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Apelin‑13, a neuropeptide that acts as a ligand for a putative receptor related to the angiotensin II type receptor, elicits neuroprotective effects in numerous neurological conditions, such as Huntington's disease and cerebral ischemia. Parkinson's disease (PD), one of the most prevalent neurodegenerative diseases, is caused by damage to neurons in the brain; however, the underlying mechanism remains unclear. The present study explored the effects of apelin‑13 on SH‑SY5Y human neuroblastoma cells treated with 1‑methyl‑4‑phenylpyridine (MPP+). Cell growth, cell viability, and apoptosis were measured by real‑time cell analysis, the Cell Counting Kit‑8 assay, and flow cytometry, respectively. In addition, the expression levels of extracellular signal‑regulated kinase (ERK) 1/2, p38 mitogen‑activated protein kinase (MAPK), glucose‑regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase‑12 were assessed by western blotting. MPP+ treatment decreased the viability of SH‑SY5Y cells and increased their apoptosis; however, these changes were attenuated by pretreatment with apelin‑13. Treatment with MPP+ for 24 h significantly increased the expression levels of phospho‑ERK1/2, phospho‑p38, GRP78, CHOP, and cleaved caspase‑12 in SH‑SY5Y cells. Pretreatment with apelin‑13 significantly attenuated the upregulation of GRP78, CHOP and cleaved caspase‑12 in MPP+‑treated SH‑SY5Y cells, and significantly enhanced the expression levels of phospho‑ERK1/2. Taken together, the present results support a model in which apelin‑13 inhibits MPP+‑induced apoptosis of SH‑SY5Y cells by decreasing the expression of GRP78, CHOP, and cleaved caspase‑12, and by increasing the expression of phospho‑ERK1/2. The present findings suggest that apelin‑13 may be useful for the treatment of PD.

Cerebral ischemia/reperfusion (I/R) injury-induced neuronal apoptosis contributes to the death and disability in patients with ischemic stroke. However, underlying mechanisms remain elusive and it lacks effective treatment. Here we reported that the expression of casein kinase 2 (CK2) was significantly reduced in brains of middle cerebral artery occlusion/reperfusion (MACO/R) model rats and oxygen-glucose deprivation/reperfusion (OGD/R) model neurons, which was associated with the activation of eIF2-ATF4-CHOP signaling pathway, leading to neuronal apoptosis. Moreover, we found that apelin-13 significantly upregulated CK2 expression and inhibited eIF2-ATF4-CHOP activation, attenuating cerebral I/R injury-induced infarct and neuronal apoptosis in MACO/R model rats and OGD/R model neurons. Furthermore, we demonstrated that the rescue effect of apelin-13 on I/R injury-induced neuronal apoptosis was mediated by Gα i /Gα q -CK2-dependent inhibition of eIF2-ATF4-CHOP activation. These data indicated cerebral I/R injury reduced CK2 expression and activated eIF2-ATF4-CHOP signaling contributing to neuronal apoptosis, and apelin-13 can activate Gα i /Gα q -CK2 signaling attenuating eIF2-ATF4-CHOP-mediated neuronal apoptosis. It provides a novel insight that not only apelin-13 but also CK2 agonists may have therapeutic potential for protecting neurons from I/R injury-induced apoptosis, facilitating post-stroke recovery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Orexin-A elicits multiple potent effects on a variety of tumor cells via different signaling pathways. However, it is unknown whether it has a neuroprotective effect on SH-SY5Y human neuroblastoma cells. This study investigated the neuroprotective effect of Orexin-A against hydrogen peroxide (H 2 O 2 )-induced oxidative damage in SH-SY5Y cells and the underlying mechanism. H 2 O 2 treatment decreased the viability of SH-SY5Y cells, induced apoptosis, and decreased superoxide dismutase activity. Orexin-A attenuated these effects, indicating that it protects SH-SY5Y cells against H 2 O 2 -induced oxidative damage. Pre-treatment with Orexin-A also attenuated H 2 O 2 -induced increases in phosphorylation of MEK 1/2 and ERK 1/2 . Moreover, these effects of Orexin-A were reduced in the presence of the PI3K inhibitor LY294002. Finally, pre-treatment with LY294002 abrogated attenuation of the H 2 O 2 -induced decrease in cell viability and increase in caspase-3/7 activity by Orexin-A. These results show that the PI3K/MEK 1/2 /ERK 1/2 signaling pathway is involved in the neuroprotective effects of Orexin-A against H 2 O 2 -induced oxidative damage in SH-SY5Y cells. Our findings provide insight into the neuroprotective effects of Orexin-A and the underlying mechanism, which will be useful for the treatment of nervous system diseases.

This study was purposed to explore the apoptosis-inducing effect of tetrandrine (Tet) and imatinib (IM) alone or both combined on K562/G01 cells and their mechanism. MTT assay was used to detect the inhibitory effect of drugs on cell growth, flow cytometry was used to detect the cell cycle and apoptosis rate. The expression of caspase-3/BCL-2 mRNA was determined by real time-PCR, and the expression of caspase-3/BCL-2 protein was assayed by Western blot. The results showed that after being treated by 1.0 µmol/L IM or 1.5 µmol/L Tet alone and combination of these two drugs for 48 h, the inhibitory rate was (22.74 ± 0.05)%, (20.34 ± 0.57)% and (44.28 ± 0.60)%, respectively, suggesting that inhibitory effect of two drug combination was more obvious. The arrest of cell cycle at G1/S phase could be observed after Tet treatment. Early apoptosis rate was (7.81 ± 0.16) %, (14.10 ± 0.28) % respectively after being treated by combination of 1.5 µmol/L and 3.0 µmol/L Tet with 1.0 µmol/L IM. After being treated with Tet alone, FQ-PCR and Western blot showed that the expressions of caspase-3 mRNA and caspase-3 protein were up-regulated, the expressions of BCL-2 mRNA and protein were down-regulated, the effect of both drug combination was more significant. It is concluded that IM or Tet alone can induce apoptosis of K562/G01. Combination of IM with Tet shows obvious synergistic effect, mechanism of which may associate with up-regulation of caspase-3 mRNA and protein expressions, and down-regulation of BCL-2 mRNA and protein expressions.

This study was aimed to explore the inhibitory effect of triptolide on proliferation and inducing apoptosis effect of K562/G01 cells and their possible mechanism. MTT assay was used to detect the effect of imatinib or triptolide alone and their combination on K562/G01 proliferation; the cell cycle, apoptosis rate, P-gp protein expression were detected by flow cytometry (FCM); the expression of P-gp was assessed by Western blot; the BCR/ABL gene expression was assayed by real time quantitative PCR. The results showed that triptolide could enhance the effect of imatinib on proliferation inhibition and apoptosis of K562/G01, arrested the cell cycle in G1 phase, down-regulated the expression of BCR/ABL gene and P-gp protein. It is concluded that triptolide induces K562/G01 cell proliferation inhibition and apoptosis, the mechanism may be related to cell cycle arrest, decrease of P-gp protein expression, inhibition of BCR/ABL gene expression.

Silibinin is an anticancer and chemopreventive natural compound, which is extracted from milk thistle (Silybum marianum). It is reported that silibinin has anticancer efficacy in many malignant tumors. Laryngeal carcinoma is the second most common head and neck squamous carcinoma. In the present work, we investigated the effects of silibinin on laryngeal squamous cell carcinoma (LSCC) cell line Hep-2 cells. We found that silibinin induced the decrease of cell viability in Hep-2 cells with a concentration- and time-dependent manner. Moreover, silibinin resulted in the apoptosis of Hep-2 cells and had synergy effects with arsenic trioxide. Intracellular reactive oxygen species (ROS) accumulation increased because of silibinin exposure. ROS scavenger NAC alleviated the cytotoxicity of silibinin to Hep-2 cells. The mitochondrial membrane potential (MMP) was lost in Hep-2 cells treated with silibinin. Subsequently, silibinin induced the activation of caspase-3 in Hep-2 cells and caspase inhibitor Z-VAD-FMK inhibited the cytotoxicity of silibinin in Hep-2 cells. The survivin expression decreased after Hep-2 cells were treated with silibinin. In conclusion, silibinin induced the apoptosis of Hep-2 cells via oxidative stress and down-regulating survivin expression. Therefore, silibinin is a potential therapeutical agent against LSCC in future.

Oxidative stress has an important role in neurodegenerative diseases and cerebral ischemic injury. It is reported that d-β-hydroxybutyrate (DβHB), the major component of ketone bodies, is neuroprotective in recent studies. Therefore, in the present work the neuroprotective effects of DβHB on H2O2-induced apoptosis mediated by oxidative stress was investigated. PC12 cells were exposed to H2O2 with different concentrations of H2O2 for different times after DβHB pretreatment. MTT assay, apoptotic rates, intracellular reactive oxygen species (ROS) level, GSH content, mitochondrial membrane potential (MMP) and caspase-3 activity were determined. The results showed that DβHB inhibited the decrease of cell viability induced by H2O2 in PC12 cells. DβHB decreased the apoptotic rates induced by H2O2. The changes of intracellular ROS, GSH, MMP and caspase-3 activity due to H2O2 exposure were partially reversed in PC12 cells. So DβHB inhibited the apoptosis of PC12 cells induced by H2O2 via inhibiting oxidative stress., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To investigate the effect of electroacupuncture (EA) on mitochondrial membrane potential and neuronal apoptosis in the cerebral cortex of rats with focal cerebral ischemia/reperfusion (CI/R) injury., Methods: Thirty-six male SD rats were uniformly randomized into sham operation (sham), CI/R and CI/R + EA groups. CI/R model was established by middle cerebral artery occlusion (MCAO) and reperfusion. EA (2/15 Hz, 1 mA) was applied to "Shuigou" (GV 26) and "Baihui" (GV 20) for 30 min after CI/R. The mitochondrial membrane potential and neuronal apoptosis in the cerebral cortex (fronto-parietal lobes) in each group were detected by flow cytometer (FCM)., Results: In comparison with sham group, the mitochondrial membrane potential of CI/R group decreased significantly (P<0.01), while compared with CI/R group, it increased remarkably in CI/R + EA group (P<0.01). The percentage of neuronal apoptosis in CI/R group was significantly higher than that in sham group (P<0.01), and that of CI/R + EA group was significantly lower than that of CI/R group (P<0.01)., Conclusion: EA can alleviate CI/R injury partially by up-regulating the mitochondrial membrane potential, which may contribute to its effect in reducing cerebral neuronal apoptosis.

Background and Aims: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury.Methods and Results: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly.Conclusions: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is one of the common gynecological malignant tumors. Cell division cycle-associated protein-3 (CDCA3) is involved in the regulation of cell cycle progression. The role of CDCA3 in OC was explored in this study. The expression of CDCA3 in OC was evaluated in the Gene Expression Omnibus (GEO) database and further verified by qRT-PCR and Western blot (WB). Subsequently, we established lentivirus-mediated CDCA3 knockdown in OC cell lines HO-8910 and A2780. The biological roles of CDCA3 on proliferation, sensitivity to cisplatin, apoptosis, migration and tumor formation of OC were investigated using loss-of-function assays. CDCA3 was frequently up-regulated in OC. Knockdown of CDAC3 inhibited proliferation and migration, and enhanced apoptosis as well as sensitivity of OC cells to cisplatin. In vivo results further confirmed the inhibitory effect of CDCA3 knockdown on tumor growth. Our findings indicated that CDCA3 may play an important role in OC progression, and may serve as a potential therapeutic target for the OC treatment. • CDCA3 was frequently up-regulated in ovarian cancer. • CDCA3 knockdown could potently inhibit ovarian cancer cell progression in vitro. • CDCA3 Knockdown could efficiently suppress tumor growth of ovarian cancer in vivo. • CDCA3 may be a potential molecular therapy target for ovarian cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress has an important role in neurodegenerative diseases and cerebral ischemic injury. It is reported that d-β-hydroxybutyrate (DβHB), the major component of ketone bodies, is neuroprotective in recent studies. Therefore, in the present work the neuroprotective effects of DβHB on H2O2-induced apoptosis mediated by oxidative stress was investigated. PC12 cells were exposed to H2O2 with different concentrations of H2O2 for different times after DβHB pretreatment. MTT assay, apoptotic rates, intracellular reactive oxygen species (ROS) level, GSH content, mitochondrial membrane potential (MMP) and caspase-3 activity were determined. The results showed that DβHB inhibited the decrease of cell viability induced by H2O2 in PC12 cells. DβHB decreased the apoptotic rates induced by H2O2. The changes of intracellular ROS, GSH, MMP and caspase-3 activity due to H2O2 exposure were partially reversed in PC12 cells. So DβHB inhibited the apoptosis of PC12 cells induced by H2O2 via inhibiting oxidative stress. [Copyright &y& Elsevier]

Parkinson's disease (PD) is a common neurodegenerative disease typically associated with the accumulation of α-synuclein. Autophagy impairment is thought to be involved in the dopaminergic neurodegeneration in PD. We investigate the effect of Apelin-36 on the activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/the mammalian target of rapamycin (mTOR) autophagy pathway in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells, which is involved in the cytoprotective effect of Apelin-36. SH-SY5Y cells were treated with 1-Methyl-4-phenylpyridine (MPP+) with or without Apelin-36. The cell viability, apoptotic ratio, the form of autophagic vacuoles, the expression of tyrosine hydroxylase (TH), α-synuclein, phosphorylation of PI3K, AKT, mTOR, microtubule-associated protein 1 Light Chain 3 II/I (LC3II/I) and p62 were detected to investigate the neuroprotective effect of Apelin-36. The results indicate that Apelin-36 significantly improved the cell viability and decreased the apoptosis in MPP+-treated SH-SY5Y cells. The decreased expression of tyrosine hydroxylase (TH) induced by MPP+ was significantly increased by Apelin36 pretreatment. Moreover, Apelin36 significantly increased the autophagic vacuoles. The ratio of LC3II/I was significantly increased by Apelin36, as well as the decreased p62 expression. In addition, the activated PI3K/AKT/mTOR pathway induced by MPP+ was significantly inhibited by Apelin36. Additionally, Apelin36 significantly decreased the α-synuclein expression. Furthermore, the cytoprotective effect of Apelin-36 was weakened by pretreatment with Insulin-like Growth Factor-1 (IGF-1), an activator of PI3K/Akt, and MHY1485, an mTOR activator. Our results demonstrated that Apelin-36 protects against MPP+-induced cytotoxicity through PI3K/Akt/mTOR autophagy pathway in PD model in vitro, which provides a new theoretical basis for the treatment of PD. Unlabelled Image [ABSTRACT FROM AUTHOR]

Highlights: [•] ER stress is an essential step in cerebral ischemia. [•] ER stress response is initiated by activation of PERK, ATF6 and IRE1. [•] ER stress-induced apoptosis is mediated by CHOP, caspase-12 and JNK. [•] There are links between ER stress and inflammation and mitochondrial dysfunction. [•] ER stress may be used as a therapeutic target for ischemic stroke. [Copyright &y& Elsevier]