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"Wu, Jiao"
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Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis
Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
Journal Article
New perspectives on the therapeutic potential of quercetin in non-communicable diseases: Targeting Nrf2 to counteract oxidative stress and inflammation
Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and anti-inflammatory responses to protect the cells from oxidative damage and inflammation-mediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases (NDDs), cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.
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•Quercetin, a readily available flavonoid, shows promise in anti-NCDs by strongly binding to Nrf2.•Nrf2-targeted Quercetin demonstrates robust antioxidant and anti-inflammatory capabilities.•Quercetin modulates mitochondria, apoptosis, and autophagy by Nrf2, thereby enhancing its potential against NCDs.
Journal Article
Ginsenoside CK, rather than Rb1, possesses potential chemopreventive activities in human gastric cancer via regulating PI3K/AKT/NF-κB signal pathway
Ginsenoside Rb1, a main component of ginseng, is often transformed into ginsenoside CK by intestinal flora to exert various pharmacological activity. However, it remains unclear whether ginsenoside CK is responsible for the anti-gastric cancer effect of ginsenoside Rb1 in vivo . In this study, network pharmacology was applied to predict the key signal pathways of ginsenoside Rb1 and ginsenoside CK when treating gastric cancer. The anti-proliferative effects of ginsenoside Rb1 and ginsenoside CK and the underlying mechanism in gastric cancer cells were explored by MTT, Hoechst3328 staining, ELISA, RT-qPCR and Western blotting. The results showed that PI3K-AKT/NF-κB signal pathway was the common important pathway of ginsenoside Rb1 and CK in the treatment of gastric cancer. The results of MTT assay showed that ginsenoside Rb1 could hardly inhibit the proliferation of HGC-27 cells, whereas ginsenoside CK could inhibit the proliferation of HGC-27 cells. Hoechst3328 staining showed that cells in the ginsenoside CK group were densely stained bright blue and nuclear fragmented, indicating that apoptosis occurred. ELISA results showed that ginsenoside CK could effectively downregulate the levels of cyclin CyclinB1 and CyclinD1, but ginsenoside Rb1 had no significant effect. Also, the results of Western blot and RT-qPCR showed that ginsenoside CK inhibited the expressions of anti-apoptosis-related protein Bcl-2 and apoptosis-related pathway PI3K/AKT/NF-κB, and promoted the expression of pro-apoptosis proteins Bax and Caspase 3, whereas ginsenoside Rb1 exerted no effect. In short, ginsenoside Rb1 had no anti-gastric cancer cell activity in vitro , but ginsenoside CK could effectively inhibit cell proliferation and induce cell apoptosis in HGC-27 cells. The mechanism might relate to the inhibitory effect of ginsenoside CK on the PI3K/AKT/NF-κB pathway. These results suggest that ginsenoside CK might be the in vivo material basis for the anti-gastric cancer activity of ginsenosides.
Journal Article
Fuzzy cooperative game analysis within the international railway freight coalition framework
International railway freight cooperation is essential for enhancing regional logistics efficiency, especially in the context of rising anti-globalization trends and pandemic-induced disruptions to maritime transport. This study aims to develop a stable and equitable allocation mechanism for freight volume and operating revenue (freight revenue collected by a country’s rail system or designated freight operators) under the international rail freight coalition framework. We construct a fuzzy cooperative game model that accounts for export demand, participation levels, transport resource utilization, and return empty load rates. Results from the CSERE case show that the proposed scheme increases total operating revenue by 37.85–204.88% for member countries compared to traditional mileage-based allocations, and reduces the return empty load rate from 40 to 7.83%. The fuzzy coalition model ensures fair compensation for disadvantaged countries and enhances the overall stability of cooperation. These findings offer practical insights for policymakers and rail freight operators aiming to promote efficient multilateral trade logistics. The originality of this work lies in integrating fuzzy coalition game theory with real-world data to address strategic behavior and empty return issues in international rail freight.
Journal Article
Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer
Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.
Journal Article
Emerging Significance of Ginsenosides as Potentially Reversal Agents of Chemoresistance in Cancer Therapy
Chemoresistance has become a prevalent phenomenon in cancer therapy, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of the survival rate of tumor patients. Current approaches for reversing chemoresistance are poorly effective and may cause numerous new problems. Therefore, it is urgent to develop novel and efficient drugs derived from natural non-toxic compounds for the reversal of chemoresistance. Researches in vivo and in vitro suggest that ginsenosides are undoubtedly low-toxic and effective options for the reversal of chemoresistance. The underlying mechanism of reversal of chemoresistance is correlated with inhibition of drug transporters, induction of apoptosis, and modulation of the tumor microenvironment(TME), as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (NRF2)/AKT, lncRNA cancer susceptibility candidate 2(CASC2)/ protein tyrosine phosphatase gene (PTEN), AKT/ sirtuin1(SIRT1), epidermal growth factor receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/AKT, PI3K/AKT/ mammalian target of rapamycin(mTOR) and nuclear factor- κ B (NF- κ B). Since the effects and the mechanisms of ginsenosides on chemoresistance reversal have not yet been reviewed, this review summarized comprehensively experimental data in vivo and in vitro to elucidate the functional roles of ginsenosides in chemoresistance reversal and shed light on the future research of ginsenosides.
Journal Article
Effectiveness of Omega-3 Polyunsaturated Fatty Acids in Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials
Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome with the main characteristic of diffuse liver cells with fatty changes. The clinical evolution of NAFLD includes simple non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis, and even hepatocellular carcinoma.
We conducted this review to identify the effectiveness of omega-3 polyunsaturated fatty acids (ω-3 PUFA) in NAFLD. We searched PubMed, Cochrane Library and Embase. All randomized controlled trials (RCTs) of ω-3 PUFA treatment for NAFLD were considered. Two reviewers assessed the quality of each study and collected data independently. Disagreements were resolved by discussion among the reviewers and any of the other authors of the paper. We performed a meta-analysis and reported summary estimates of outcomes as inverse variance (IV), fixed or random, with 95% confidence intervals (CIs). We included seven RCTs involving 442 patients (227 for the experimental group and 215 for the control group). All the patients were divided into two groups: one treated with ω-3 PUFA and the other was the control group (generally placebo). The demographics of the ω-3 PUFA and control groups were comparable. Beneficial changes in alanine aminotransferase (ALT) (IV 95% CI: -7.61 [-12.83 to -2.39], p = 0.004), total cholesterol (TC) (IV 95% CI: -13.41 [-21.44 to -5.38], p = 0.001), triglyceride (TG) (IV 95% CI: -43.96 [-51.21 to -36.71], p<0.00001) and high-density lipoprotein cholesterol (HDL-C) (IV 95% CI: 6.97 [2.05 to 11.90], p = 0.006) favored ω-3 PUFA treatment. Omega-3 PUFA tended towards a beneficial effect on aspartate aminotransferase (AST) (IV 95% CI: -6.89 [-17.71 to 3.92], p = 0.21), γ-glutamyl transferase (GGT) (IV 95% CI: -8.28 [-18.38 to 1.83], p = 0.11) and low-density lipoprotein cholesterol (LDL-C) (IV 95% CI: -7.13 [-14.26 to 0.0], p = 0.05).
Supplementation with ω-3 PUFA is a practical and effective treatment for NAFLD to decrease ALT, TC and increase HDL-C, especially to decrease TG. Omega-3 PUFA also has a tendency toward a beneficial effect on AST, GGT and LDL-C. More high-quality, large RCTs are needed to validate our findings.
Journal Article
Hellinger distance-based stable sparse feature selection for high-dimensional class-imbalanced data
Background
Feature selection in class-imbalance learning has gained increasing attention in recent years due to the massive growth of high-dimensional class-imbalanced data across many scientific fields. In addition to reducing model complexity and discovering key biomarkers, feature selection is also an effective method of combating overlapping which may arise in such data and become a crucial aspect for determining classification performance. However, ordinary feature selection techniques for classification can not be simply used for addressing class-imbalanced data without any adjustment. Thus, more efficient feature selection technique must be developed for complicated class-imbalanced data, especially in the context of high-dimensionality.
Results
We proposed an algorithm called sssHD to achieve stable sparse feature selection applied it to complicated class-imbalanced data. sssHD is based on the Hellinger distance (HD) coupled with sparse regularization techniques. We stated that Hellinger distance is not only class-insensitive but also translation-invariant. Simulation result indicates that HD-based selection algorithm is effective in recognizing key features and control false discoveries for class-imbalance learning. Five gene expression datasets are also employed to test the performance of the sssHD algorithm, and a comparison with several existing selection procedures is performed. The result shows that sssHD is highly competitive in terms of five assessment metrics. In addition, sssHD presents limited differences between performing and not performing re-balance preprocessing.
Conclusions
sssHD is a practical feature selection method for high-dimensional class-imbalanced data, which is simple and can be an alternative for performing feature selection in class-imbalanced data. sssHD can be easily extended by connecting it with different re-balance preprocessing, different sparse regularization structures as well as different classifiers. As such, the algorithm is extremely general and has a wide range of applicability.
Journal Article
Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis
The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies.
Journal Article