Journal of Receptors and Signal Transduction最新文献

Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating condition that affects neurodevelopment and results in brain injury in infants. Morroniside (MOR), a natural secoiridoid glycoside, has been found to possess neuroprotective effect. However, the effects of MOR on neonatal HIE are unclear. An in vitro HIE model was established in murine hippocampal neurons HT-22 cells using oxygen-glucose deprivation/reoxygenation (OGD/R) stimulation. Our results showed that MOR improved OGD/R-caused cell viability reduction in HT-22 cells. MOR suppressed the production of reactive oxygen species (ROS) and malondialdehyde (MDA) in OGD/R-induced HT-22 cells in a dose-dependent manner. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GP_X) were significantly elevated by MOR. Moreover, MOR treatment caused a significant increase in bcl-2 expression, and obvious decreases in the expression levels of bax, cleaved caspase-3, and cleaved caspase-9 expression. Furthermore, MOR significantly upregulated the expression levels of nuclear Nrf2 and HO-1 in OGD/R-treated HT-22 cells. Additionally, knockdown of Nrf2 or HO-1 abrogated the effects of MOR on OGD/R-induced oxidative stress and apoptosis in HT-22 cells. In conclusion, these findings suggested that MOR protects HT-22 cells against OGD/R via regulating the Nrf2/HO-1 signaling pathway.

Purpose: Pulsatilla saponins from pulsatilla chinensis (Bunge) Regel have potential anti-tumor activities to certain human cancers. However, the roles of pulsatilla saponin E separated from pulsatilla saponins in non-small cell lung cancer (NSCLC) have not been reported.

Materials and methods: After treating NSCLC cells by pulsatilla saponin E at different concentrations, cell viability was measured by MTT and CCK-8 assays, and cell migration, invasion and apoptosis were detected by scratch wound-healing, transwell and flow cytometry assays. The contents of free cholesterol (FC) and total cholesterol (TC) were measured by high performance liquid chromatography (HPLC). The expression levels of flotillin-1, flotillin-2, Akt, fatty acid synthase (FASN) were detected by qRT-PCR and Western blot assays.

Results: Pulsatilla saponin E suppressed viability, migration, invasion and promoted apoptosis of NSCLC cells followed by regulation of apoptosis-related proteins, reduced contents of FC and TC, and the expression levels of flotillin-1, flotillin-2, Akt, and FASN in a concentration-dependent manner. However, the inhibitory effects of pulsatilla saponin E on viability, migration, invasion of A549 cells and the expression levels of flotillin-1, flotillin-2, Akt, and FASN were reversed by flotillin-2 overexpression.

Conclusions: Our study revealed that pulsatilla saponin E suppressed migration, invasion and promoted apoptosis of NSCLC cells through negatively regulating Akt/FASN signaling pathway via the inhibition of flotillin-2 in lipid raft (LR). The current findings could be explored for developing a novel therapeutic drug for NSCLC treatment.

The reputation of conventional treatment in acute lymphoblastic leukemia (ALL) has recently been questioned due to the considerable increment in the number of relapsed patients. The remarkable role of histone deacetylase (HDAC) enzymes in induction of chemo-resistance has provided an opportunity for HDAC inhibitors to be used as a treatment strategy in ALL; however, the compensatory activation of oncogenic pathways may negatively affect their promising effects. In the present study, we found an attenuating effect for PI3K axis on the anti-leukemic effects of panobinostat in pre-B ALL-derived Nalm-6 cells, as the harnessing of this pathway using BKM120 or CAL-101 resulted in a significant reduction in the number of viable cells as well as the metabolic activity. Moreover, we found the altered expression of p21, p27, c-Myc, and CDK4 upon co-treatment of the cells with panobinostat and BKM120, which was associated with a substantial blockage of cell cycle progression at G2/M phase. The companionship of the PI3K inhibitor with HDAC inhibitor also potentiated panobinostat-induced apoptotic cell death and enhanced the mRNA of Foxo3a and Foxo4. Conclusively, this study sheds light on the adjuvantive effects of BKM120 on panobinostat efficacy and outlined that the simultaneous inhibition of PI3K and HDACs may be a promising therapeutic approach to improve the cure rates of ALL.

Long noncoding RNAs (lncRNAs) are a class of RNAs participating in many biological processes such as imprinting, alternative splicing and RNA decay. Recently, lncRNAs have drawn a great deal of attention for their critical role in cancer progression. LINC00461, a newly identified lncRNA, has been reported to be significantly overexpressed in breast cancer and markedly expedited breast cancer progression. However, the specific role of LINC00461 in nonsmall cell lung cancer (NSCLC) remains unknown. In this study, we for the first time showed the biological functions of LINC00461 in NSCLC. Our results demonstrated that LINC00461 was significantly up-regulated in NSCLC tissues and cell lines. Furthermore, knockdown of LINC00461 inhibited NSCLC cell proliferation and invasion in vitro as well as suppressed tumor growth and metastasis in vivo. We also performed luciferase reporter assays and found that LINC00461 functioned as a sponge for miR-518a-3p and WDR1 was a target of miR-518a-3p. Taken together, we suggested an essential role of LINC00461/miR-518a-3p/WDR1 axis in NSCLC, which could be used as a potential therapeutic target for NSCLC treatment.

Age-related macular degeneration (AMD) is a complex multifactorial disease associated with the dysfunction of retinal pigment epithelium (RPE). Aloperine is a quinolizidine alkaloid that has been proven to possess broad pharmacological activities. However, the effects of aloperine on AMD remain unclear. In the present study, we used hydrogen peroxide (H₂O₂) to induce oxidative injury in human RPE cells (ARPE-19 cells). ARPE-19 cells were pretreated with different concentrations of aloperine for 2 h, followed by H₂O₂ exposure. Cell cytotoxicity was determined using lactate dehydrogenase (LDH) release assay. Cell viability was measured using Cell Counting Kit-8 (CCK-8) assay. The reactive oxygen species (ROS) generation, malondialdehyde (MDA) level, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-PX) activity were detected to reflect oxidative status. Western blot was performed to detect the expressions of bcl-2, bax, nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). The activity of caspase-3 was also assessed to indicate cell apoptosis. In addition, ARPE-19 cells were transfected with siNrf2 to knock down Nrf2. Our results showed that pretreatment with aloperine elevated the reduced cell viability of H₂O₂-induced ARPE-19 cells in a dose-dependent manner. Aloperine greatly decreased the production of ROS and MDA, and increased the activities of SOD and GSH-PX in H₂O₂-stimulated ARPE-19 cells. H₂O₂-caused a decrease in bcl-2 expression and increases in bax expression and caspase-3 activity were mitigated by aloperine. Moreover, aloperine treatment enhanced the expression levels of Nrf2 in nuclear fraction and the HO-1 expression in lysates. Knockdown of Nrf2 reversed the protective effects of aloperine on H₂O₂-induced ARPE-19 cells. In conclusion, these findings demonstrated that aloperine protected ARPE-19 cells from H₂O₂-induced oxidative stress and apoptosis in part via activating the Nrf2/HO-1 signaling pathway. The findings suggested a therapeutic potential of aloperine for the treatment of ADM.

Atherosclerosis is a chronic disease of arteries, which constitutes the pathological basis of a series of cardiovascular diseases. The inflammatory response of vascular endothelial cells mediated by oxidized low density lipoprotein (ox-LDL) is the early behavior and main signal of atherosclerosis. In this study, the damage model of vascular endothelial cells treated with ox-LDL was used to reproduce the damage process of vascular endothelial cells in the process of atherosclerosis. Cell viability was detected by CCK-8. The release levels of reactive oxygen species, nitric oxide, and superoxide dismutase (SOD) were detected by commercial kits. EdU cell proliferation assay was used to detect cell proliferation, real-time fluorescent quantitative PCR and Western blot were used to detect the expression level of related genes. The results showed we successfully constructed a vascular endothelial injury model by incubating vascular endothelial cells with gradient concentrations of ox-LDL. The incubation of safflor yellow A (SYA) partially restored the loss of viability of vascular endothelial cells mediated by ox-LDL, and SYA could promote the proliferation of injured vascular endothelial cells. In addition, SYA may transmit related signals through the AMPK pathway to protect vascular endothelial cells from ox-LDL-mediated damage. All these results provide a further understanding of the occurrence and development of atherosclerosis, provide a theoretical basis for the use of SYA-related drugs in the treatment of cardiovascular diseases, and provide a reference paradigm for studying the pharmacology, toxicology, and mechanism of action of key active substances in TCM.

Parkinson's disease is a brain disorder that is featured by shaking palsy, which affect the motor system. The pathogenesis of Parkinson's disease has been ascribed to neurodegenerative disorder, neural oxidative stress, neuroinflammation, and neurotransmitter disorder. In the present study, we explored the influence of Sirt1/PGC1α pathway in regulating BV-2 cells viability under TNFα treatment. Our results demonstrated that the activity of Sirt1/PGC1α pathway was significantly downregulated in response to TNFα treatment. Reactivation of Sirt1/PGC1α pathway through supplementation of SRT1720 significantly elevated the viability of BV-2 cells under an in vitro neuroinflammation model. Therefore, our results report a novel signaling pathway responsible for the survival of neuron under neuroinflammation. Re-activation of Sirt1/PGC1α pathway may be a potential therapeutic approach for the treatment of Parkinson's disease through enhancing neuronal viability.