles showed that exposure to HBCD at concentrations of 20-200 nM resulted in obvious changes in stress-related gene expressions, which were more increased in F0 generation than in F1 generation. The increased expressions were pronounced in several genes related to oxidative stress and cell apoptosis, e.g., hsp-16.2, hsp-16.48, sod-1, sod-3 and cep-1 genes. Exposure to 200 nM of HBCD could significantly increase ROS production and degree of cell apoptosis in the F0 and F1 generations. Therefore, it was speculated that HBCD exposure induced oxidative stress and cell apoptosis, which resulted in the adverse physiological effects. This finding is helpful for understanding the multi-generational effects and evaluating the potential risk of HBCD.
    Keywords:  Caenorhabditis elegans; Cell apoptosis; Hexabromocyclododecane; Multi-generational effect; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jenvman.2019.05.103
  19. Chem Biol Interact. 2019 May 31. pii: S0009-2797(19)30344-8. [Epub ahead of print]
    Notoginsenoside R1 protects human renal proximal tubular epithelial cells from lipopolysaccharide-stimulated inflammatory damage by up-regulation of miR-26a.
    Jinrong Liu, Cun Hou, Xiaoyuan Chen, Lin Wu, Xinyue Wang.
      BACKGROUND: Notoginsenoside R1 (NGR1) is the main saponin isolated from the roots of Panax notoginseng (Burk.) F.H. Chen (Araliaceae). This study explored the protective effects of NGR1 on human renal proximal tubular epithelial cell inflammatory damage caused by lipopolysaccharide (LPS), as well as possible internal molecular mechanisms.METHODS: Cell viability and apoptosis were assessed using CCK-8 assay and Annexin V-FITC/PI Apoptosis Detection kit, respectively. Reactive oxygen species (ROS) level was tested using DCFH-DA staining. qRT-PCR was used to measure microRNA-26a (miR-26a), interleukin 1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) expressions. miRNA transfection was conducted to knock down miR-26a. The protein expression levels of key molecules related to cell apoptosis, inflammatory response and nuclear factor kappa B (NF-κB) pathway were detected using western blotting.
    RESULTS: LPS stimulation caused human renal proximal tubular epithelial cell viability reduction, apoptosis and inflammatory cytokines expression. NGR1 treatment protected human renal proximal tubular epithelial cells from LPS-caused viability reduction, ROS level elevation, apoptosis and inflammatory cytokines expression. Mechanistically, NGR1 enhanced miR-26a expression in LPS-treated human renal proximal tubular epithelial cells. Knockdown of miR-26a reversed the protective effect of NGR1 on LPS-treated cells. Besides, NGR1 inactivated NF-κB pathway in LPS-treated human renal proximal tubular epithelial cells via up-regulating miR-26a.
    CONCLUSION: NGR1 protected human renal proximal tubular epithelial cells from LPS-caused inflammatory damage at least partially via up-regulating miR-26a and then inactivating NF-κB pathway.
    Keywords:  Chronic kidney disease; Lipopolysaccharide; MicroRNA-26a; NF-κB pathway; Notoginsenoside R1; Renal proximal tubular epithelial cells
    DOI:  https://doi.org/10.1016/j.cbi.2019.05.053
  20. Mol Med Rep. 2019 Jun 06.
    Lipid storage droplet protein 5 reduces sodium palmitate‑induced lipotoxicity in human normal liver cells by regulating lipid metabolism‑related factors.
    Xueqiang Ma, Feiyong Cheng, Keyu Yuan, Kexiang Jiang, Tieming Zhu.
      Lipid storage droplet protein 5 (LSDP5) is specifically expressed in tissues with high oxidative metabolism such as liver and heart. The present study aimed to explored the role of LSDP5 in sodium palmitate‑induced lipotoxicity in LO2 normal human liver cells. LO2 cells were treated with various concentrations of sodium palmitate (25, 50, 75, 100, 125 and 150 µmol/l) for 12, 24 and 48 h, and cell viability was determined by Cell Counting Kit‑8. Subsequently, LO2 cells were exposed to 100 µmol/l sodium palmitate for 48 h to induce lipotoxicity (Model). Lipotoxicity Model LO2 cells were also transfected with pCMV5‑LSDP5 overexpression vector, and reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) and apoptotic rates were measured. The contents of non‑esterified fatty acid (NEFA), malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured. The expression levels of LSDP5, and apoptosis‑, mitochondrial‑, lipid metabolism‑related factors were detected using reverse transcription‑quantitative polymerase chain reaction and western blot assays. The results indicated that sodium palmitate exposure inhibited cell viability and induced lipotoxicity in LO2 cells. LSDP5 overexpression decreased ROS and apoptotic rates, and reduced NEFA and MDA content. LSDP5 transfection rescued the loss of MMP and elevated SOD content in lipotoxicity Model LO2 cells. In addition, LSDP5 upregulated the expression levels of B‑cell lymphoma‑2, acetyl‑CoA carboxylase1/2 and fatty acid synthase (Fas), whereas the expression levels of activated‑caspase‑3, Bcl‑2‑associated X protein, cytochrome c, cytochrome c oxidase subunits IV, carnitine palmitoyltransferase 1a and peroxisome proliferator‑activated receptors α levels were downregulated. LSDP5 may produce a protective effect on sodium palmitate‑induced lipotoxicity in LO2 cells by regulating lipid metabolism‑related factors.
    DOI:  https://doi.org/10.3892/mmr.2019.10360
  21. J Cell Physiol. 2019 Jun 07.
    Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway.
    Qiang Wang, Junnan Xu, Xiaoli Li, Zhijia Liu, Yong Han, Xiaoguang Xu, Xiubin Li, Yuzhe Tang, Yubao Liu, Tao Yu, Xiang Li.
      Mitochondrial fusion is linked to heart and liver ischemia-reperfusion (IR) insult. Unfortunately, there is no report to elucidate the detailed influence of mitochondrial fusion in renal IR injury. This study principally investigated the mechanism by which mitochondrial fusion protected kidney against IR injury. Our results indicated that sirtuin 3 (Sirt3) was inhibited after renal IR injury in vivo and in vitro. Overexpression of Sirt3 improved kidney function, modulated oxidative injury, repressed inflammatory damage, and reduced tubular epithelial cell apoptosis. The molecular investigation found that Sirt3 overexpression attenuated IR-induced mitochondrial damage in renal tubular epithelial cells, as evidenced by decreased reactive oxygen species production, increased antioxidants sustained mitochondrial membrane potential, and inactivated mitochondria-initiated death signaling. In addition, our information also illuminated that Sirt3 maintained mitochondrial homeostasis against IR injury by enhancing optic atrophy 1 (OPA1)-triggered fusion of mitochondrion. Inhibition of OPA1-induced fusion repressed Sirt3 overexpression-induced kidney protection, leading to mitochondrial dysfunction. Further, our study illustrated that OPA1-induced fusion could be affected through ERK; inhibition of ERK abolished the regulatory impacts of Sirt3 on OPA1 expression and mitochondrial fusion, leading to mitochondrial damage and tubular epithelial cell apoptosis. Altogether, our results suggest that renal IR injury is closely associated with Sirt3 downregulation and mitochondrial fusion inhibition. Regaining Sirt3 and/or activating mitochondrial fission by modifying the ERK-OPA1 cascade may represent new therapeutic modalities for renal IR injury.
    Keywords:  ERK-OPA1 signaling pathway; Sirt3; mitochondrial fusion; renal IR injury
    DOI:  https://doi.org/10.1002/jcp.28918
  22. J Toxicol Sci. 2019 ;44(6): 415-424
    Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells.
    Ji Soo Park, Yong Joo Park, Ha Ryong Kim, Kyu Hyuck Chung.
      Polyhexamethylene guanidine phosphate (PHMG-p) is an active ingredient of humidifier disinfectants and causes severe lung injury resulting in pulmonary fibrosis. Current evidence indicates that pulmonary fibrosis is initiated as a result of epithelial damage, which can lead to an inflammatory response and fibrotic cell infiltration; however, the toxic mechanism of PHMG-p on the epithelium is still unknown. In this study, the toxic response of PHMG-p on human lung epithelial cells was evaluated, and its mechanisms associated with reactive oxygen species (ROS), DNA damage, and its relationship with p53 activation were investigated. The toxic responses of epithelial cells were assessed by flow cytometry analysis and western blot analysis. The results revealed that PHMG-p induced G1/S arrest and apoptosis in A549 cells. Interestingly, p53 was activated by PHMG-p treatment and p53 knockdown suppressed PHMG-p-induced apoptosis and cell cycle arrest. PHMG-p promoted ROS generation and consequently increased the expression of DNA damage markers such as ATM and H2AX phosphorylation. The antioxidant N-acetylcysteine reduced the expression of phosphorylated ATM and H2AX, and the ATM inhibitor, caffeine, inhibited p53 activation. Taken together, our results demonstrate that PHMG-p triggered G1/S arrest and apoptosis through the ROS/ATM/p53 pathway in lung epithelial cells.
    Keywords:  Apoptosis; Cell cycle arrest; DNA damage; Polyhexamethylene guanidine phosphate; Reactive oxygen species; p53
    DOI:  https://doi.org/10.2131/jts.44.415
  23. Front Oncol. 2019 ;9 387
    Triptolide Induces Glioma Cell Autophagy and Apoptosis via Upregulating the ROS/JNK and Downregulating the Akt/mTOR Signaling Pathways.
    Xihong Liu, Peiyuan Zhao, Xiujuan Wang, Lei Wang, Yingjun Zhu, Wei Gao.
      Apoptosis and autophagy are the two prominent forms of developmental cell death, and researches have shown that crosstalk exists between these two processes. A prior study demonstrated that triptolide inhibited the proliferation of malignant glioma cells. However, whether apoptosis and autophagy participate in the inhibitory effect of triptolide in glioma cells has not been clarified. In the present study, we demonstrated that triptolide potently inhibited the growth of glioma cells by inducing cell cycle arrest at the G2/M phase. Additionally, the treatment with triptolide induced apoptosis and autophagy in various glioma cell lines. Triptolide-induced autophagy may have tumor-supporting effects. Autophagy and apoptosis could cross-inhibit each other in glioma cells treated with triptolide. Moreover, we found that triptolide induced ROS production and JNK activation and inhibited the activity of Akt and mTOR. Finally, we demonstrated that triptolide suppressed tumor growth in an orthotopic xenograft glioma model. Collectively, these data indicated that triptolide induced G2/M phase arrest, apoptosis, and autophagy via activating the ROS/JNK and blocking the Akt/mTOR signaling pathways in glioma cells. Triptolide may be a potential anti-tumor drug targeting gliomas.
    Keywords:  LC3; ROS; apoptosis; autophagy; triptolide
    DOI:  https://doi.org/10.3389/fonc.2019.00387
  24. Front Pharmacol. 2019 ;10 517
    METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway.
    Jian Wang, Muhammad Ishfaq, Liang Xu, Chunli Xia, Chunli Chen, Jichang Li.
      Nephrotoxicity of colistin is the major factor limiting its clinical application. However, the exact mechanism of colistin-induced nephrotoxicity is still elusive. N6-Methyladenosine (m6A) modification has been implicated in many biological processes, however, its role in colistin-induced nephrotoxicity needs to be elucidated. Mouse renal tubular epithelial cells (mRTECs) were treated with 200 μM colistin with or without METTL3 overexpression. Cells injury, m6A assay, oxidative stress and apoptosis were examined. Levels of m6A are decreased after colistin treatment in mRTECs. METTL3 is the major factor involved in abnormal m6A modification. METTL3 overexpression plays a protective role against colistin-induced oxidative stress and apoptosis. Moreover, METTL3 interacts with the microprocessor protein DGCR8 and positively modulates miR-873-5p mature process in an m6A-dependent manner. Further experiments show that miR-873-5p could regulate Keap1-Nrf2 pathway against colistin-induced oxidative stress and apoptosis. These studies revealed an important role of METTL3/m6A in colistin-induced nephrotoxicity and provide a new insight on m6A modification in drug induced toxicity.
    Keywords:  apoptosis; colistin; m6A modification; miRNA; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2019.00517
  25. Eur J Pharmacol. 2019 May 29. pii: S0014-2999(19)30373-5. [Epub ahead of print] 172422
    Tetramethylpyrazine guards against cisplatin-induced nephrotoxicity in rats through inhibiting HMGB1/TLR4/NF-κB and activating Nrf2 and PPAR-γ signaling pathways.
    Haidy E Michel, Esther T Menze.
      Cisplatin-induced acute renal injury is the most common and serious side effect, sometimes requiring discontinuation of the treatment. Thus, the development of new protective strategies is essential. The present study aimed to investigate the potential nephroprotective effect of tetramethylpyrazine (TMP) against acute renal damage induced by cisplatin in rats. Rats were administered 50 and 100 mg/kg TMP intraperitoneally before cisplatin (7 mg/kg). Acute nephrotoxicity was evident in cisplatin-treated rats where relative kidney weight, BUN and serum creatinine were markedly elevated. Cisplatin administration resulted in enhanced oxidative stress, evidenced by depleted GSH level as well as catalase and superoxide dismutase activities. Also, lipid peroxidation was boosted in comparison to the control. This was associated with inhibition of Nrf2 defense pathway. Moreover, cisplatin increased the expression of pro-inflammatory mediators in the kidney tissues. Cisplatin-induced apoptosis was depicted by elevated Bax mRNA expression and caspase-3 activity, as well as decreased Bcl2 mRNA expression. In addition, high mobility group box 1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway was significantly upregulated, while peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression was significantly diminished in cisplatin-treated rats. Cisplatin-induced nephrotoxicity, oxidative stress, inflammation, apoptosis and the effect on Nrf2 defense pathway and HMGB1/TLR4/NF-κB as well as PPAR-γ expression were markedly ameliorated by TMP administration. Given the major nephrotoxicity of cisplatin cancer chemotherapy, TMP might be a potential candidate for neoadjuvant chemotherapy due to its antioxidant, anti-inflammatory and anti-apoptotic effects, in addition to its effect on Nrf2, HMGB1/TLR4/NF-κB signaling pathway and PPAR-γ expression.
    Keywords:  Cisplatin nephrotoxicity; Nrf2; PPAR-γ; Tetramethylpyrazine; Toll-like receptor 4
    DOI:  https://doi.org/10.1016/j.ejphar.2019.172422
  26. Int J Mol Med. 2019 Jun 06.
    Role of TXNIP/NLRP3 in sepsis-induced myocardial dysfunction.
    Chun Yang, Wan Xia, Xiaolin Liu, Jian Lin, Aiping Wu.
      Myocardial injury is one of the main symptoms of sepsis. However, the mechanisms underlying sepsis‑induced myocardial dysfunction remain unclear. In the present study, the concentration of cardiac troponin T (CTnT) in serum was measured using an enzyme‑linked immunosorbent assay kit. The levels of interleukin (IL)‑1β and IL‑18 were assessed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis and the level of malondialdehyde (MDA) was determined using a corresponding kit. Myocardial pathology was analyzed via hematoxylin and eosin staining. RT‑qPCR analysis and western blotting and/or immunohistochemistry were used to quantify the expression levels of thioredoxin‑interacting protein (TNXIP), NOD‑like receptor pyrin domain containing 3 (NLRP3), cleaved caspase‑1, caspase‑1, catalase and manganese‑superoxide dismutase (MnSOD). The viability of cells was determined using a cell counting kit‑8. Apoptosis and reactive oxygen species (ROS) were examined using flow cytometry. Models of sepsis‑induced myocardial injury were successfully established; evidence included increases in the levels of CTnT, IL‑1β, IL‑18 and MDA and myocardial tissue damage in vivo, and decreased cell viability and improvements in IL‑1β and IL‑18 in vitro. The levels of TXNIP, NLRP3 and cleaved caspase‑1 were upregulated in the sepsis models. Small interfering RNA targeting TNXNIP (siTXNIP) increased cell viability, reduced the apoptotic rate and attenuated the release of IL‑1β and IL‑18. The levels of TXNIP, NLRP3 and cleaved caspase‑1 and production of ROS were suppressed by siTXNIP, accompanied by increases in catalase and MnSOD. TXNIP/NLRP3 serves an important role in the development of sepsis‑induced myocardial damage.
    DOI:  https://doi.org/10.3892/ijmm.2019.4232
  27. Neural Regen Res. 2019 Oct;14(10): 1734-1742
    Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress.
    Yun-Kai Xie, Xin Zhou, Hong-Tao Yuan, Jie Qiu, Dan-Qing Xin, Xi-Li Chu, Da-Chuan Wang, Zhen Wang.
      Previous studies have shown that resveratrol, a bioactive substance found in many plants, can reduce early brain injury after subarachnoid hemorrhage, but how it acts is still unclear. This study explored the mechanism using the experimental subarachnoid hemorrhage rat model established by injecting autologous blood into the cerebellomedullary cistern. Rat models were treated with an intraperitoneal injection of 60 mg/kg resveratrol 2, 6, 24 and 46 hours after injury. At 48 hours after injury, their neurological function was assessed using a modified Garcia score. Brain edema was measured by the wet-dry method. Neuronal apoptosis in the prefrontal cortex was detected by terminal deoxyribonucleotidyl transferase-mediated biotin-16-dUTP nick-end labeling assay. Levels of reactive oxygen species and malondialdehyde in the prefrontal cortex were determined by colorimetry. CHOP, glucose-regulated protein 78, nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 mRNA expression levels in the prefrontal cortex were measured by reverse transcription polymerase chain reaction. Tumor necrosis factor-alpha content in the prefrontal cortex was detected by enzyme linked immunosorbent assay. Immunohistochemical staining was used to detect the number of positive cells of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78, CHOP and glial fibrillary acidic protein. Western blot assay was utilized to analyze the expression levels of nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, glucose-regulated protein 78 and CHOP protein expression levels in the prefrontal cortex. The results showed that resveratrol treatment markedly alleviated neurological deficits and brain edema in experimental subarachnoid hemorrhage rats, and reduced neuronal apoptosis in the prefrontal cortex. Resveratrol reduced the levels of reactive oxygen species and malondialdehyde, and increased the expression of nuclear factor-erythroid 2-related factor 2, heme oxygenase-1 mRNA and protein in the prefrontal cortex. Resveratrol decreased glucose-regulated protein 78, CHOP mRNA and protein expression and tumor necrosis factor-alpha level. It also activated astrocytes. The results suggest that resveratrol exerted neuroprotective effect on subarachnoid hemorrhage by reducing oxidative damage, endoplasmic reticulum stress and neuroinflammation. The study was approved by the Animals Ethics Committee of Shandong University, China on February 22, 2016 (approval No. LL-201602022).
    Keywords:  endoplasmic reticulum stress; glucose-regulated protein 78; heme oxygenase-1; nerve regeneration; neural regeneration; neuroinflammation; nuclear factor-erythroid 2-related factor 2; oxidative stress; resveratrol; subarachnoid hemorrhage
    DOI:  https://doi.org/10.4103/1673-5374.257529
  28. Chemosphere. 2019 May 21. pii: S0045-6535(19)31071-9. [Epub ahead of print]232 171-179
    Hepatotoxicity of tricyclazole in zebrafish (Danio rerio).
    Lingyu Qiu, Kun Jia, Lirong Huang, Xinjun Liao, Xinchun Guo, Huiqiang Lu.
      Tricyclazole is widely used in agriculture as a pesticide, but its toxicity in vertebrates is currently poorly evaluated. In this study, we used zebrafish to assess the toxicity of tricyclazole. We found that tricyclazole induces liver damage, or hepatotoxicity, in zebrafish, during both development and adulthood. In embryos, we found that tricyclazole affected the liver development rather than other endodermal tissues such as gut and pancreas. In both embryos and adult zebrafish livers, tricyclazole disrupted the relationship between oxidant and antioxidant system and resulted in reactive oxygen species (ROS) overload. Meanwhile, it triggered hepatocyte apoptosis and disturbed carbohydrate/lipid metabolism and energy demand systems. These results suggested that tricyclazole could cause severe consequences for vertebrate hepatic development and function.
    Keywords:  Hepatotoxicity; Metabolism disorder; Oxidative stress; Tricyclazole; Zebrafish
    DOI:  https://doi.org/10.1016/j.chemosphere.2019.05.159
  29. Int Immunopharmacol. 2019 Jun 03. pii: S1567-5769(18)30601-5. [Epub ahead of print]73 471-481
    Dexmedetomidine alleviates LPS-induced apoptosis and inflammation in macrophages by eliminating damaged mitochondria via PINK1 mediated mitophagy.
    Yanyan Wang, Xing Mao, Hongguang Chen, Jingcheng Feng, Mengying Yan, Yaoqi Wang, Yonghao Yu.
      The macrophage is an innate immune response cell that plays an important role in the development of sepsis. Dexmedetomidine (DEX) is a sedation drug, which have anti-oxidative, anti-inflammatory and anti-apoptosis effects and can be used on sepsis patients in the ICU. However, its mechanisms of action remain poorly understood. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine protein kinase that recognizes damaged mitochondria and leads to mitophagy. This study investigated the effects of DEX on Lipopolysaccharides(LPS)-induced macrophage injury and explained the underlying mechanisms. The results showed that LPS treatment caused mitochondrial damage, mitochondria-dependent apoptosis and PINK1-mediated mitophagy; at the same time, PINK1 has a protective effect on LPS-induced macrophage apoptosis and inflammation by mitophagy that eliminates dysfunctional mitochondria. DEX could promote the clearance of damaged mitochondria characterized by low Mitochondrial membrane potential (MMP) and high reactive oxygen species(ROS), thus exerting a protective effect in LPS treated macrophages, and PINK1 mediated mitophagy is required for this protective effect.
    DOI:  https://doi.org/10.1016/j.intimp.2019.05.027
  30. Neurosci Lett. 2019 May 30. pii: S0304-3940(19)30369-6. [Epub ahead of print] 134296
    Oxidative stress and Parkinson's disease: conflict of oxidant-antioxidant systems.
    Mohsen Hemmati-Dinarvand, Samira Saedi, Mohammad Valilo, Ashkan Kalantary-Charvadeh, Mahmood Alizadeh Sani, Roya Kargar, Hossein Safari, Nasser Samadi.
      Parkinson's disease (PD) is defined as a chronic neurodegenerative disorder which is diagnosed mostly by its clinical manifestations. Reactive oxygen species (ROS) are considered as key modulators in the development of PD. Despite the intensive investigations, antioxidant-dependent molecular mechanisms of initiation and development of PD are controversial. Free radicals cause serious damage and death of dopamine producing cells when antioxidant capacity of the cells is reduced against oxidative stress (OxS). Many intracellular reactions create ROS, including activation of NADPH oxidase (NOX), mitochondrial dysfunction, and hydrogen peroxide (H₂O₂) decomposition. On the contrary, natural antioxidants, vitamins, proteins, and antioxidant signaling pathways are major factors to neutralize ROS and its destructive effects. The functional role of nuclear factor E2-related factor 2, Heme oxygenase-1, and selenium against ROS-dependent initiation and progression of PD is elucidated. In this review, we collected multiple factors that play the main role in the initiation, development, and pathogenesis of PD and we discussed their function in the PD.
    Keywords:  Natural antioxidants; Oxidative stress; Parkinson’s disease; Reactive oxygen species; Vitamins
    DOI:  https://doi.org/10.1016/j.neulet.2019.134296
  31. Eur J Med Chem. 2019 May 25. pii: S0223-5234(19)30477-5. [Epub ahead of print]177 338-349
    The synthesis and anticancer activity of 2-styrylquinoline derivatives. A p53 independent mechanism of action.
    Anna Mrozek-Wilczkiewicz, Michał Kuczak, Katarzyna Malarz, Wioleta Cieślik, Ewelina Spaczyńska, Robert Musiol.
      A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance.
    Keywords:  2-Styrylquinoline derivatives; Anticancer activity; Apoptosis; Cell cycle inhibition; Reactive oxygen species; p53 protein
    DOI:  https://doi.org/10.1016/j.ejmech.2019.05.061
  32. J Med Food. 2019 Jun 03.
    Gamma-Irradiated Chrysin Improves Anticancer Activity in HT-29 Colon Cancer Cells Through Mitochondria-Related Pathway.
    Ha-Yeon Song, Hye-Min Kim, Sajid Mushtaq, Woo Sik Kim, Young Jun Kim, Seung-Taik Lim, Eui-Baek Byun.
      Irradiation technology can improve the biological activities of natural molecules through a structural modification. This study was conducted to investigate the enhancement of the anticancer effects of chrysin upon exposure to gamma irradiation. Gamma irradiation induces the production of new radiolytic peaks simultaneously with the decrease of the chrysin peak, which increases the cytotoxicity in HT-29 human colon cancer cells. An isolated chrysin derivative (CM1) exhibited a stronger apoptotic effect in HT-29 cells than intact chrysin. The apoptotic characteristics induced by CM1 in HT-29 cells was mediated through the intrinsic signaling pathway, including the excessive production of included reactive oxygen species, the dissipation of the mitochondrial membrane potential, regulation of the B cell lymphoma-2 family, activation of caspase-9, 3, and cleavage of poly (adenosine diphosphate-ribose) polymerase. Our findings suggest that CM1 can be a potential anticancer candidate for the treatment of colon cancer.
    DOI:  https://doi.org/10.1089/jmf.2018.4320
  33. Int J Mol Med. 2019 Jun 05.
    Curcumin‑loaded PEG‑PDLLA nanoparticles for attenuating palmitate‑induced oxidative stress and cardiomyocyte apoptosis through AMPK pathway.
    Jingyi Zhang, Ying Wang, Cuiyu Bao, Tao Liu, Shuai Li, Jiaxi Huang, Ying Wan, Jing Li.
      Curcumin (CUR) has the ability to attenuate oxidative stress in the myocardium and to protect the myocardium from lipotoxic injury owing to its lipid‑reducing properties. However, the use of CUR is limited due to its hydrophobicity and instability. In this study, CUR‑loaded nanoparticles (CUR NPs) were developed using an amphiphilic copolymer, monomethoxy poly (ethylene glycol)‑b‑poly (DL‑lactide), as a vehicle material. CUR NPs with high drug loading and small size were prepared under optimized conditions. The effects of CUR NPs on palmitate‑induced cardiomyocyte injury were investigated and the possible protective mechanism of CUR NPs was also examined. It was found that CUR NPs were able to control the release of CUR and to deliver CUR to H9C2 cells, and they could prevent palmitate‑treated H9C2 cells from apoptosis. In addition, CUR NPs could regulate the Bax and Bcl‑2 levels of palmitate‑treated H9C2 cells back to their respective normal levels. A prospective mechanism for the function of CUR NPs is that they may activate the AMP‑activated protein kinase (AMPK)/mammalian target of rapamycin complex‑1/p‑p70 ribosomal protein S6 kinase signaling pathway, regulate the expression of downstream proteins and resist the palmitate‑induced cardiomyocyte injury. Results suggest that CUR NPs can attenuate palmitate‑induced oxidative stress in cardiomyocytes and protect cardiomyocytes from apoptosis through the AMPK pathway. In view of the safety and efficiency of these CUR NPs, they have potential for application in protecting the myocardium from lipotoxic injury.
    DOI:  https://doi.org/10.3892/ijmm.2019.4228
  34. Free Radic Biol Med. 2019 Jun 01. pii: S0891-5849(19)30646-X. [Epub ahead of print]
    Myricetin prevents thapsigargin-induced CDK5-P66Shc signalosome mediated pancreatic β-cell dysfunction.
    Udayakumar Karunakaran, Ji Eun Lee, Suma Elumalai, Jun Sung Moon, Kyu Chang Won.
      Chronic endoplasmic reticulum (ER) stress has deleterious effects on pancreatic β-cell function and survival in type 2 diabetes (T2D). Cyclin-dependent kinase 5 (CDK5) plays a critical role in β-cell failure under diabetic milieu conditions. However, little information is available on CDK5's ability to impair the function of β-cells via a chemical ER stress inducer thapsigargin. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. Therefore, we examined the effect of CDK5 on thapsigargin-induced β-cell apoptosis, and explored the relationship between myricetin and CDK5. Exposure of beta cells with thapsigargin, induced a Src-mediated redox signaling (VAV2-Rac1-NOX) formation and CDK5 activation. Activated CDK5 induced antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) degradation which was associated with p66Shc serine 36 phosphorylation, causing beta cell apoptosis via mitochondrial dysfunction. Exposure of beta cells to myricetin resulted in an acute inhibition of Src-mediated redox signaling (VAV2-Rac1-NOX) formation and CDK5 activation. Myricetin inhibited CDK5 activation by directly binding to its ATP-binding pocket. Treatment with myricetin also enhanced the stability of Mcl-1 after thapsigargin treatment. Inhibition of CDK5 with myricetin or roscovitine, a CDK5 inhibitor attenuates thapsigargin induced p66Shc serine 36 phosphorylation and also reduced mitochondrial dysfunction by decreasing mitochondrial ROS and caspase-3 activation. In addition, myricetin was observed to enhance PDX-1 and insulin mRNA expression and potentiate glucose stimulated insulin secretion (GSIS). Taken together, these findings indicate that thapsigargin-induced early molecular events lead to CDK5-p66Shc signalosome contributes to thapsigargin-induced pancreatic β-cell dysfunction. Myricetin blocked thapsigargin induced CDK5-p66Shc signalosome formation and prevented pancreatic beta cell dysfunction. In this study, we demonstrated for the first time that thapsigargin initiated CDK5-p66Shc signalosome mediates the pancreatic beta cell dysfunction and myricetin protects the pancreatic beta cells through the inhibition of CDK5-p66Shc signalosome.
    Keywords:  Cyclin dependent kinase 5; Endoplasmic reticulum stress; Myricetin; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.05.038
  35. Regul Toxicol Pharmacol. 2019 May 29. pii: S0273-2300(19)30153-9. [Epub ahead of print]
    Garlic and allopurinol attenuate hepatic apoptosis induced by fipronil in male albino rats.
    Amira A Sayed, Mohamed A El-Desouky, Khairy A Ibrahim.
      Fipronil (FPN) can induce oxidative tissue damage and may be contemplated as an apoptosis inducer. Our aim is to investigate the possible hepatoprotective roles of garlic or allopurinol (ALP) against fipronil subacute toxicity. Thirty-six mature male albino rats were randomly divided into six groups; the first group was saved as control (C), the 2nd (G) was orally intubated with 500 mg/kg aqueous garlic extract, and the 3rd (A) received 150 mg/L allopurinol in their drinking water. The 4th group (F) was administered 13.277 mg/kg fipronil by gavage, while the 5th (G + F) and 6th (A + F) groups received the same doses of garlic and allopurinol, respectively two hours before fipronil intoxication. Our results revealed that FPN significantly increased the hepatic malondialdehyde, protein carbonyl levels, and the enzymatic activities of superoxide dismutase, catalase, glutathione peroxidase, and xanthine oxidase, but it decreased glutathione-S-transferase compared to the control group. Moreover, FPN exhibited significant up-regulation in the hepatic pro-apoptotic (Bax) and caspase-3 genes expression, down-regulation in the anti-apoptotic (Bcl-2) mRNA gene expression and induced DNA fragmentation. Surprisingly, garlic or allopurinol co-treatment ameliorated the hepatic lipid peroxidation, antioxidants disruption, and apoptosis induced by FPN. In conclusion, garlic and allopurinol relieved the oxidative injury and reduced the fipronil-induced apoptosis probably by improving the tissue antioxidant defense system.
    Keywords:  Allopurinol; Apoptosis; Fipronil; Garlic; Liver; Oxidative stress
    DOI:  https://doi.org/10.1016/j.yrtph.2019.05.025
  36. Environ Sci Pollut Res Int. 2019 Jun 04.
    Protective effects of zingerone on cisplatin-induced nephrotoxicity in female rats.
    Fatih Mehmet Kandemir, Serkan Yildirim, Cuneyt Caglayan, Sefa Kucukler, Gizem Eser.
      Zingerone (ZO), one of the active components of ginger (Zingiber officinale), is a phenolic alkanone with antioxidant, antiapoptotic, and anti-inflammatory properties. Cisplatin (CP) is a widely used chemotherapeutic drug for solid tumors, but its therapeutic use is limited due to dose-dependent nephrotoxicity. In the present study, we investigated the ameliorative effect of ZO against CP-induced nephrotoxicity. Intraperitoneal administration of single-dose CP (7 mg/kg body weight) on the first day enhanced kidney lipid peroxidation and reduced antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). CP increased serum urea and creatinine levels and disrupted histological integrity while causing a decrease aquaporin 1 (AQP1) level in the kidney tissues. CP induced inflammatory responses by elevating the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-33 (IL-33) and nuclear factor kappa B (NF-κB), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, it also caused oxidative DNA damage and activation of apoptotic pathway by increasing of 8-hydroxy-2'-deoxyguanosine (8-OHdG), p53, cysteine aspartate-specific protease-3 (caspase-3), and Bcl-2-associated x protein (bax) while decreasing B cell lymphoma-2 (Bcl-2). However, treatment with ZO at a dose of 25 and 50 mg/kg b.wt. for 7 days significantly decreased oxidative stress, apoptosis, inflammation, and histopathological alterations while increased AQP1 levels in the kidney tissue. The results of the current study suggested that ZO as an effective natural product attenuates CP-induced nephrotoxicity.
    Keywords:  Apoptosis; Cisplatin; Inflammation; Nephrotoxicity; Oxidative stress; Zingerone
    DOI:  https://doi.org/10.1007/s11356-019-05505-3
  37. Med Pr. 2019 May 24. pii: 103350. [Epub ahead of print]
    Are platinum nanoparticles safe to human health?
    Ewelina Czubacka, Sławomir Czerczak.
      Platinum nanoparticles (PtNPs) have been widely used not only in industry, but above all in medicine and diagnostics. However, there are disturbing reports related to the toxic effects of nanoplatinum, which is the main reason why the authors of this study have decided to review and analyze literature data related to its toxicity and impact on human health. While PtNPs may be absorbed by the respiratory and digestive tract, and can penetrate through the epidermis, there is no evidence concerning their absorption through the skin. Platinum nanoparticles accumulate mainly in the liver and spleen although they also reach other internal organs, such as lungs, kidneys or heart. Toxicokinetics of platinum nanoparticles depends strongly on the particle size. Only few studies regarding platinum nanoparticles toxicity have been conducted. Animals intratracheally exposed to platinum nanoparticles have demonstrated an increased level of proinflammatory cytokines in bronchoalveolar lavage which confirms inflammatory response in the lungs. Oral administration of PtNPs can cause inflammatory response and induce oxidative stress. Nanoplatinum has been found to induce hepatotoxicity and nephrotoxicity via the intravenous route. It can cause DNA damage and cellular apoptosis without significant cytotoxicity. There are no research studies on its carcinogenicity. Fetal or maternal toxicity has not been observed, but an increased mortality and a decreased growth of the offspring have been demonstrated. Platinum nanoparticles may permeate the skin barrier but there is no evidence for their absorption. Due to the insufficient number of tests that have been carried out to date, it is not possible to clearly determine the occupational exposure limit value; however, caution is recommended to employees exposed to their effects. Med Pr. 2019;70(4).
    Keywords:  health effects; nanoparticles; occupational exposure; occupational health; platinum; toxicology
    DOI:  https://doi.org/10.13075/mp.5893.00847
  38. Cancers (Basel). 2019 May 31. pii: E761. [Epub ahead of print]11(6):
    Contribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells.
    Roberta Peruzzo, Ildiko Szabo.
      Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells.
    Keywords:  mitochondrial ion channels; permeabilization and cytochrome c release; resistance to apoptosis
    DOI:  https://doi.org/10.3390/cancers11060761
  39. J Cell Biochem. 2019 Jun 03.
    Centaurea cyanus extracted 13-O-acetylsolstitialin A decrease Bax/Bcl-2 ratio and expression of cyclin D1/Cdk-4 to induce apoptosis and cell cycle arrest in MCF-7 and MDA-MB-231 breast cancer cell lines.
    Mohammad Keyvanloo Shahrestanaki, Mahboobeh Bagheri, Mustafa Ghanadian, Mahmoud Aghaei, Seyyed Mehdi Jafari.
      Natural products are considered recently as one of the source for production of efficient therapeutical agents for breast cancer treatment. In this study, a sesquiterpene lactone, 13-O-acetylsolstitialin A (13ASA), isolated from Centaurea cyanus, showed cytotoxic activities against MCF-7 and MDA-MB-231 breast cancer cell lines using standard 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. To find the mechanism of action of cytotoxicity, annexin V/propidium iodide (PI) staining was performed for evaluation of apoptosis. This process was further confirmed by immunoblotting of anti- and proapoptotic, Bcl-2 and Bax, proteins. Cell cycle arrest was evaluated by measurement of fluorescence intensity of PI dye and further confirmed by immunoblotting of Cdk-4 and cyclin D1. Mitochondrial transmembrane potential (ΔΨm) and generation of reactive oxygen species (ROS) were measured using the JC-1 and DCFDA fluorescence probes, respectively. These experiments showed that 13ASA is a potent cytotoxic agent, which activates apoptosis-mediated cell death. In response to this compound, Bax/Bcl-2 ratio was noticeably increased in MCF-7 and MDA-MB-231 cells. Moreover, 13ASA induced cell cycle arrest at subG1 and G1 phases by decreasing protein levels of cyclin D1 and Cdk-4. It was done possibly through the decrease of ΔΨm and increase of ROS levels which induce apoptosis. In conclusion, this study mentioned that 13ASA inhibit the growth of MCF-7 and MDA-MB-231 breast cancer cell lines through the induction of cell cycle arrest, which triggers apoptotic pathways. 13ASA can be considered as a susceptible compound for further investigation in breast cancer study.
    Keywords:  apoptosis; breast cancer; natural product; solstitialin
    DOI:  https://doi.org/10.1002/jcb.29141
  40. Int J Mol Med. 2019 May 28.
    Autophagy protects nucleus pulposus cells from cyclic mechanical tension‑induced apoptosis.
    Minghui Yang, Chencheng Feng, Yang Zhang, Chang Liu, Bin Li, Qi Zhu, Bo Huang, Yue Zhou.
      Intervertebral disc (IVD) degeneration (IDD) is considered to be a primary cause of lower back pain. Mechanical stress is one of the most important factors affecting IDD. It has been demonstrated that apoptosis is important in the decrease of functional IVD cells, and that mechanical stress influences disc cell apoptosis. Autophagy, an adaptive response of the cells to survival when faced with different conditions of stress, has been documented in IDD. Apoptosis and autophagy share the same stimuli and regulatory proteins, but have different threshold responses. Recently, cyclic mechanical tension (CMT) has been shown to influence IVD cell apoptosis and autophagy. However, the conversion and coordination between apoptosis and autophagy induced by CMT remains to be fully elucidated. In the present study, it was found that CMT with 20% elongation generated by the Flexercell Tension system induced the apoptosis of nucleus pulposus (NP) cells in a time‑dependent manner. When the cells were stretched for >6 h, autophagy was increased, and showed a tendency to decrease with the duration of CMT. The autophagic activity of NP cells was partially decreased by 3‑MA and was not significantly regulated by rapamycin. CMT‑induced apoptosis was partially enhanced by the decreased autophagic activity induced by 3‑MA. In addition, the level of reactive oxygen species (ROS) in NP cells induced by CMT was significantly upregulated by 3‑MA. These results suggested that abnormal mechanical stress enhanced disc cell apoptosis and consequently accelerated the process of IDD. Autophagy helps to protect against CMT‑induced apoptosis in disc cells and ROS may be important in this process. These findings are beneficial for further understanding the mechanism of disc cell apoptosis and autophagy.
    DOI:  https://doi.org/10.3892/ijmm.2019.4212
  41. Cancer Lett. 2019 Jun 01. pii: S0304-3835(19)30343-X. [Epub ahead of print]
    p53-dependent upregulation of miR-16-2 by sanguinarine induces cell cycle arrest and apoptosis in hepatocellular carcinoma.
    Beilei Zhang, Xinan Wang, Jiacong Deng, Haifeng Zheng, Wei Liu, Si Chen, Jie Tian, Fu Wang.
      MicroRNAs (miRNAs) were involved in cancer progression, and the targeting of miRNAs by natural agents has opened avenues for cancer treatment and drug development. miR-16 functions as a tumor suppressor and is frequently deleted or downregulated in various human cancers, including hepatocellular carcinoma (HCC). In the present study, we employed a miR-16-responsive luciferase reporter to screen candidate compounds that modulate miR-16 expression from a natural product library. One compound, sanguinarine (SG), was capable of activating miR-16 in HCC cells with wildtype or mutated p53 expression but not in p53-deleted HCC cells. Mechanistic investigations revealed that SG increased p53 occupancy on the miR-16-2 promoter and decreased the expression of miR-16 target genes, including Bcl-2 and cyclin D1. Moreover, SG significantly inhibited HCC cell proliferation in a p53-dependent manner by inducing cell cycle arrest and reactive oxygen species (ROS)-associated apoptosis. Silencing miR-16 by treatment with anti-miR16 miRNA inhibitors rescued the cell viability repression effect caused by SG. Importantly, SG dramatically suppressed tumor growth in an HCC xenograft model, with little cytotoxicity. Taken together, our results provide a preclinical proof-of-concept for SG as a potential strategy for HCC treatment based on the restoration of miR-16 tumor suppressor function.
    Keywords:  apoptosis; cell cycle; miRNA-16; p53; sanguinarine
    DOI:  https://doi.org/10.1016/j.canlet.2019.05.042
  42. Life Sci. 2019 Jun 03. pii: S0024-3205(19)30442-4. [Epub ahead of print]
    3,4-dimethoxybenzyl isothiocyanate enhances doxorubicin efficacy in LoVoDX doxorubicin-resistant colon cancer and attenuates its toxicity in vivo.
    Mateusz Psurski, Beata Filip-Psurska, Monika Cuprych, Joanna Wietrzyk, Józef Oleksyszyn.
      AIMS: The aim of the study was to evaluate the potential of naturally occurring isothiocyanates and doxorubicin in combined treatment of doxorubicin-resistant colon cancer. Doxorubicin is a cytostatic commonly used to treat many different types of cancer but its usage is often abrogated by severe side-effects and drug-induced resistance.MAIN METHODS: The antiproliferative potential of the combined treatment was analyzed in vitro by the SRB method (sulforhodamine B) and further evaluated for the mechanisms that determine the treatment outcome using a series of assays which included oxidative stress, apoptosis and compounds accumulation assessment. Ultimately, a combined treatment potential was assessed in vivo utilizing doxorubicin-resistant colon cancer model.
    KEY FINDING: The results indicate that naturally occurring isothiocyanates, represented by 3,4-dimethoxybenzyl isothiocyanate (dMBITC) increase doxorubicin the efficacy in doxorubicin-resistant human colon adenocarcinoma model by attenuated drug efflux, an increased reactive oxygen species production and an increased rate of apoptosis. In in vitro studies, over a 3-fold decrease in doxorubicin IC50 value was observed on the LoVoDX cell line when used in combination with suboptimal concentrations of dMBITC. The combined therapy exhibited a significantly higher efficacy than doxorubicin-alone treatment (c.a. 50% tumor growth inhibition in comparison to c.a. 25% for doxorubicin-alone treatment) in vivo. At the same time, the combined treatment attenuates doxorubicin toxicity as evidenced by improved animals body mass, main organs weight and biochemical markers of toxicity.
    SIGNIFICANCE: The adopted approach provides evidence that isothiocyanates can be successfully applied in the treatment of doxorubicin-resistant colon cancer, which warrants further studies.
    Keywords:  Cardiotoxicity; Chemoresistance; Combined therapy; Doxorubicin; Drugs interaction; Isothiocyanates
    DOI:  https://doi.org/10.1016/j.lfs.2019.06.005
  43. Semin Cell Dev Biol. 2019 May 30. pii: S1084-9521(18)30187-3. [Epub ahead of print]
    Mitochondria as playmakers of apoptosis, autophagy and senescence.
    Marianna Abate, Agostino Festa, Michela Falco, Angela Lombardi, Amalia Luce, Anna Grimaldi, Silvia Zappavigna, Pasquale Sperlongano, Carlo Irace, Michele Caraglia, Gabriella Misso.
      Mitochondria are the key energy-producing organelles and cellular source of reactive species. They are responsible for managing cell life and death by a balanced homeostasis passing through a network of structures, regulated principally via fission and fusion. Herein we discuss about the most advanced findings considering mitochondria as dynamic biophysical systems playing compelling roles in the regulation of energy metabolism in both physiologic and pathologic processes controlling cell death and survival. Precisely, we focus on the mitochondrial commitment to the onset, maintenance and counteraction of apoptosis, autophagy and senescence in the bioenergetic reprogramming of cancer cells. In this context, looking for a pharmacological manipulation of cell death processes as a successful route for future targeted therapies, there is major biotechnological challenge in underlining the location, function and molecular mechanism of mitochondrial proteins. Based on the critical role of mitochondrial functions for cellular health, a better knowledge of the main molecular players in mitochondria disfunction could be decisive for the therapeutical control of degenerative diseases, including cancer.
    Keywords:  apoptosis; autophagy; cancer; metabolism; mitochondrion; senescence
    DOI:  https://doi.org/10.1016/j.semcdb.2019.05.022
  44. Cell Stress Chaperones. 2019 Jun 05.
    Cadmium stress effects indicating marine pollution in different species of sea urchin employed as environmental bioindicators.
    Roberto Chiarelli, Chiara Martino, Maria Carmela Roccheri.
      In recent years, researches about the defense strategies induced by cadmium stress have greatly increased, invading several fields of scientific research. Mechanisms of cadmium-induced toxicity continue to be of interest for researchers given its ubiquitous nature and environmental distribution, where it often plays the role of pollutant for numerous organisms. The presence in the environment of this heavy metal has been constantly increasing because of its large employment in several industrial and agricultural activities. Cadmium does not have any biological role and, since it cannot be degraded by living organisms, it is irreversibly accumulated into cells, interacting with cellular components and molecular targets. Cadmium is one of the most studied heavy metal inductors of stress and a potent modulator of several processes such as apoptosis, autophagy, reactive oxygen species, protein kinase and phosphatase, mitochondrial function, metallothioneins, and heat-shock proteins. Sea urchins (adults, gametes, embryos, and larvae) offer an optimal opportunity to investigate the possible adaptive response of cells exposed to cadmium, since these cells are known to accumulate contaminants. In this review, we will examine several responses to stress induced by cadmium in different sea urchin species, with a focus on Paracentrotus lividus embryos. The sea urchin embryo represents a suitable system, as it is not subjected to legislation on animal welfare and can be easily used for toxicological studies and as a bioindicator of environmental pollution. Recently, it has been included into the guidelines for the use and interpretation of assays to monitor autophagy.
    Keywords:  Apoptosis; Autophagy; Cadmium-stress; Defense strategies; Pollution; Sea urchin
    DOI:  https://doi.org/10.1007/s12192-019-01010-1
  45. Biochem Biophys Res Commun. 2019 May 30. pii: S0006-291X(19)30900-3. [Epub ahead of print]
    DUSP26 regulates podocyte oxidative stress and fibrosis in a mouse model with diabetic nephropathy through the mediation of ROS.
    Feng Huang, Xu-Xiang Sheng, Hong-Juan Zhang.
      Diabetic nephropathy (DN) is a leading cause of renal failure worldwide. Unfortunately, the pathogenetic mechanism of DN is far from to be understood. Dual-specificity phosphatase 26 (DUSP26) is a member of the Dusp protein family, and is suggested to be involved in divers biological and pathological processes, such as cell growth, differentiation, inflammation and apoptosis. However, its role in the development of DN is still vague. In this study, we found that DUSP26 expression was increased in kidney of DN patients. Then, the wild type (DUSP26+/+) and gene knockout (DUSP26-/-) mice were used to further explore the effects of DUSP26 on DN development induced by streptozotocin (STZ). DUSP26 deficiency accelerated renal injury and dysfunction, as evidenced by the elevated glomerulosclerosis, reduced expression of Nephrin and promoted glomerular basement membrane thickness. In addition, STZ treatment resulted in reactive oxygen species (ROS) accumulation, H2O2 overproduction and superoxide dismutase (SOD) reduction in renal cortex or glomeruli of mice. The ROS production caused the activation of mitogen-activated protein kinase (MAPKs) signaling in kidney glomeruli of STZ-induced mice. These in vivo pathological processes were further confirmed in the differentiated podocytes stimulated by glucose (GLU). Intriguingly, we found that STZ-induced DN as mentioned above was further accelerated by DUSP26-/- in mice following STZ injection. Moreover, STZ-induced fibrosis in kidney glomeruli of DN mice was markedly prolonged in DUSP26-knockout mice through potentiating transforming growth factor-β1 (TGF-β1) expression. More importantly, reducing ROS generation could significantly abolish DUSP26 knockdown-exacerbated TGF-β1 expression and MAPKs activation, thereby protecting podocytes from GLU-induced podocyte injury. Thus, DUSP26-regulated DN development was largely dependent on ROS generation. Taken together, we concluded that DUSP26 might be a promising therapeutic target for developing effective treatments against DN progression.
    Keywords:  DUSP26; Diabetic nephropathy (DN); Podocyte injury; ROS; TGF-β1 and MAPKs
    DOI:  https://doi.org/10.1016/j.bbrc.2019.05.032
  46. J Cell Physiol. 2019 Jun 06.
    Melatonin attenuates inflammation-related venous endothelial cells apoptosis through modulating the MST1-MIEF1 pathway.
    Kai Lu, Xiaoping Liu, Wei Guo.
      Chronic venous disease (CVD) is a prevalent and potentially debilitating condition that affects millions of individuals. An excessive endothelial inflammatory response is reportedly involved in the development of CVD. In this study, we explored the effect and mechanism of melatonin on venous endothelial damage induced by tumor necrosis factor α (TNF-α). Our data demonstrated that inflammation injury triggered mitochondrial dysfunction, activated reactive oxygen species-related oxidative damage, inhibited mitochondrial potential and ultimately initiated caspase-involved cellular death. Interestingly, melatonin preserved inflammation-attacked mitochondrial performance and thus increased cell survival under TNF-α. Cellular experiments illustrated that inflammation injury promoted the levels of mammalian sterile 20-like kinase 1 (MST1) and mitochondrial elongation factor 1 (MIEF1); active MST1-MIEF1 pathway disturbed mitochondria-related energy production, leading to mitochondria-induced cell damage. Interestingly, melatonin effectively suppressed MST1-MIEF1 axis and thus improved cell survival ratio under TNF-α-mediated inflammation injury. Reactivation of MST1-MIEF1 pathway attenuated melatonin-related endothelial protective actions. Herein, our results illuminate that melatonin is an effective approach to attenuate inflammation-related venous endothelial cell damage through handling the MST1-MIEF1 signaling pathway.
    Keywords:  MIEF1; MST1; inflammation; melatonin; mitochondria
    DOI:  https://doi.org/10.1002/jcp.28935
  47. Iran J Basic Med Sci. 2019 Apr;22(4): 445-451
    Mechanistic assessment of cadmium toxicity in association with the functions of estrogen receptors in the Langerhans islets.
    Perham Mohammadi, Mahban Rahimifard, Maryam Baeeri, Mohammad Abdollahi, Sara Mostafalou.
      Objectives: Diabetes is a metabolic disease with an increasing prevalence for which finding new and efficient therapeutic approaches has always been a challenge. Preserving integrity and functionality of pancreatic β-cells as the only source of insulin in the body is such a case. To achieve this goal different cellular targets have been proposed among which pancreatic estrogen receptors have gotten much attention. In this work, we evaluated the integrity and function of islets of Langerhans under the influence of factors known to intervene with estrogen receptors. Cadmium, a toxic heavy metal, has been recently shown to interact with estrogen receptors but its toxicity in the pancreatic islets regarding this mechanism remains unclear.Materials and Methods: Isolated islets of Langerhans from the pancreas of rats were grouped and treated with cadmium chloride and also cadmium chloride plus β-estradiol. After 24 hr incubation, parameters of cellular viability, oxidative stress, apoptosis, and insulin secretion were measured .
    Results: The results indicated that cadmium reduced viability of the islets along with an increase in the formation of reactive oxygen species and apoptosis markers, and β-estradiol, in turn, was able to alleviate these disturbances to some extent, implicating the protective role of β-estradiol against pancreatic toxicity of cadmium.
    Conclusion: It can be concluded that modification of estrogen receptors in the endocrine pancreas and especially β-cells may be a promising target to find a new therapeutic strategy for diabetes and even uncovering mechanisms of environmental toxicants that have been known as risk factors of diabetes.
    Keywords:  Cadmium; Diabetes mellitus; Estradiol; Estrogen receptors; Insulin; Islets of Langerhans Pancreas
    DOI:  https://doi.org/10.22038/ijbms.2019.33939.8076
  48. Ecotoxicol Environ Saf. 2019 May 30. pii: S0147-6513(19)30607-4. [Epub ahead of print]180 762-769
    Neurodevelopmental toxicity assessments of alkyl phenanthrene and Dechlorane Plus co-exposure in zebrafish.
    Xiangping Chen, Yuanhong Chen, Changjiang Huang, Qiaoxiang Dong, Courtney Roper, Rorbet L Tanguay, Yaxian Zhu, Yong Zhang.
      Alkyl phenanthrene (A-Phen) and Dechlorane Plus (DP) are ubiquitous environmental pollutants that widely co-exist in the environment. It has been established that both A-Phen and DP elicit neurotoxicity, but the potential interactive toxicity of these contaminants is not well-known. To determine whether a mixture of A-Phen and DP would exhibit interactive effects on neurodevelopment, we co-exposed 3-methylphenanthrene (3-MP), a representative of A-Phen, with DP. Our results illustrated that exposure to 5 or 20 μg/L 3-MP alone or in combination with 60 μg/L DP caused neurobehavioral anomalies in zebrafish. In accordance with the behavioral deficits, 3-MP alone or co-exposed with DP significantly decreased axonal growth of secondary motoneurons, altered intracellular Ca2+ homeostasis and induced cell apoptosis in the muscle of zebrafish. Additionally, 3-MP alone or co-exposed with DP significantly increased reactive oxygen species (ROS) and the mRNA levels of apoptosis-related genes. These findings indicate that 3-MP alone or co-exposed with DP induces neurobehavioral deficits through the combined effects on neuronal connectivity and muscle function. Chemical analysis revealed significant increases in 3-MP and DP bioaccumulation in zebrafish co-exposed with 3-MP and DP. Elevated bioaccumulation resulting from mixture exposure may represent a significant contribution of the synergistic effects observed in combined chemical exposure.
    Keywords:  Alkyl phenanthrene; Co-exposure; Dechlorane plus; Neurodevelopmental toxicity; Synergistic effect
    DOI:  https://doi.org/10.1016/j.ecoenv.2019.05.066
  49. Am J Physiol Heart Circ Physiol. 2019 Jun 07.
    Embryonic Stem Cell-Derived Exosomes Inhibit Doxorubicin Induced TLR4-NLRP3 Mediated Cell Death - Pyroptosis.
    Zahra Tavakoli Dargani, Dinender K Singla.
      Doxorubicin (Dox) induced cardiac side effects are regulated through increased oxidative stress and apoptosis. However, it remains unknown whether Dox induces the specific inflammatory-mediated form of cell death called pyroptosis. The current study is undertaken to determine whether Dox induces pyroptosis in an in vitro model, and to test the potential of exosomes-derived from embryonic stem cells (ES-Exos) in inhibiting pyroptosis. H9c2 cells were exposed to Dox to generate pyroptosis, and then subsequently treated with exosomes to investigate the protective effects of ES-Exos. Mouse embryonic fibroblast-exosomes (MEF-Exos) were used as a cell line control. We confirmed pyroptosis by analyzing presence of TLR4-NLRP3 inflammasome that initiates pyroptosis which was further confirmed with pyroptotic markers; caspase-1, IL-1β, caspase-11, and gasdermin-D. The presence of inflammation was confirmed for pro-inflammatory cytokines, TNF-α and IL-6. Our data shows that Dox exposure significantly (p<0.05) increases expression of TLR4, NLRP3, pyroptotic markers (caspase-1, IL-1β, caspase-11, and gasdermin-D), and pro-inflammatory cytokines (TNF-α and IL-6) in H9c2 cells. The increased expression of inflammasome, pyroptosis, and inflammation was significantly (p<0.05) inhibited by ES-Exos. Interestingly, our cell line control, MEF-Exos, did not show any protective effects. Furthermore, our cytokine array data suggests increased anti-inflammatory (IL-4, IL-9 and IL-13) and decreased pro-inflammatory cytokines (Fas ligand, IL-12 and TNF-α) in ES-Exos, suggesting that anti-inflammatory cytokines might be mediating the protective effects of ES-Exos. In conclusion, our data shows that Dox induces pyroptotic cell death in the H9c2 cell culture model, and is attenuated via treatment with ES-Exos.
    Keywords:  Doxorubicin; H9c2 cells; Inflammation; exosomes; pyroptosis
    DOI:  https://doi.org/10.1152/ajpheart.00056.2019
  50. Iran J Basic Med Sci. 2019 Apr;22(4): 384-390
    Empagliflozin alleviates renal inflammation and oxidative stress in streptozotocin-induced diabetic rats partly by repressing HMGB1-TLR4 receptor axis.
    Zahra Ashrafi Jigheh, Amir Ghorbani Haghjo, Hassan Argani, Leila Roshangar, Nadereh Rashtchizadeh, Davoud Sanajou, Saeed Nazari Soltan Ahmad, Jalil Rashedi, Siavoush Dastmalchi, Mehran Mesgari Abbasi.
      Objectives: Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, possesses verified anti-inflammatory and anti-oxidative stress effects against diabetic nephropathy. The present investigation aims to examine empagliflozin effects on the renal levels of high mobility group box-1 (HMGB1), a potent inflammatory cytokine, and its respective receptor toll-like receptor-4 (TLR-4) in STZ-induced diabetic rats.Materials and Methods: Empagliflozin at 10 mg/kg per os (p.o.) was administered for 4 weeks, starting 8 weeks after the induction of diabetes. Renal function, kidney inflammation, oxidative stress, and apoptosis markers as well as renal HMGB1, receptor for advanced glycation end products (RAGE), and TLR-4 levels were assessed.
    Results: In addition to down-regulating NF-κB activity in renal cortices, empagliflozin reduced renal levels of HMGB1, RAGE, and TLR-4. It alleviated renal inflammation as indicated by diminished renal expressions of inflammatory cytokines and chemokines like tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and also decreased urinary levels of interleukin-6 (IL-6) and alpha-1 acid glycoprotein (AGP). Moreover, empagliflozin ameliorated renal oxidative stress as demonstrated by decreased renal malondialdehyde (MDA) and elevated renal activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). It also suppressed renal caspase-3, the marker of apoptosis; and furthermore, enhanced renal function noticed by the declined levels of serum urea and creatinine.
    Conclusion: These findings underline that empagliflozin is able to attenuate diabetes-related elevations in renal HMGB1 levels, an influential inflammatory cytokine released from the necrotic and activated cells, and its correspondent receptors, i.e., RAGE and TLR-4.
    Keywords:  Diabetic nephropathy; Empagliflozin; HMGB1; Inflammation; TLR-4
    DOI:  https://doi.org/10.22038/ijbms.2019.31788.7651
  51. Pestic Biochem Physiol. 2019 Jun;pii: S0048-3575(18)30439-5. [Epub ahead of print]157 13-18
    Modulatory effects of swimming exercise against malathion induced neurotoxicity in male and female rats.
    Ola A Salama, Maha M Attia, Mohamed A S Abdelrazek.
      Malathion is one of the most commonly used organophosphorus (OP) pesticides. It is important to regard that exposure to OP poisoning may cause anxiety and depression. Malathion toxicity induces cholinergic symptoms. Brain-derived neurotrophic factor (BDNF) is the most profusely expressed neurotrophin in the central nervous system; it promotes the survival of neurons. Regular exercise improves brain well-being and enhances recovery from brain Injuries. It is suggested that BDNF may mediate these effects. Therefore, this study was planned to assess the modulatory effects of regular exercise performance on brain BDNF level, cholinergic activity, oxidative stress and apoptosis in male and female rats subjected to neurotoxicity induced by malathion administration.MATERIALS AND METHODS: Thirty-two adult male and thirty-two adult female albino rats were included in this study. The rats were divided into four equal groups (8rats). Control group, malathion treated group, exercised group, malathion exercised group. Acetylcholinesterase (AchE) activity, total antioxidant capacity (TAC), BDNF level and Caspase 3 activity were assessed.
    RESULTS: Female rats had higher baseline content of BDNF in brain homogenate than male rats. Malathion administration induced a significant decrease in BDNF level in female rats and in the total antioxidant capacity in both male and female rats. A significant elevation in caspase 3 activity was detected in the malathion treated groups, with more elevation in female rats. Swimming exercise improved BDNF level, AchE activity, and apoptosis in both male and female rats in all groups. In addition, male rats were more cholinergic system responders to regular exercise than female rats.
    CONCLUSION: It could be concluded that malathion induced elevation in oxidative stress and apoptosis in all rats, with reduction in BDNF level in female rats. Meanwhile, regular swimming exercise was found to improve brain health through modulation of BDNF level and cholinergic activity. It is recommended to practice regular exercise to maintain brain health. Further studies are required to clarify the involvement of sex hormones in BDNF regulation.
    DOI:  https://doi.org/10.1016/j.pestbp.2019.01.014
  52. Mol Pharmacol. 2019 Jun 04. pii: mol.119.115725. [Epub ahead of print]
    Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring.
    Nadine Wenningmann, Merle Knapp, Anusha Ande, Tanaya R Vaidya, Sihem Ait-Oudhia.
      Doxorubicin (DOX) is one of the most effective anticancer drugs to treat various forms of cancers, however, its therapeutic utility is severely limited by its associated cardiotoxicity. Despite the enormous amount of research conducted in this area, the exact molecular mechanisms underlying DOX toxic effects on the heart are still an area that warrants further investigations. Here, we reviewed literature to gather the best-known molecular pathways related to DOX-induced cardiotoxicity (DIC). They include mechanisms dependent on mitochondrial dysfunction such as DOX influence on the mitochondrial electron transport chain, redox cycling, oxidative stress, calcium dysregulation, and apoptosis pathways. Further, we discuss the existing strategies to prevent and/or alleviate DIC along with various techniques available for therapeutic drug monitoring (TDM) in cancer patients treated with DOX. Finally, we propose a step-wise flowchart for TDM of DOX, and present our perspective at curtailing this deleterious side effect of DOX. SIGNIFICANCE STATEMENT: In this minireview article, we reviewed literature reports, gathered, and summarized the best-known molecular pathways related to doxorubicin-induced cardiotoxicity (DIC). We emphasized on the mechanisms dependent on mitochondrial dysfunction such as doxorubicin influence on the mitochondrial electron transport chain, redox cycling, oxidative stress, calcium dysregulation, and apoptosis pathways. Further, we discuss the existing strategies to prevent and/or alleviate DIC along with various techniques available for therapeutic drug monitoring (TDM) in cancer patients treated with doxorubicin. Finally, we propose a step-wise flowchart for TDM of doxorubicin and present our perspective at curtailing this deleterious side effect of doxorubicin.
    Keywords:  Cancer chemotherapy; Cardiac toxicity; Mitochondria
    DOI:  https://doi.org/10.1124/mol.119.115725
  53. Photodermatol Photoimmunol Photomed. 2019 Jun 05.
    Cyanidin-3-o-glucoside inhibits UVA-induced human dermal fibroblast injury by upregulating autophagy.
    Shi Wu, Yunfeng Hu, Weibin Bai, Jiayi Zhao, Cuiqin Huang, Caiyan Wen, Liehua Deng, Daxiang Lu.
      BACKGROUND/PURPOSE: Ultraviolet (UV) A (315-400 nm) is the UV light that most frequently reaches the Earth's surface and can penetrate the epidermis through to the dermis, causing various issues, including skin aging and skin cancer. The results of our previous studies have shown that the flavonoid monomer cyanidin-3-o-glucoside (C3G) can effectively inhibit primary human dermal fibroblast (HDF) oxidative damage and apoptosis caused by UVA radiation. Many flavonoids can regulate the level of autophagy. However, whether C3G inhibits UVA-induced oxidative damage to primary HDFs by regulating autophagy levels remains unclear.METHODS AND RESULTS: In this study, we used different doses (0-12 J/cm2 ) of UVA to irradiate cells and showed that the expression levels of autophagy-related gene 5 (Atg5) and microtubule-associated protein 1 light chain 3 (LC3)-II in primary HDFs first increased and then decreased. The expression of Atg5 and LC3-II was significantly decreased under 12 J/cm2 (light-damage model). C3G increased the levels of Atg5 and LC3-II. Primary HDFs were pretreated with C3G, followed by treatment with the autophagy inhibitor 3-methyladenine (3-MA) after 12 J/cm2 UVA irradiation. The inhibitory effects of C3G on morphological changes, oxidative damage and apoptosis in primary HDFs induced by UVA were significantly decreased.
    CONCLUSION: C3G can inhibit UVA-induced damage to primary HDFs by inducing autophagy. These results provide a theoretical basis for the application of natural compounds to resist light damage to the skin in the future. This article is protected by copyright. All rights reserved.
    Keywords:  Apoptosis; Autophagy; Cyanidin-3-o-glucoside; Human dermal fibroblasts; Ultraviolet-A
    DOI:  https://doi.org/10.1111/phpp.12493
  54. Int J Mol Med. 2019 May 31.
    Protective effects of salvianolic acid B against hydrogen peroxide‑induced apoptosis of human umbilical vein endothelial cells and underlying mechanisms.
    Shan Gao, Shiqin Li, Qin Li, Fuyong Zhang, Mengqi Sun, Zilin Wan, Shurong Wang.
      Salvianolic acid B (Sal B) is a water‑soluble active component of Danshen and has anti‑atherosclerotic effects. The present study aimed to evaluate the cytoprotective effects of Sal B against hydrogen peroxide (H2O2)‑induced oxidative stress damage in human umbilical vein endothelial cells (HUVECs) and investigate the underlying mechanisms. It was revealed that Sal B protected the cells from H2O2‑induced damage, as indicated by MTT results showing enhanced cell viability and by flow cytometric analysis showing reduced apoptosis of cells challenged with H2O2. Furthermore, as an underlying mechanism, the enhancement of autophagy was indicated to be accountable for the decrease in apoptosis, as Sal B caused the upregulation of light chain 3‑Ⅱ and Beclin‑1, and downregulation of p62 under H2O2‑induced oxidative stress. Finally, Sal B increased the phosphorylation of AMP kinase (AMPK) and decreased the phosphorylation of mammalian target of rapamycin (mTOR), but had no effect on the phosphorylation of AKT. In conclusion, the present study revealed that Sal B protects HUVECs from oxidative stress, at least partially by promoting autophagy via activation of the AMPK pathway and downregulation of the mTOR pathway.
    DOI:  https://doi.org/10.3892/ijmm.2019.4227
  55. J Exp Biol. 2019 Jun 06. pii: jeb.200246. [Epub ahead of print]
    Muscular apoptosis but not oxidative stress increases with old age in a long-lived diver, the Weddell seal.
    Kaitlin N Allen, José Pablo Vázquez-Medina, John M Lawler, Jo-Ann E Mellish, Markus Horning, Allyson G Hindle.
      Seals experience repeated bouts of ischemia-reperfusion while diving, potentially exposing their tissues to increased oxidant generation and thus oxidative damage and accelerated aging. We contrasted markers of oxidative damage with antioxidant profiles across age and sex for propulsive (longissismus dorsi, LD) and maneuvering (pectoralis, P) muscles of Weddell seals to determine whether previously observed morphological senescence is associated with oxidative stress. In LD, old (age 17-26 years) seals exhibited a nearly 2-fold increase in apoptosis over young (age 9-16 years) seals. There was no evidence of age-associated changes in lipid peroxidation or enzymatic antioxidant profiles. In P, 4-hydroxynonenal-Lys (4-HNE-Lys) levels increased 1.5-fold in old versus young seals, but lipid hydroperoxide levels and apoptotic index did not vary with age. Glutathione peroxidase activity was 1.5-fold higher in P of old versus young animals, but no other antioxidants changed with age in this muscle. With respect to sex, no differences in lipid hydroperoxides or apoptosis were observed in either muscle. Males had higher HSP70 expression (1.4-fold) and glutathione peroxidase activity (1.3-fold) than females in LD, though glutathione reductase activity was 1.4-fold higher in females. No antioxidants varied with sex in P These results show that apoptosis is not associated with oxidative stress in aged Weddell seal muscles. Additionally, the data suggest that adult seals utilize sex-specific antioxidant strategies in LD but not P to protect skeletal muscles from oxidative damage.
    Keywords:  Aging; Antioxidants; Ischemia-reperfusion; Pinniped; Redox; Senescence
    DOI:  https://doi.org/10.1242/jeb.200246
  56. Front Neurosci. 2019 ;13 461
    A Nutraceutical Strategy to Slowing Down the Progression of Cone Death in an Animal Model of Retinitis Pigmentosa.
    Ilaria Piano, Vanessa D'Antongiovanni, Lara Testai, Vincenzo Calderone, Claudia Gargini.
      Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by progressive degeneration of the visual cells and abnormalities in retinal pigment epithelium, the vision is lost slowly, and the final outcome is total blindness. RP primarily affects rods, but cones can also be affected as a secondary effect. Photoreceptor cell death is usually triggered by apoptosis, however the molecular mechanisms linking the rod degeneration to the secondary cone death are poorly understood. Possible causes of the secondary cone death are oxidative stress and/ or the release of toxic factors from dying rods. The aim of this study is to analyze the effect of nutraceutical molecules with antioxidant properties, on the progression of the disease in an established animal model of RP, and rd10 mice. We show that chronic treatment per os with a flavanone (naringenin) or a flavonol (quercetin) present in citrus fruits, grapes and apples, preserves retinal morphology, and ameliorates functionality. These actions are associated with a significant reduction of stress-oxidative markers, such as the detoxifying enzymes Sod1 and Sod2. In addition, naringenin and quercetin treatment reduces the levels of acrolein staining associated with a reduction of ROS in the cellular environment. The study demonstrates the beneficial effects of naringenin and quercetin, two molecules that possess antioxidant properties, limiting neurodegeneration, and thus preventing cone damage.
    Keywords:  nutraceutical treatment; oxidative stress; photoreceptors; retinal degeneration; retinitis pigmentosa
    DOI:  https://doi.org/10.3389/fnins.2019.00461
  57. Biochem Biophys Res Commun. 2019 May 31. pii: S0006-291X(19)31054-X. [Epub ahead of print]
    TIGAR suppresses seizures induced by kainic acid through inhibiting oxidative stress and neuronal apoptosis.
    Chunyou Chen, Qin Mei, Linlin Wang, Xuewen Feng, Xiaoxiao Tao, Chenfeng Qiu, Jingang Zhu.
      TP53-induced glycolysis and apoptosis regulator (TIGAR) activates the pentose phosphate pathway (PPP), which feeds reduced nicotinamide adenine dinucleotide phosphate (NADPH) to the antioxidant glutathione pathway. Oxidative stress-induced neuronal apoptosis is the pathological basis of several neurological disorders, including epilepsy. To determine the potential anti-epileptic action TIGAR in a rodent kainic acid (KA)-induced seizure model. Seizures were induced by the intra-cerebroventricular injection of KA, followed by injection of empty or TIGAR-expressing lentiviral vectors. Immunofluorescence was used to detect the localization of TIGAR in the cortices and hippocampi, and the expression levels of relevant proteins were determined by Western blotting. Oxidative stress-related markers were detected using commercially available kits. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. TIGAR were mainly expressed in the neurons and rarely located in the astrocytes, and increased in the cortices and hippocampi of KA-treated rats in a time-dependent manner. Lentivirus-mediated TIGAR overexpression significantly decreased the oxidative stress and neuronal apoptosis induced by KA, resulting in prolonged seizure latency and lower Racine scores. Our findings indicate that TIGAR has anti-epileptic, anti-oxidant and anti-apoptotic effects, and is therefore a promising therapeutictarget for epilepsy.
    Keywords:  Epilepsy; Neuronal apoptosis; Oxidative stress; TIGAR
    DOI:  https://doi.org/10.1016/j.bbrc.2019.05.156
  58. J Biol Chem. 2019 Jun 05. pii: jbc.RA118.003311. [Epub ahead of print]
    An integrated PKD1-dependent signaling network amplifies IRE1 pro-survival signaling.
    Shiyong Wu, Shumin Ma, Xueliang Yin, Ping Yi, Jianfeng Liu.
      Following the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), a condition known as ER stress in this compartment triggers an adaptive signaling pathway referred to as the unfolded protein response (UPR). The UPR aims at restoring ER homeostasis; if the ER stress cannot be resolved, apoptosis is triggered. However, the mechanisms responsible for regulating the balance between cell life and death decisions that occur after exposure to ER stress remain unclear. Protein kinase D1 (PKD1) has been reported to initiate protective signaling against oxidative stress or ischemia, two conditions that impinge on the induction of ER stress. In addition, the high levels of expression of PKD1, observed in highly proliferative cancers and tumors with poor prognosis, contribute to enhanced resistance to chemotherapy. In this study, we show that the ER stress inducers tunicamycin and thapsigargin lead to the activation of PKD1 in human prostate cancer PC-3 cells and in hepatoma HepG2 cells through a PKCδ-dependent mechanism. Moreover, our data indicate that PKD1 is required for the stabilization of inositol-requiring enzyme 1 (IRE1) and the subsequent regulation of its activity. PKD1 activation contributes to the phosphorylation of MAP kinase phosphatase 1, resulting in decreased IRE1-mediated c-Jun N-terminal kinase activation. This study unveils the existence of a novel PKD1-dependent pro-survival mechanism that is activated upon ER stress and selectively enhances IRE1 pro-survival signaling.
    Keywords:  IRE1; MKP1; c-Jun N-terminal kinase (JNK); cell death; endoplasmic reticulum stress (ER stress); protein kinase D (PKD); signal transduction
    DOI:  https://doi.org/10.1074/jbc.RA118.003311
  59. Biochem Pharmacol. 2019 Jun 03. pii: S0006-2952(19)30217-5. [Epub ahead of print]
    Semaphorin 3E regulates apoptosis in the intestinal epithelium during the development of colitis.
    Nour Eissa, Hayam Hussein, Abdoulaye Diarra, Omar Elgazzar, Abdelilah S Gounni, Charles N Bernstein, Jean-Eric Ghia.
      Semaphorin3E (SEMA3E) has emerged as an axon-guiding molecule that regulates various biological processes including the immune responses and apoptosis. However, its role in the pathophysiology of colitis remains elusive. We investigated the role of SEMA3E in intestinal epithelial cells (IECs) activation, using biopsies from patients with active ulcerative colitis (UC), a mouse model of UC, and an in-vitro model of intestinal mucosal healing. In this study, we confirmed that the mRNA level of SEMA3E is reduced significantly in patients with UC and demonstrated a negative linear association between SEMA3E mRNA and p53-associated genes. In mice, genetic deletion of Sema3e resulted in an increase onset and severity of colitis, p53-associated genes, apoptosis, and IL-1beta production. Recombinant SEMA3E treatment protected against colitis and decreased these effects. Furthermore, in stimulated epithelial cells, recombinant SEMA3E treatment enhanced wound healing, resistance to oxidative stress and decreased apoptosis and p53-associated genes. Together, these findings identify SEMA3E as a novel regulator in intestinal inflammation that regulates IECs apoptosis and suggest a potential novel approach to treat UC.
    Keywords:  Cell Death; Epithelial Cells; Mucosal Drug Action; Ulcerative Colitis; Wound Healing
    DOI:  https://doi.org/10.1016/j.bcp.2019.05.029
  60. Arq Bras Oftalmol. 2019 Jun 03. pii: S0004-27492019005009101. [Epub ahead of print]
    Long-term treatment with 3,4-methylenedioxymethamphetamine caused retina damage in C57BL/6 mice.
    Xiangqin Liu, Hong Ye.
      PURPOSE: As a class of psychostimulant drugs, amphetamines are widely abused for their stimulant, euphoric, and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Following the onset of these effects, 3,4 methylenedioxymethamphetamine produces persistent damage to dopamine and serotonin nerve terminals, resulting in long-lasting neurotoxicity. The purpose of this investigation was to assess the effects of treatment with low dose of methylenedioxymethamphetamine on retinal function of C57BL/6 mice and its underlying mechanisms.METHODS: C57BL/6 mice were divided randomly into two groups (n=10): one group was treated with phosphate buffered saline by intraperitoneal injection daily; the other group was treated with 1 mg/kg methylenedioxymethamphetamine by intraperitoneal injection daily for three months. Electroretinography was used to test retinal function every month. H&E staining and terminal deoxynucleotidyl transferase assay were used to evaluate the retinal morphology and histology. Enzyme-linked immunosorbent assay assays were used to measure markers of oxidative stress and inflammatory factors. Gene and protein expression was detected by real-time PCR and western blot.
    RESULTS: Three-month treatment with methylenedioxymethamphetamine induced significant retinal dysfunction via photoreceptor cell apoptosis by oxidative stress and inflammatory responses.
    CONCLUSIONS: These results suggest that long-term treatment with methylenedioxymethamphetamine increases inflammatory responses in photoreceptor cells resulting in retinal dysfunction in C57BL/6 mice. Thus, this investigation provides preclinical rationale for the retina damage caused by the methylenedioxymethamphetamine abuse.
    DOI:  https://doi.org/10.5935/0004-2749.20190070
  61. Acupunct Med. 2019 Jun 05. acupmed2017011491
    Acupuncture attenuates cognitive impairment, oxidative stress and NF-κB activation in cerebral multi-infarct rats.
    Jing-Wen Yang, Xue-Rui Wang, Si-Ming Ma, Na-Na Yang, Qian-Qian Li, Cun-Zhi Liu.
      BACKGROUD: Patients with multiple infarct dementia (MID) have subtle deficits that commonly go unnoticed, and are at risk of developing Alzheimer's disease. Oxidative stress induced by ischaemic injury results in intracellular calcium accumulation and neuronal apoptosis, leading to cognitive impairment by triggering various cellular signal transduction pathways. Several studies have suggested that NF-κB in the presence of p53 has a pro-apoptotic function in various models, but the mechanism is unclear.AIMS: The aim of this study was to investigate whether acupuncture could protect cognitive function against cerebral multi-infarction (CMi) induced oxidative stress by inhibiting the activation of NF-κB and its target gene p53.
    METHODS: An animal model of CMi was established by injecting homologous blood emboli into the right internal carotid artery of male Wistar rats. After 2 weeks of acupuncture treatment, cognitive function was detected by novel object recognition. Electron spin resonance and Fluo-3 fuorescence imaging were used to test the generation of ROS and intracellular calcium accumulation, respectively. Expression of NF-κB and p53 was examined by Western blot analysis and immunofluorescence.
    RESULTS: CMi induced spatial learning and memory impairment, overproduction of intracellular hydroxyl radicals, and elevations of Ca2+, which were ameliorated by verum acupuncture treatment. Acupuncture inhibited activation of NF-κB and its downstream target gene p53.
    CONCLUSION: These findings suggest that acupuncture could protect cognitive function against oxidative stress induced by CMi, which is partially associated with suppression of NF-κB-p53 activation.
    Keywords:  acupuncture; cerebral multi-infarct; neurobiology; nuclear factor kappa B; stroke
    DOI:  https://doi.org/10.1136/acupmed-2017-011491
  62. Pharmacol Res. 2019 Jun 03. pii: S1043-6618(19)30472-4. [Epub ahead of print] 104261
    The Beneficial Roles of Metformin on the Brain with Cerebral Ischaemia/Reperfusion Injury.
    Tom Leech, Nipon Chattipakorn, Siriporn C Chattipakorn.
      Cerebral ischaemia/reperfusion (I/R) injury is the transient loss, followed by rapid return, of blood flow to the brain. This condition is often caused by strokes and heart attacks. The underlying mechanisms resulting in brain damage during cerebral I/R injury include mitochondrial dysregulation, increased oxidative stress/reactive oxygen species, blood-brain-barrier breakdown, inflammation of the brain, and increased neuronal apoptosis. Metformin is the first-line antidiabetic drug which has recently been shown to be capable of acting through the aforementioned pathways to improve recovery following cerebral I/R injury. However, some studies have suggested that metformin therapy may have no effect or even worsen recovery following cerebral I/R injury. The present review will compile and examine the available in vivo, in vitro, and clinical data concerning the neuroprotective effects of metformin following cerebral I/R injury. Any contradictory evidence will also be assessed and presented to determine the actual effectiveness of metformin treatment in stroke recovery.
    Keywords:  Metformin; brain; ischemia/reperfusion injury
    DOI:  https://doi.org/10.1016/j.phrs.2019.104261
  63. Cell Chem Biol. 2019 May 13. pii: S2451-9456(19)30140-0. [Epub ahead of print]
    Small-Molecule-Targeting Hairpin Loop of hTERT Promoter G-Quadruplex Induces Cancer Cell Death.
    Jin H Song, Hyun-Jin Kang, Libia A Luevano, Vijay Gokhale, Kui Wu, Ritu Pandey, H-H Sherry Chow, Laurence H Hurley, Andrew S Kraft.
      Increased telomerase activity is associated with malignancy and poor prognosis in human cancer, but the development of targeted agents has not yet provided clinical benefit. Here we report that, instead of targeting the telomerase enzyme directly, small molecules that bind to the G-hairpin of the hTERT G-quadruplex-forming sequence kill selectively malignant cells without altering the function of normal cells. RG260 targets the hTERT G-quadruplex stem-loop folding but not tetrad DNAs, leading to downregulation of hTERT expression. To improve physicochemical and pharmacokinetic properties, we derived a small-molecule analog, RG1603, from the parent compound. RG1603 induces mitochondrial defects including PGC1α and NRF2 inhibition and increases oxidative stress, followed by DNA damage and apoptosis. RG1603 injected as a single agent has tolerable toxicity while achieving strong anticancer efficacy in a tumor xenograft mouse model. These results demonstrate a unique approach to inhibiting the hTERT that functions by impairing mitochondrial activity, inducing cell death.
    Keywords:  G-quadruplex; NRF2; ROS; docetaxel resistance; hTERT; oxidative stress; prostate cancer; telomerase
    DOI:  https://doi.org/10.1016/j.chembiol.2019.04.009
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