Temozolomide (TMZ) is the first-line chemotherapy drug for glioblastoma (GBM) but acquired TMZ resistance is frequently observed. Thus, a TMZ resistant GBM cell line U87-R was established to search for potential long noncoding RNAs (lncRNAs) used in TMZ resistance. In our study, LINC00511 was identified as a TMZ resistanceassociated lncRNA in U87-R cells by transcriptome RNA sequencing. The potential functions of LINC00511 were evaluated by quantitative real-time polymerase chain reaction, cell viability assay, colony formation assay, western blot, soft agar assay, flow cytometry, tumor xenograft model, immunofluorescence, sphere formation assay, fluorescent in situ hybridization, luciferase reporter assay, and RNA pull-down assay. We found that LINC00511 was upregulated in U87-R cells and GBM samples, and correlated with poor prognosis of GBM patients. Silencing LINC00511 impaired TMZ tolerance of U87-R cells, while LINC00511 overexpression increased TMZ resistance of sensitive GBM cells. Wnt/β-catenin signaling was activated in U87-R cells, and inhibiting Wnt/β-catenin signaling enhanced TMZ sensitivity. Furthermore, LINC00511 was mainly distributed in the cytoplasm of GBM cells and regulated Wnt/β-catenin activation by acting as a molecular sponge for miR-126-5p. Multiple genes of Wnt/β-catenin signaling such as DVL3, WISP1, and WISP2 were targeted by miR-126-5p. MiR-126-5p restoration impaired TMZ resistance of GBM cells. In conclusion, our results provided a novel insight into acquired TMZ resistance of GBM cells and suggested LINC00511 as a potential biomarker or therapeutic target for GBM patients.
ObjectiveAccumulating evidence suggests that cancer survivors may have a relatively higher risk of stroke. The aim of this meta-analysis was to determine whether cancer survivors have a relatively higher risk of stroke than cancer-free populations on the basis of published data from population-based cohort studies.MethodsPubMed, Embase, and Cochrane Library were searched from inception to February 8, 2020, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. We conducted subgroup analyses and meta-regression to explore sources of heterogeneity and the stability of the results.ResultsTwenty population-based cohort studies involving 10,479,530 participants were identified. Overall, the relative risk (RR) for stroke in cancer survivors was 1.66 (95% CI 1.35–2.04; p < 0.001) compared with that in cancer-free controls; survivors of head and neck, hematologic, lung, pancreas, and stomach cancer (all p < 0.05) showed consistently significant results, whereas no significant increased risk was observed for patients with other cancer types. The effects were more prominent in cancer survivors with female sex (RR 1.38, 95% CI 1.18–1.61; p < 0.001), younger age at cancer diagnosis (<45 years) (RR 2.57, 95% CI 1.27–5.19; p = 0.009), and shorter cancer survival duration (≥1–2 years) (RR 1.69, 95% CI 1.18–2.42; p = 0.004). Moreover, cancer survivors had a significantly increased risk of ischemic stroke (RR 1.53, 95% CI 1.28–1.84; p < 0.001) compared with hemorrhagic stroke.ConclusionsCancer plays a critical role in the etiologic of stroke. Due to the existence of substantial heterogeneity among the included studies, the results should be interpreted with caution. However, early prevention and effective intervention of stroke in cancer survivors require attention from health policy makers.
IntroductionRedox signaling initiates pathogenesis of neuronal degeneration. Plumbagin is a potential antioxidant with anti-inflammatory, anti-cancer and radio sensitizing properties. In the present study, we aimed to determine the protective role of plumbagin against H2O2-induced neurotoxicity in PC12 cells by determining nuclear factor κB (NF-κB) and nuclear factor E2-related factor 2 (Nrf-2) pathways.Material and methodsWe analyzed oxidative stress by determining reactive oxygen species (ROS) and nitrite levels, and antioxidant enzyme activities. Nrf-2 and NF-κB p65 nuclear localization was determined through immunofluorescence. Further, nuclear levels of p-Nrf-2 and downstream expression of NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase-1 (HO-1) and glutathione-s-transferase (GST) were determined by western blot. Anti-inflammatory activity was analyzed by evaluating NF-κB p65, cyclooxygenase-2 (COX-2) and interleukin (IL-6, IL-8, and MCP-1) expression.ResultsThe results showed that plumbagin increased (p < 0.01) the cell viability against H2O2-induced cell death in PC12 cells. Plumbagin effectively ameliorated H2O2-induced oxidative stress through reducing oxidative stress (p < 0.01) and activating p-Nrf-2 levels. Further, plumbagin up-regulated antioxidant enzyme activities (p < 0.01) against H2O2-induced oxidative stress. Plumbagin showed anti-inflammatory effect by suppressing NF-κB p65 activation and down-regulating NF-κB p65 and COX-2 expression. In addition, plumbagin modulated (p < 0.01) inflammatory cytokine expression against H2O2-induced neurotoxic effects.ConclusionsTogether, our results show that plumbagin modulated NF-κB and Nrf-2 signaling. Thus, plumbagin might be an effective compound in preventing H2O2-induced neurotoxicity and its associated inflammatory responses.
When being stressed, plants require a balance between the resistance pathway and metabolism. Glucosinolates (GS) are secondary metabolics that widely exist in Brassicaceae. Glutathione (GSH) not only participates in plant processing reactive oxygen species (ROS) but also directly participates in GS synthesis as a sulfur donor. Therefore, we used transcriptomic to identify antioxidant and GS metabolism responses in GSH-treated pakchoi. Our study elucidated that GSH can be used as priming to improve oxidative resistance and preferentially stimulate the expression of resistance genes such as CAT1. The reduction in transcription factor expression inhibits the key steps of the GS synthesis pathway. When ROS returned to normal level, the resistance gene decreased and returned to normal level, while GSH restored the gene expression of GS biosynthesis. This work puts forward the mechanism of GSH in regulating the antioxidant system and glucosinolate metabolic pathway, which provides a basis for further study on the relationship between environmental signals and plant metabolism and provides ideas for follow-up research.
Cholecystokinin (CCK) is an essential modulator for neuroplasticity in sensory and emotional domains. Here, we investigated the role of CCK in motor learning using a single pellet reaching task in mice. Mice with a knockout of cck gene (CCK-/-) or blockade of CCK-B receptor (CCKBR) showed defective motor learning ability; the success rate of retrieving reward remained at the baseline level compared to the wildtype mice with significantly increased success rate. We observed no long-term potentiation (LTP) upon high-frequency stimulation (HFS) in the motor cortex of CCK-/- mice, indicating a possible association between motor learning deficiency and neuronal plasticity in the motor cortex. In vivo calcium imaging demonstrated that the deficiency of CCK signalling disrupted the refinement of population neuronal activity in the motor cortex during motor skill training. Anatomical tracing revealed direct projections from CCK-expressing neurons in the rhinal cortex to the motor cortex. Inactivating the CCK neurons in the rhinal cortex using chemogenetic methods significantly suppressed motor learning, and intraperitoneal application of CCK4, a tetrapeptide CCK agonist, rescued the motor learning deficits of CCK-/- mice. In summary, our results suggest that CCK, which could be provided from the rhinal cortex, enables neuroplasticity in the motor cortex leading to motor skill learning.
Powdery mildew (PM) is the main disease that afflicts bottle gourd. Previous studies on PM mainly focused on its effects on pumpkin, melon, and other crops; however, the exact molecular mechanism of bottle gourd resistance to PM remains unclear. RNA sequencing (RNA-Seq) technology was used to investigate the dynamic changes in leaf transcriptome profiles between resistant and susceptible gourd at 12, 24, 48, and 72 h post-inoculation with powdery mildew. Compared with a susceptible variety (G3), the expression levels of the differentially expressed genes of phenylpropanoid biosynthesis, starch, and sucrose metabolism, and plant–pathogen interaction pathways in disease-resistant plants were upregulated. We propose that disease resistance and tolerance in bottle gourd are enhanced via several pathways, including the antioxidant system, phenylalanine biosynthesis, and cell wall cellulose synthesis. Our research will provide an important basis for further screening and breeding PM resistance in bottle gourd.
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