Investigating the Impact of SN-38 on Mouse Brain Metabolism Based on Metabolomics.

Purpose: SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan, has been extensively studied in drug delivery systems. However, its impact on neural metabolism remains unclear. This study aims to investigate the toxic effects of SN-38 on mouse brain metabolism. Methods: Male mice were divided into an SN-38 group and a control group. The SN-38 group received SN-38 (20 mg/kg/day) via intraperitoneal injection, while the control group was given an equal volume of a blank solvent mixture (DMSO and saline, ratio 1:9). Gas chromatography-mass spectrometry (GC-MS) was employed to analyze differential metabolites in the cortical and hippocampal regions of the SN-38-treated mice. Results: SN-38 induced metabolic disturbances in the central nervous system. Eighteen differential metabolites were identified in the hippocampus and twenty-four in the cortex, with six common to both regions. KEGG pathway enrichment analysis revealed statistically significant alterations in six metabolic pathways in the hippocampus and ten in the cortex (P<0.05). Conclusion: This study is the first to demonstrate the neurotoxicity of SN-38 in male mice through metabolomics. Differential metabolites in the hippocampal and cortical regions were closely linked to purine metabolism, pyrimidine metabolism, amino acid metabolism, and glyceride metabolism, indicating disruptions in the blood-brain barrier, energy metabolism, and central signaling pathways.

New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival.

Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.

Therapeutic effect of extracellular vesicles from different cell sources in traumatic brain injury.

Extracellular vesicles (EVs) are biologically active membrane vesicles secreted by many cells in the body. A variety of nucleic acids, proteins, and other biologically active substances in EVs can be used to exchange and transmit information between cells, thereby affecting the progression of various diseases. Numerous studies have demonstrated that EVs not only regulate changes in brain physiology but also regulate synaptic plasticity and neuronal regeneration in traumatic brain injury (TBI), which opens a new approach for the treatment of TBI. In view of the fact that most human cells can secrete EVs, and relevant experiments have proved that different doses of EVs have different therapeutic effects on TBI. To this end, this paper reviews the therapeutic effects of EVs from different cell sources and their doses on TBI.

Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio in Patients With Newly Diagnosed Moyamoya Disease: A Cross-Sectional Study.

Inflammation has been proven to be one of the key factors in the pathogenesis of moyamoya disease (MMD). Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are cheap and reliable biomarkers of inflammation. Nevertheless, evidence regarding the relationship among PLR and NLR in patients with MMD is limited. The focus of this subject was to explore the relationship between PLR and NLR in patients with newly diagnosed MMD. Patients and methods: A cross-sectional study was performed including 261 patients with diagnosed MMD for the first time who were enrolled from our hospital, from 24 March 2013 to 24 December 2018. The clinical characteristics were collected for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were showed. Results: The mean levels or median values (interquartile range) of PLR and NLR were 146.979 ± 51.203 and 2.241 (1.589-2.984), respectively. A significant positive correlation between PLR and NLR levels (P < 0.001) was showed by the univariate analysis. Furthermore, a non-linear relationship was detected between PLR and NLR by smooth curve fitting after adjusting for potential confounders. A multivariate piecewise linear regression model revealed a significant positive correlation between PLR and NLR when the PLR level was lower than 219.82 (ß 0.012, 95% CI 0.005, 0.019; P = 0.001). PLR was also significantly positively associated with NLR when PLR concentrations were >219.82 (ß 0.098, 95% CI 0.069, 0.128; P < 0.001). Conclusion: There seemed to be a positive association between PLR and NLR in patients with MMD. This may help to further explain the role of inflammation in the occurrence and progress of MMD.

LncRNA PSMB8-AS1 acts as ceRNA of miR-22-3p to regulate DDIT4 expression in glioblastoma.

Glioblastoma (GBM) is known to be one of the most fatal malignanies in central nerve system. Unfortunately, the therapies for glioblastoma still calls for further improvements. Increasing evidences have shown that the aberrant expression of long non-coding RNAs (lncRNAs) is highly relevant to glioma tumorigenesis and prognosis of GBM patients. High expression trends of lncRNA PSMB8-AS1 was observed in both glioblastoma tissues and cells. In return, GBM cell proliferation, apoptosis and radioresistance were regulated by PSMB8-AS1. In the meantime, PSMB8-AS1 mainly located in cytoplasm of glioblastoma cells, indicating post-transcriptional regulation. MiRNA-22-3p was found to contain potential binding site with PSMB8-AS1. On the other hand, low expression of miR-22-3p was exhibited in glioblastoma tissues and cells. Besides, PSMB8-AS1 and miR-22-3p had mutual suppression on the expression of each other in GBM cells. Furthermore, overexpression of PSMB8-AS1 promoted the level of DDIT4 through inhibiting miR-22-3p. Rescue assays demonstrated that overexpression of DDIT4 counteracted the impact of proliferation, apoptosis and radioresistance silencing PSMB8-AS1 lay on glioblastoma cell. Taken together, lncRNA PSMB8-AS1 acts as miR-22-3p sponge to mediate DDIT4 expression and regulate glioblastoma progression. PSMB8-AS1 might become a therapeutic target in the future.

Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway.

Emodin, an anthraquinone compound extracted from rhubarb and other traditional Chinese medicines, has been proven to have a wide range of pharmacological effects, such as anti-inflammatory, antiviral, and antitumor activities. Previous studies have confirmed that emodin has inhibitory effects on various solid tumors, such as osteosarcoma, liver cancer, prostate cancer and glioma. This study aimed to investigate the effects and mechanisms of emodin-induced necroptosis in the glioma cell line U251 by targeting the TNF-α/RIP1/RIP3 signaling pathway. We found that emodin could significantly inhibit U251 cell proliferation, and the viability of U251 cells treated with emodin was reduced in a dose- and time-dependent manner. Flow cytometry assays and Hoechst-PI staining assays showed that emodin induced apoptosis and necroptosis. Real-time PCR and western blot analysis showed that emodin upregulated the levels of TNF-α, RIP1, RIP3 and MLKL. Furthermore, the RIP1 inhibitor Nec-1 and the RIP3 inhibitor GSK872 attenuated the killing effect of emodin on U251 cells. In addition, emodin could increase the levels of TNF-α, RIP1, RIP3 and MLKL in vivo. The results demonstrate that emodin could induce necroptosis in glioma possibly through the activation of the TNF-α/RIP1/RIP3 axis. These studies provide novel insight into the induction of necroptosis by emodin and indicate that emodin might be a potential candidate for treating glioma through the necroptosis pathway.

Serum Uric Acid and Triglycerides in Chinese Patients with Newly Diagnosed Moyamoya Disease: A Cross-Sectional Study.

BACKGROUND: Evidence regarding the relationship between serum uric acid and triglycerides is limited. Therefore, the specific objective of this study was to investigate whether serum uric acid was independently related to triglycerides in Chinese patients with newly diagnosed moyamoya disease after adjusting for other covariates. METHODS: The present study was a cross-sectional study. A total of 261 Chinese patients with newly diagnosed moyamoya disease were recruited from a hospital in China from 24 March 2013 to 24 December 2018. The independent variable and the dependent variable were serum uric acid measured at baseline and triglycerides, respectively. The covariates involved in this study included age, sex, body mass index, smoking status, and alcohol consumption. RESULTS: The average age of the 227 selected participants was 47.5 ± 12.6 years old, and approximately 48.5% of them were male. The results of the fully adjusted linear regression showed that serum uric acid (10 µmol/L) was positively associated with triglycerides (mmol/L) after adjusting for confounders (ß 0.048, 95% CI 0.032, 0.064). CONCLUSIONS: In patients with moyamoya disease, there seemed to be a positive association between serum uric acid and triglycerides.

Difference in the Inhibitory Effect of Temozolomide on TJ905 Glioma Cells and Stem Cells.

This study aims to determine the difference in the inhibitory effect of temozolomide (TMZ) on TJ905 glioma cells and stem cells. TJ905 cancer stem cells were isolated. Livin is a member of the inhibitor of apoptosis protein family. The TJ905 cells and cancer stem cells were transfected with a Livin-shRNA and negative-shRNA, respectively, and then treated with TMZ. At 48 h post-transfection, a cell counting kit 8 assay, flow cytometry, and real-time qPCR were performed to detect cell proliferation, the cell cycle, and the expression of the Caspase-3, -7, and -9 mRNAs, respectively. As a result, the suppressive effect of TMZ on TJ905 cells was more significant than its effect on TJ905 cancer stem cells. TMZ exerted an inhibitory effect on the growth of TJ905 glioma cells by arresting them at G0/G1 phase and arresting cancer stem cells at S phase in a dose-dependent manner. TMZ inhibited Livin mRNA expression and increased the expression of the Caspase-3, -7, and -9 mRNAs. Low Livin mRNA expression induced high levels of Caspase-3, -7, and -9 expressions, thus promoting the apoptosis of both TJ905 cells and cancer stem cells in response to TMZ treatment. The TJ905 cells transfected with the Livin-shRNA were more sensitive to TMZ, whereas the TJ905 glioma stem cells transfected with the Livin-shRNA showed no significant changes in their sensitivity to TMZ. In conclusion, the Livin gene may play an important role in the resistance mechanisms of TJ905 glioma cells and cancer stem cells. However, Livin had a more distinct role in TMZ resistance, cell proliferation, and the cell cycle in TJ905 glioma cells than in cancer stem cells.

Effect of Corilagin on the Proliferation and NF-κB in U251 Glioblastoma Cells and U251 Glioblastoma Stem-Like Cells.

Background. This study is to explore the effect of corilagin on the proliferation and NF-κB signaling pathway in U251 glioblastoma cells and U251 glioblastoma stem-like cells. Methods. CD133 positive U251 glioblastoma cells were separated by immunomagnetic beads to isolate glioblastoma stem-like cells. U251 cells and stem-like cells were intervened by different corilagin concentrations (0, 25, 50, and 100 µg/mL) for 48 h, respectively. Cell morphology, cell counting kit-8 assay, flow cytometry, dual luciferase reporter assay, and a western blot were used to detect and analyze the cell proliferation and cell cycle and investigate the expression of IKBα protein in cytoplasm and NF-κB/p65 in nucleus. Results. Corilagin inhibited the cell proliferation of U251 cells and their stem-like cells and the inhibition role was stronger in U251 stem-like cells (P < 0.05). The cell cycle was arrested at G2/M phase in the U251 cells following corilagin intervention; the proportion of cells in G2/M phase increased as the concentration of corilagin increased (P < 0.05). The U251 stem-like cells were arrested at the S phase following treatment with corilagin; the proportion of cells in the S phase increased as the concentration of corilagin increased (P < 0.05). The ratio of dual luciferase activities of U251 stem-like cells was lower than that of U251 cells in the same corilagin concentration. With increasing concentrations of corilagin, the IKBα expression in cytoplasm of U251 cells and U251 stem-like cells was increased, but the p65 expression in nucleus of U251 cells and U251 stem-like cells was decreased (P < 0.05). Conclusion. Corilagin can inhibit the proliferation of glioblastoma cells and glioblastoma stem-like cells; the inhibition on glioblastoma stem-like cell proliferation is stronger than glioblastoma cells. This different result indicates that the effect of corilagin on U251 cells and U251 stem-like cells may have close relationships with mechanism of cell cycle and NF-κB signaling pathway; however, the real antitumor mechanism of corilagin is not yet clear and requires further study.

Pathological features of transplanted tumor established by CD133 positive TJ905 glioblastoma stem-like cells.

BACKGROUND: This study is to explore the pathological features of transplanted tumor established by CD133 positive TJ905 glioblastoma stem-like cells. METHODS: CD133 positive TJ905 glioma cells were separated by immunomagnetic beads to isolate glioma stem-like cells. TJ905 cells and stem-like cells were inoculated subcutaneously into the mice to establish model of transplanted tumor, respectively. Mice growing condition and behavior were observed. HE staining assay, immunohistochemical assay for GFAP, Ki-67 and Olig-2, and CD34 marked microvascular density (MVD) test were performed. RESULTS: The growing condition and behavior of mice in TJ905 stem cell group was more exaggerated and the models showed stronger malignant features pathologically than that in TJ905 cell group. Glial fibrillary acidic protein (GFAP) in TJ905 cell and stem-like cell group showed the transplanted tumor originated from astrocytes. Expression of Ki-67 and oligodendrocyte transcription factor-2 (Olig-2) in TJ905 stem cells was higher notably and CD34 expression in stem cell group was significantly higher than that in the other two groups. CONCLUSIONS: Pathological features of transplanted tumor established by CD133 positive glioblastoma stem-like cells show more malignant. Use of TJ905 stem cells to establish transplanted tumor model in nude mice is excellent for glioma research.

[Treatment of moyamoya disease by superficial temporal artery-middle cerebral artery anastomosis].

OBJECTIVE: To explore the clinical efficacy and experiences of superficial temporal artery-middle cerebral artery anastomosis (STA-MCA) for the treatment of adult Moyamoya disease. METHOD: Preoperative and postoperative clinical data of 60 patients with moyamoya disease from affiliated hospital of jining medical college were analyzed retrospectively, including 46 cases of ischemic lesion and 14 cases of hemorrhage lesion. All patients were diagnosed with moyamoya disease by DSA and received STA-MCA anastomosis. RESULTS: The clinical symptoms of 52 patients disappeared after surgery; the clinical symptoms were improved in 6 patients; 1 patient complicated with cerebral infarction; 1 patients reoccurred cerebral hemorrhage broken into ventricles 1 year after anastomosis. CONCLUSION: STA-MCA anastomosis can improve the symptoms of ischemic moyamoya disease effectively and reduce the recurrence of cerebral hemorrhage. STA-MCA anastomosis is a rational and effective approach for the treatment of adult Moyamoya disease.