Cerium oxide nanoparticles: potential applications for cancer and other diseases

The diverse abilities of cerium oxide nanoparticles (CONPs) have encouraged researchers to pursue CONPs as a therapeutic agent to treat a number of diseases, including cancer. In vitro and in vivo studies have shown CONPs to be toxic to cancer cells, inhibit invasion, and sensitize cancer cells to radiation therapy. However, CONPs display minimal toxicity to normal tissues and provide protection from various forms of reactive oxygen species (ROS) generation. The antioxidant capabilities of CONPs, which enable radiation protection, have also resulted in the exploration of these particles as a potential treatment for other disorders characterized by ROS accumulation, such as diabetes and macular degeneration. While critical information regarding the uptake, retention, and clearance of these particles is incomplete and conflicting reports exist about in vitro toxicity, most research into the various applications of CONPs has yielded promising data. This review highlights the current research into cerium oxide nanoparticles as a novel therapeutic for the treatment of cancer and other diseases

Kruppel-like factor 8 emerges as an important regulator of cancer

Kruppel-like factor 8 (KLF8) is a young member of the KLF transcription factor family proteins. It is highly overexpressed in several types of human cancers and regulates various cellular processes important for tumor progression. Increasing evidence has made KLF8 a new focus in cancer research and a potential target for cancer therapy. This review highlights the role of KLF8 in cancer by summarizing the up-to-date studies into its structure, function as a dual transcription factor, target genes and mechanisms of expression and modifications

Using “Digital Black Hole” to Help Student in Learning Arithmetic and Enhance Students' Interest in Learning

For most students, mathematics is difficult, boring, and not fun. However, mathematics is of great help in terms of academic performance and the development of students' calculation ability and abstract logical thinking. So how to make students like mathematics? How to improve students' mathematical ability? In response to these two doubts, this article designed the following teaching links based on HPM. The research method in this research is descriptive qualitative by describing the lesson plan on arithmetic material. The sample and population were grade 3, Elementary school, in Guilin, China. The results showed that in the real class, it was found that students were very interested in the "Digital Black Hole" game, their mathematical calculation ability and the ability to find problems All have improved a lot. This shows that under the guidance of HPM, eliciting mathematics teaching through mathematics culture can help increase students’ interest in mathematics, and students are also more aware that there are many magical relationships between numbers and numbers, which are worthy of us. Go explore and discover

Research on a safety evaluation system for railway-tunnel structures by fuzzy comprehensive evaluation theory

Long-term health detection of railway-tunnel is the development direction and trend of future railway tunnel research. Based on the actual engineering of a railway tunnel, this study developed a safety evaluation model for railway tunnel structures using a fuzzy comprehensive evaluation method and examined a health state evaluation method suitable for most railway tunnel structures. The results showed that the evaluation method comprehensively reflected the impact of various factors, which had strong practicality. The evaluation results were clear, accurate, and consistent with engineering practice. When using the safety factor index to study the stress of a railway tunnel structure, Midas/civil analysis showed that different levels of the surrounding rock structural vault in railway tunnels were in a tensile, control-bearing capacity state. When calculating safety factors, the range of a 60° central angle of a railway tunnel vault was calculated according to the tensile control-bearing capacity. Theoretical formulas of the range of the center angle φ0 of the vault tension zone were derived and then verified by experiments and numerical analysis

Identification of Poly (ADP-ribose) Polymerase-1 (PARP-1) as a Novel Kruppel-like Factor 8-interacting and -regulating Protein

Kruppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, KLF8-interacting proteins remain largely unidentified. Using co-immunoprecipitation (co-IP), mass spectrometry, and GST pulldown assays, we identified poly(ADP-ribose) polymerase-1(PARP-1) as a novel KLF8-interacting protein. Co-IP and Western blotting indicated that KLF8 is also a PARP-1 substrate. Mutation of the cysteines in the zinc finger domain of KLF8 abolished PARP-1 interaction. Surprisingly, immunofluorescent staining revealed a cytoplasmic mislocalization of KLF8 in PARP-1(-/-) cells or when the interaction was disrupted. This mislocalization was prevented by either PARP-1 re-expression or inhibition of CRM1-dependent nuclearexport. Interestingly, co-IP indicated competition between PARP-1 and CRM1 for KLF8 binding. Cycloheximide chase assay showed a decrease in the half-life of KLF8 protein when PARP-1 expression was suppressed or KLF8-PARP-1 interaction was disrupted. Ubiquitination assays implicated KLF8 as a target of ubiquitination that was significantly higher in PARP-1(-/-) cells. Promoter reporter assays and chromatin immunoprecipitation assays showed that KLF8 activation on the cyclin D1 promoter was markedly reduced when PARP-1 was deleted or inhibited or when KLF8-PARP-1 interaction was disrupted. Overall, this work has identified PARP-1 as a novel KLF8-binding and-regulating protein and provided new insights into the mechanisms underlying the regulation of KLF8 nuclear localization, stability, and functions

Krüppel-like factor 8 promotes tumorigenic mammary stem cell induction by targeting miR-146a

The properties of stem cells can be induced during the epithelial to mesenchymal transition (EMT). The responsible molecular mechanisms, however, remain largely undefined. Here we report the identification of the microRNA-146a (miR-146a) as a common target of Krüppel-like factor 8 (KLF8) and TGF-β, both of which are known EMT-inducers. Upon KLF8 overexpression or TGF-β treatment, a significant portion of the MCF-10A cells gained stem cell traits as demonstrated by an increased expression of CD44(high)/CD24(low), activity of aldehyde dehydrogenase (ALDH), mammosphere formation and chemoresistance. Along with this change, the expression of miR-146a was highly upregulated in the cells. Importantly, we found that miR-146a was aberrantly co-overexpressed with KLF8 in a panel of invasive human breast cancer cell lines. Ectopic expression of KLF8 failed to induce the stem cell traits in the MCF-10A cells if the cells were pre-treated with miR-146a inhibitor, whereas overexpression of miR-146a in the MCF-10A cells alone was sufficient to induce the stem cell traits. Co-staining and luciferase reporter analyses indicated that miR-146a targets the 3’-UTR of the Notch signaling inhibitor NUMB for translational inhibition. Overexpression of KLF8 dramatically potentiated the tumorigenecity of MCF-10A cells expressing the H-Ras oncogene, which was accompanied by a loss of NUMB expression in the tumors. Taken together, this study identifies a novel role and mechanism for KLF8 in inducing pro-tumorigenic mammary stem cells via miR-146a potentially by activating Notch signaling. This mechanism could be exploited as a therapeutic target against drug resistance of breast cancer

Detergent-insoluble PFN1 inoculation expedites disease onset and progression in PFN1 transgenic rats

Accumulating evidence suggests a gain of elusive toxicity in pathogenically mutated PFN1. The prominence of PFN1 aggregates as a pivotal pathological hallmark in PFN1 transgenic rats underscores the crucial involvement of protein aggregation in the initiation and progression of neurodegeneration. Detergent-insoluble materials were extracted from the spinal cords of paralyzed rats afflicted with ALS and were intramuscularly administered to asymptomatic recipient rats expressing mutant PFN1, resulting in an accelerated development of PFN1 inclusions and ALS-like phenotypes. This effect diminished when the extracts derived from wildtype PFN1 transgenic rats were employed, as detergent-insoluble PFN1 was detected exclusively in mutant PFN1 transgenic rats. Consequently, the factor influencing the progression of ALS pathology in recipient rats is likely associated with the presence of detergent-insoluble PFN1 within the extracted materials. Noteworthy is the absence of disease course modification upon administering detergent-insoluble extracts to rats that already displayed PFN1 inclusions, suggesting a seeding rather than augmenting role of such extracts in initiating neuropathological changes. Remarkably, pathogenic PFN1 exhibited an enhanced affinity for the molecular chaperone DNAJB6, leading to the sequestration of DNAJB6 within protein inclusions, thereby depleting its availability for cellular functions. These findings shed light on a novel mechanism that underscores the prion-like characteristics of pathogenic PFN1 in driving neurodegeneration in the context of PFN1-related ALS

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

Background: Metabolic homeostasis is central to normal cardiac function. The molecular mechanisms underlying metabolic plasticity in the heart remain poorly understood. Results: Kruppel-like factor 15 (KLF15) is a direct and independent regulator of myocardial lipid flux. Conclusion: KLF15 is a core component of the transcriptional circuitry that governs cardiac metabolism. Significance: This work is the first to implicate the KLF transcription factor family in cardiac metabolism. The mammalian heart, the body\u27s largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15-deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co-activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabolism

Cancer Stem Cells And Chemoresistance: The Smartest Survives The Raid

Chemoresistant metastatic relapse of minimal residual disease plays a significant role for poor prognosis of cancer. Growing evidence supports a critical role of cancer stem cell (CSC) behind the mechanisms for this deadly disease. This review briefly introduces the basics of the conventional chemotherapies, updates the CSC theories, highlights the molecular and cellular mechanisms by which CSC smartly designs and utilizes multiple lines of self-defense to avoid being killed by chemotherapy, and concisely summarizes recent progress in studies on CSC-targeted therapies in the end, with the hope to help guide future research toward developing more effective therapeutic strategies to eradicate tumor cells in the patients