bims-aporos 2018-07-08 papers

bims-aporos

Biomed News

on Apoptosis and reactive oxygen species

Issue of 2018‒07‒08
nine papers selected by
Gavin McStay
Staffordshire University

A new xanthatin analogue 1β-hydroxyl-5α-chloro-8-epi-xanthatin induces apoptosis through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition in human hepatocellular carcinoma.
ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine.
Orientin-mediated Nrf2/HO-1 signal alleviates H2O2-induced oxidative damage via induction of JNK and PI3K/AKT activation.
Salidroside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro.
Pinostrobin exerts neuroprotective actions in neurotoxin-induced Parkinson's disease models through Nrf2 induction.
Inhibition of Nrf2 alters cell stress induced by chronic iron exposure in human proximal tubular epithelial cells.
Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings.
Verbascoside Inhibits Glioblastoma Cell Proliferation, Migration and Invasion While Promoting Apoptosis Through Upregulation of Protein Tyrosine Phosphatase SHP-1 and Inhibition of STAT3 Phosphorylation.
Neuroprotection by ethanolic extract of Syzygium aromaticum in Alzheimer's disease like pathology via maintaining oxidative balance through SIRT1 pathway.

Biochimie. 2018 Jun 27. pii: S0300-9084(18)30177-9. [Epub ahead of print]

A new xanthatin analogue 1β-hydroxyl-5α-chloro-8-epi-xanthatin induces apoptosis through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition in human hepatocellular carcinoma.

Xin-Yi Fang, Hai Zhang, Lin Zhao, Shuai Tan, Qing-Cuo Ren, Lun Wang, Xiao-Fei Shen.

  1β-hydroxyl-5α-chloro-8-epi-xanthatin (XTT), a sesquiterpene lactone isolated from Xanthium sibiricum, possessed potent cytotoxicity on cancer cells in vitro. The objective of this study was to investigate the anti-tumor effect and underlying mechanisms of XTT on human hepatocellular carcinoma (HCC). Firstly, XTT inhibited the cell growth and induced apoptosis in human HCC cells, which was associated with the induction of Bax and cleaved-caspase-3, inhibition of Bcl-2 and survivin expression. Importantly, XTT induced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), and depletion of glutathione (GSH) in HCC cells through covalently modification of GSH. Furthermore, XTT caused obvious activation of extracellular regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and inactivation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) in HCC cells. ROS scavenger N-acetyl cysteine abrogated the effects of XTT on ERK/p38 MAPK activation and JAK2/STAT3 inhibition, and rescued HCC cells from XTT-induced apoptosis. Additionally, inhibitors of ERK/p38 MAPKs or activator of JAK2/STAT3 partially abolished XTT-mediated effect. In summary, XTT inhibited cell growth and induced apoptosis in HCC cells through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition by GSH depletion. These findings also show the therapeutic potential of XTT in HCC.

Keywords:  1β-hydroxyl-5α-chloro-8-epi-xanthatin; Apoptosis; Glutathione; Hepatocellular carcinoma; MAPKs and JAK2/STAT3 cascades; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biochi.2018.06.018
Biomed Pharmacother. 2018 Jun 27. pii: S0753-3322(18)31931-0. [Epub ahead of print]106 200-209

ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine.

Mahendra Seervi, Ankita Rani, Abhay K Sharma, T R Santhosh Kumar.

  A dopamine receptor antagonist, Thioridazine (TDZ) is known for its cytotoxic activity against various cancers and its role in combinational chemotherapy is being actively investigated. Several molecular targets of TDZ have been studied to delineate its anticancer activities, with contrasting findings in different cancer types. Moreover, the underlying mechanism of cell death from TDZ treatment is not well defined. In the current study, we studied TDZ mediated cell death mechanism employing cervical cancer cells. TDZ treatment induced nuclear condensation, mitochondrial membrane potential loss, mitochondrial cytochrome c release, activation of caspase-9 and caspase-3 substantiating mitochondrial pathways of apoptosis in cells. TDZ induced ROS generation and up-regulation of ER stress linked proteins, such as CHOP, BiP etc. ER stress and apoptosis caused by TDZ were prevented by ROS inhibitor N-acetyl-L-cysteine (NAC) and protein synthesis inhibitor cycloheximide. In TDZ mediated cytocidal cellular process, autophagy acted as a cell survival factor as the inhibition of autophagy by 3-Methyladenine resulted in increased cell death. TDZ induced apoptosis was associated with decreased Bcl-2 expression and the overexpression of Bcl-2 resulted in inhibition of apoptosis. Studies in Bax-Bak knock-out cell model indicated that TDZ trigger both the Bax-Bak dependent and independent apoptosis through ROS. In the presence of Bax and Bak, cells are more sensitised to death than in the absence of these proteins. Both Bax-Bak dependent and independent apoptosis were significantly inhibited by ROS inhibitor NAC. Conclusively, TDZ induced Bax-Bak dependent and independent apoptosis by enhancing ROS production followed by ER stress.

Keywords:  Apoptosis; Autophagy; Bcl-2; ER stress; Reactive oxygen species; Thioridazine

DOI:  https://doi.org/10.1016/j.biopha.2018.06.123
Int J Biol Macromol. 2018 Jun 27. pii: S0141-8130(18)30679-2. [Epub ahead of print]118(Pt A): 747-755

Orientin-mediated Nrf2/HO-1 signal alleviates H2O2-induced oxidative damage via induction of JNK and PI3K/AKT activation.

Qingfei Xiao, Rongli Piao, Hongyue Wang, Chenhao Li, Liangsong Song.

  Oxidative stress is closely associated with the pathogenesis of various diseases. Orientin (Ori), a flavonoid component isolated from natural plants, possesses antioxidant activity. Accordingly, we focused on exploring the potential therapeutic effects of Ori on hydrogen peroxide (H2O2)-induced oxidative impairment in RAW 264.7 cells and the underlying antioxidative mechanisms. Our findings suggested that Ori exposure effectively alleviated H2O2-stimulated cytotoxicity, inhibited reactive oxygen species (ROS) generation, and glutathione (GSH) depletion, which were involved in induction of heme oxygenase-1 (HO-1) by enhancing the nuclear factor-erythroid 2-related factor 2 (Nrf2) translocation, decreasing the Keap1 protein expression, and increasing the antioxidant response element (ARE) activity. However, knockdown of Nrf2 and HO-1 with siRNA mostly abolished the cytoprotective effects against H2O2-induced cell oxidative injury, reduced the expression of Nrf2 and HO-1, respectively. Moreover, Ori exposure significantly induced a c-Jun NH2-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) phosphorylation, but JNK and PI3K/AKT inhibitors treatment effectively reduced levels of Ori-enhanced Nrf2 nuclear translocation and HO-1 protein expression, and blocked Ori-inhibited cytotoxicity and ROS accumulation triggered by H2O2 respectively. Taken together, Ori might exhibit a protective role against H2O2-stimulated oxidative damage by the induction of HO-1 expression through the activation of the JNK- and PI3K/AKT-Nrf2 signaling pathways.

Keywords:  Hydrogen peroxide; Orientin; Oxidative stress; Signaling pathway

DOI:  https://doi.org/10.1016/j.ijbiomac.2018.06.130
J Pharmacol Sci. 2018 Jun 18. pii: S1347-8613(18)30105-1. [Epub ahead of print]

Salidroside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro.

Yan Sun, Liru Xun, Gang Jin, Lei Shi.

  Oxidative stress, inﬂammation and cell apoptosis are important mechanisms of renal ischemia/reperfusion (I/R) injury. Salidroside, a natural phenylpropanoid glycoside, possesses anti-inflammatory, anti-oxidative, and anti-apoptotic effects. However, the effect of salidroside on renal I/R injury has not been fully elucidated. The present study aimed to investigate the effect of salidroside on renal I/R injury in vitro. Our results showed that salidroside improved the viability of human renal tubular epithelial cells (HK-2) in response to hypoxia/reoxygenation (H/R). Salidroside caused apparent decrease in the levels of reactive oxygen species (ROS) and malondiaidehyde (MDA), and significant increase in superoxide dismutase (SOD) activity in HK-2 cells. Pretreatment with salidroside markedly inhibited the production levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 in a dose-dependent manner. Salidroside treatment exhibited significant increase in Bcl-2 expressions, and decrease in Bax expressions and caspase-3 activity when compared with the H/R group. Salidroside decreased the levels of toll-like receptor 4 (TLR4) and p-p65 in HK-2 cells. Overexpression of TLR4 significantly attenuated the effects of salidroside on cell viability, oxidative stress, cytokine production and cell apoptosis in HK-2 cells. These findings indicated that salidroside protected HK-2 cells from H/R stimulation, which was mediated by the TLR4/NF-κB pathway.

Keywords:  Acute kidney injury (AKI); Hypoxia/reoxygenation (H/R); Inﬂammation; Ischemia/reperfusion (I/R); Oxidative stress; Salidroside

DOI:  https://doi.org/10.1016/j.jphs.2018.05.011
J Agric Food Chem. 2018 Jul 01.

Pinostrobin exerts neuroprotective actions in neurotoxin-induced Parkinson's disease models through Nrf2 induction.

Chuwen Li, Benqin Tang, Yu Feng, Fan Tang, Maggie Pui Man Hoi, Ziren Su, Simon Ming-Yuen Lee.

The aim of the present study was to assess the neuroprotective effects of pinostrobin (PSB), a dietary bioflavonoid, and its underlying mechanisms in neurotoxin-induced PD models. Firstly, PSB could attenuate MPTP-induced loss of dopaminergic neurons and improve behavior deficiency in zebrafish, supporting its potential neuroprotective actions in vivo. Next, PSB could decreased apoptosis and death in the MPP+-intoxicated SH-SY5Y cells, evidenced by MTT, LDH, Annexin V-FITC/PI and DNA fragmentation assay. PSB also blocked MPP+-induced apoptotic cascades, including loss of mitochondrial membrane potential, activation of caspase 3, and reduced ratio of Bcl-2/Bax. In addition, PSB suppressed MPP+-induced oxidative stress but increased antioxidant enzymes, evidenced by decrease of ROS generation and lipid peroxidation and up-regulation of GSH-Px, SOD, CAT, GSH/GSSG and NAD/NADH. Further investigations showed that PSB significantly enhanced Nrf2 expression and nuclear accumulation, improved ARE promoter activity and up-regulated expression of HO-1 and GCLC. Furthermore, Nrf2 knockdown via specific Nrf2 siRNA abolished PSB-induced anti-oxidative and anti-apoptotic effects against MPP+ insults. Interestingly, we then found that PSB promoted phosphorylation of PI3K/AKT and ERK, and pharmacological inhibition of PI3K/AKT or ERK signaling diminished PSB-induced Nrf2/ARE activation and protective actions. In summary, PSB confers neuroprotection against MPTP/MPP+-induced neurotoxicity in Parkinson's disease models. Promoting activation of Nrf2/ARE signaling contributes to PSB-mediated anti-oxidative and neuroprotective actions, which, in part is mediated by PI3K/AKT and ERK.

DOI: https://doi.org/10.1021/acs.jafc.8b02607
Toxicol Lett. 2018 Jun 27. pii: S0378-4274(18)31468-1. [Epub ahead of print]

Inhibition of Nrf2 alters cell stress induced by chronic iron exposure in human proximal tubular epithelial cells.

S E G van Raaij, R Masereeuw, D W Swinkels, R P L van Swelm.

 Iron can catalyze reactive oxygen species (ROS) formation, causing cellular injury. In systemic iron overload, renal tubular epithelial cells are luminally exposed to high iron levels due to glomerular filtration of increased circulating iron. Reports of tubular dysfunction and iron deposition in β-thalassemia major support an association between increased chronic iron exposure and renal tubular injury. In acute iron exposure, Nuclear factor-erythroid 2-related factor 2 (Nrf2) may protect from iron-induced injury, whereas chronic renal stress may lead to Nrf2 exhaustion. We studied the cytotoxic mechanisms of chronic iron exposure using human conditionally immortalized proximal tubular epithelial cells (ciPTECs). Long-term iron exposure resulted in iron accumulation, cytosolic ROS formation and increased heme oxygenase 1 (HMOX-1) mRNA expression (all p < 0.001). This was accompanied by nuclear translocation of Nrf2 and induction of its target protein NQO1, which both could be blocked by the Nrf2 inhibitor trigonelline. Interestingly, iron and trigonelline incubation reduced ROS production, but did not affect HMOX-1 mRNA levels. Moreover, ferritin protein and CHOP mRNA expression were induced in combined iron and trigonelline incubated cells (p < 0.05). Together, these findings suggest that chronic iron exposure induces oxidative stress and that exhaustion of the antioxidant Nrf2 pathway may lead to renal injury.

Keywords: ER stress; Iron overload; Nrf2; oxidative stress; renal proximal tubular epithelial cell

DOI: https://doi.org/10.1016/j.toxlet.2018.06.1218
Food Chem Toxicol. 2018 Jun 27. pii: S0278-6915(18)30428-9. [Epub ahead of print]

Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings.

Qinghua Wu, Xu Wang, Eugenie Nepovimova, Yun Wang, Hualin Yang, Kamil Kuca.

  Cyclosporine A (CsA) is a widely used immunosuppressive agent that greatly reduces the rates of kidney-, heart-, and liver-transplant rejection. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. While the mechanisms underlying CsA nephrotoxicity are still not fully understood, increasing lines of evidence suggest that oxidative stress plays an important role in this phenomenon. Specifically, CsA induces endoplasmic reticulum stress and increases mitochondrial reactive oxygen species production: this modifies the redox balance, which causes lipid peroxidation and thereby induces nephrotoxicity. Recent studies on the pathogenesis of CsA nephrotoxicity suggest that CsA-induced autophagy can alleviate the deleterious effects of CsA-induced endoplasmic reticulum stress, thereby preventing nephrotoxicant-induced renal injury. A variety of signaling pathways participate in the pathogenesis of CsA nephrotoxicity. Specifically, the p38, ERK, and JNK MAPK subfamilies are all involved in CsA nephrotoxicity, while NF-κB is a target molecule of CsA. Moreover, the fibrogenic cytokine TGF-β1 contributes to CsA-induced renal fibrosis, while Nrf2 modulates CsA-induced cellular oxidative stress. In addition, CsA generally inhibits nitric oxide synthesis and impairs endothelium-dependent relaxation in the renal artery. However, some reports also suggest that nitric oxide synthesis is enhanced in the kidney cortex during CsA nephrotoxicity. Notably, the biomarkers of CsA nephrotoxicity associated with CsA have not been reviewed previously. Therefore, in this review, we will first provide an update on CsA nephrotoxicity in humans and describe the potential biomarkers of CsA nephrotoxicity. The molecular and cellular mechanisms that underlie CsA nephrotoxicity and the roles played by oxidative stress, autophagy, and signaling pathways will then be comprehensively summarized and discussed. Finally, the current therapeutical strategies for CsA nephrotoxcixity are summarized. We hope this review will provide a better understanding of CsA nephrotoxicity, thereby improving the management of patients who are treated with CsA.

Keywords:  Autophagy; Biomarker; Cyclosporine; Nephrotoxicity; Oxidative stress; Therapy

DOI:  https://doi.org/10.1016/j.fct.2018.06.054
Cell Physiol Biochem. 2018 Jun 29. 47(5): 1871-1882

Verbascoside Inhibits Glioblastoma Cell Proliferation, Migration and Invasion While Promoting Apoptosis Through Upregulation of Protein Tyrosine Phosphatase SHP-1 and Inhibition of STAT3 Phosphorylation.

Wei-Qiang Jia, Zhao-Tao Wang, Ming-Ming Zou, Jian-Hao Lin, Ye-Hai Li, Liang Zhang, Ru-Xiang Xu.

  BACKGROUND/AIMS: As a natural antioxidant, verbascoside (VB) is proved to be a promising method for the treatment of oxidative-stress-related neurodegenerative diseases. Thus, this study aimed to investigate the effects of VB on glioblastoma cell proliferation, apoptosis, migration, and invasion as well as the mechanism involving signal transducer and activator of transcription 3 (STAT3) and Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1).METHODS: U87 cells were assigned to different treatments. The MTT assay was used to test cell proliferation, flow cytometry was used to detect cell apoptosis, and a Transwell assay was used for cell migration and invasion. We analyzed the glioblastoma tumor growth in a xenograft mouse model. Western blot analysis was employed to determine the protein expression of related genes.
RESULTS: Glioblastoma cells exhibited decreased cell proliferation, migration, invasion, and increased apoptosis when treated with VB or TMZ. Western blot analysis revealed elevated SHP-1 expression and reduced phosphorylated (p)-STAT3 expression in glioblastoma cells treated with VB compared with controls. Correspondingly, in a xenograft mouse model treated with VB, glioblastoma tumor volume and growth were decreased. Glioblastoma xenograft tumors treated with VB showed elevated SHP-1, Bax, cleaved caspase-3, and cleaved PARP expression and reduced p-STAT3, Bcl-2, survivin, MMP-2, and MMP-9 expression. siRNA-SHP-1 inhibited the VB effects on glioblastoma.
CONCLUSION: This study demonstrates that VB inhibits glioblastoma cell proliferation, migration, and invasion while promoting apoptosis via SHP-1 activation and inhibition of STAT3 phosphorylation.

Keywords:  Apoptosis; Glioblastoma; Invasion; Migration; Proliferation; Signal transducer and activator of transcription 3; Src homology 2 domain-containing protein tyrosine phosphatase 1; Verbascoside

DOI:  https://doi.org/10.1159/000491067
Exp Gerontol. 2018 Jun 27. pii: S0531-5565(18)30302-4. [Epub ahead of print]110 277-283

Neuroprotection by ethanolic extract of Syzygium aromaticum in Alzheimer's disease like pathology via maintaining oxidative balance through SIRT1 pathway.

Shashank Shekhar, Yudhishthir Yadav, Amrendra Pratap Singh, Rashmita Pradhan, Gaurav Rajesh Desai, A B Dey, Sharmistha Dey.

  The oxidative stress plays a key role in Alzheimer's disease (AD) and Sirtuin (SIRT1) is potential mediator of oxidative pathway. This study explored the role of Syzygium aromaticum on SIRT1 and oxidative balance in amyloid beta induced toxicity. Anti-oxidative capacity of Syzygium aromaticum was performed in Aβ25-35 induced neurotoxicity in neuronal cells. Superoxide dismutase, Catalase and Glutathione enzyme activity were determined by the treatment of Syzygium aromaticum. Both recombinant and endogenous SIRT1 activity were performed in its presence. The expression of γ-secretase and SIRT1 were evaluated by western blot. Syzygium aromaticum was capable to scavenge ROS and elevate the percentage of anti-oxidant enzymes. It also activated and elevated the level of SIRT1 and downregulated γ-secretase level. These findings show a holistic approach towards the neurodegenerative disease management by Syzygium aromaticum which could lead to the formulation of new drug for AD. This Ayurvedic product can give a healthy aging with no side effects and also be cost effectives. It may meet unmet medical needs of current relevance.

Keywords:  Alzheimer's disease; SH-SY5Y; SIRT1; Serum; Syzygium aromaticum

DOI:  https://doi.org/10.1016/j.exger.2018.06.026