Nrf2 in human cancers: biological significance and therapeutic potential.

The nuclear factor-erythroid 2-related factor 2 (Nrf2) is able to control the redox balance in the cells responding to oxidative damage and other stress signals. The Nrf2 upregulation can elevate the levels of antioxidant enzymes to support against damage and death. In spite of protective function of Nrf2 in the physiological conditions, the stimulation of Nrf2 in the cancer has been in favour of tumorigenesis. Since the dysregulation of molecular pathways and mutations/deletions are common in tumors, Nrf2 can be a promising therapeutic target. The Nrf2 overexpression can prevent cell death in tumor and by increasing the survival rate of cancer cells, ensures the carcinogenesis. Moreover, the induction of Nrf2 can promote the invasion and metastasis of tumor cells. The Nrf2 upregulation stimulates EMT to increase cancer metastasis. Furthermore, regarding the protective function of Nrf2, its stimulation triggers chemoresistance. The natural products can regulate Nrf2 in the cancer therapy and reverse drug resistance. Moreover, nanostructures can specifically target Nrf2 signaling in cancer therapy. The current review discusses the potential function of Nrf2 in the proliferation, metastasis and drug resistance. Then, the capacity of natural products and nanostructures for suppressing Nrf2-mediated cancer progression is discussed.

GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

Simvastatin Inhibits Endometrial Cancer Malignant Behaviors by Suppressing RAS/Mitogen-Activated Protein Kinase (MAPK) Pathway-Mediated Reactive Oxygen Species (ROS) and Ferroptosis.

This paper was designed to explore the function of simvastatin as a chemotherapeutic drug on the endometrial cancer (EC) cell proliferation, invasion, and ferroptosis. Firstly, a number of in vitro experiments were conducted to determine the impact of different treatments of simvastatin on the Ishikawa cell invasion, proliferation, and colony formation. The concentration of DCFH-DA-labeled reactive oxygen species (ROS) in cells was assessed by flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was performed to examine the intracellular contents of Fe2+, malondialdehyde (MDA), and glutathione (GSH). Additionally, Western blot was utilized to measure the expression level of RAS/mitogen-activated protein kinase (MAPK)-related proteins and ferroptosis-related proteins in cells. The results showed that simvastatin at 10 µM and 15 µM apparently suppressed the proliferation of Ishikawa cells, colony formation, and invasion ability of Ishikawa cells, and upregulated the level of MDA and ROS, but downregulated the level of GSH. Besides, 10 µM and 15 µM of simvastatin promoted cell ferroptosis (up-regulation of Fe2+ and TRF 1 protein level; down-regulation of SLC7A11 and FPN protein level) and lowered the RAS, p-MEK, and ERK protein level. Furthermore, experiments also revealed that the inhibitory effects of simvastatin on Ishikawa cell proliferation, colony formation, and invasion, as well as the promoting effects on oxidation and ferroptosis were reversed. All in all, simvastatin reduces the RAS/MAPK signaling pathway to inhibit Ishikawa cell proliferation, colony formation, and invasion, and promote cell oxidation and ferroptosis. This paper demonstrates the potential of simvastatin as a new anticancer drug for EC.

Design of functionalized magnetic silica multi-core composite nanoparticles for synergistic magnetic hyperthermia/radiotherapy in cancer cells.

Nanomaterials in particular the magnetic nanoparticles (MNPs) offer tremendous potential for cancer treatment due to their unique intrinsic properties. Combining materials with a variety of functional groups, and forming a multifunctional nanosystem to overcome the limitations of monotherapy for cancer treatment has always been a research focus with notable difficulties. Considering the many challenges faced by radiotherapy and hyperthermia, in this study, we designed a rational strategy for magnetic hyperthermia using Fe3O4@SiO2@Sec2@FA nanoparticles as a novel nano-radiosensitizer to simultaneously enhance the therapeutic effects of radiotherapy in the future. Fe3O4@SiO2 core-shell structured nanoparticles were synthesized with an appropriate silica layer thickness to maintain good saturation magnetization. The as-prepared Fe3O4@SiO2@Sec2@FA nanoparticles had the specific absorption rate (SAR)value of 57 W/g, which was below the clinically acceptable alternating magnetic field value of 4.9 × 109 Am-1s-1, indicating good heat generation efficiency (the temperature level ΔT=6-10 °C). Moreover, Folate-modified nanoparticles exhibited approximately 6-fold higher cellular internalization of Hela cells with no obvious cytotoxicity for the Hela and MDA-MB-231 cells, and lower cytotoxicity for the HUVECs in a concentration range of 0-150 µg/mL. In addition, these nanoparticles were modified on the silica surface by L-selenocystine, which could enhance the elimination of tumor cells by producing reactive oxygen species under X-rays, resulting in a novel radiosensitization effect. Therefore, the as-prepared Fe3O4@SiO2@Sec2@FA nanoparticles with good biocompatibility and active targeting would possess synergistic magnetic hyperthermia/radiotherapy effect.

Levels and Distributions of 210Pb and 210Po in Selected Seafood Samples in China and Assessment of Related Dose to Population.

In this study, the activity concentrations levels of 210Pb and 210Po in the edible portions of eight seafood samples collected from the Fujian coast of China were determined. The activity concentrations ranged from 0.74 ± 0.08 to 12.6 ± 1.0 Bq/kg for 210Po and from the minimum detectable limit (MDL, 0.80 Bq/kg) to 11. 7 ± 1.1 Bq/kg for 210Pb. The 210Po activity concentration in all the fish organs ranged from 0.68 to 204 Bq/kg (w.w.), and the 210Po activity was mainly concentrated in the stomach, spleen, heart, liver, gonad, and intestine samples. The 210Pb activity concentration in all the fish organs ranged from the MDL to 15.2 Bq/kg (w.w.), and the 210Pb activity was concentrated in the head, fish scale, and gill samples. The annual effective ingestion doses ranged from 82.8 to 255 µSv/a for all age groups, and the lifetime risk of cancers were estimated. Both the effective ingestion doses and cancer risk to humans were within the acceptable ranges.

Simultaneous determination of 210Pb and 210Po in seafood samples using liquid scintillation counting.

The measurement of 210Pb and 210Po in seafood samples has attracted tremendous interest because of their radiotoxicity. In this study, a fast and cost-efficient method for the simultaneous determination of 210Pb and 210Po in seafood samples by ultralow-level liquid scintillation counting after separation on a Sr•spec column was developed. The recoveries of 210Pb and 210Po were ~70% and ~85%, respectively. The minimum detectable activity of the proposed method for 210Pb and 210Po was 3.85 Bq/kg and 1.50 Bq/kg, respectively, which is suitable for the determination of 210Pb and 210Po in seafood samples. The radiochemical procedure was validated by measuring 210Pb and 210Po activity concentrations in IAEA-certified reference materials and successfully applied to shrimp and clam samples.

Estimation of Inhaled Effective Doses of Uranium and Thorium for Workers in Bayan Obo Ore and the Surrounding Public, Inner Mongolia, China.

Uranium and thorium are two common natural radioactive elements with high concentrations in Earth's crust. The main aim of this study is to estimate the inhaled effective dose of uranium and thorium caused by a typical radioactive rare earth ore to the occupational population and the surrounding public. The particulate matter (PM) concentrations in the atmosphere of four typical workplaces and one surrounding living area were obtained by a high-flow sampling equipment with a natural cellulose filter membrane. The critical parameter for the inhaled effective dose estimation-the activity median aerodynamic diameter (AMAD)-was determined. The AMAD values of uranium and thorium in the atmosphere PM were 3.36 and 3.64 µm, respectively. The estimated median effective dose caused by inhalation thorium among the occupational population ranged from 15.3 to 269.0 µSv/a, and the corresponding value for the surrounding public was 2.3 µSv/a. All values for the effective dose caused by the inhalation of uranium were in the nSv magnitude.

A Novel Circulating MiRNA-Based Signature for the Diagnosis and Prognosis Prediction of Early-Stage Cervical Cancer.

BACKGROUND: MicroRNAs (miRNAs) have been shown to play a key role in regulating the progression of cervical cancer (CC). This study aimed to develop a circulating miRNA-based molecular signature for the diagnosis and prognosis prediction of early-stage CC. METHODS: This study included 112 patients diagnosed with early-stage CC, 45 patients confirmed with cervical intraepithelial neoplasia (CIN) and 90 healthy subjects. Compared to the normal controls, the expression level of miR-21 was increased, while the levels of miR-125b and miR-370 were decreased in CC in both GSE30656 and The Cancer Genome Atlas (TCGA) cohort. The expression levels and diagnostic value of these candidate miRNAs were then validated through qRT-PCR. Their diagnostic and prognostic values for early-stage CC were further explored. RESULTS: Compared to the patients with CIN and healthy subjects, serum miR-21 was increased, while serum miR-125b and serum miR-370 were reduced in early-stage CC. In addition, combining these molecules yielded good performance for differentiating early-stage CC from CIN or healthy subjects. Moreover, strong association was found between serum miR-21 and lymph node metastasis (LNM) as well as recurrence-free survival of early-stage CC. Similar observations were found for serum miR-125b and serum miR-370. Patients with simultaneously high serum miR-21 + low serum miR-125b + low serum miR-370 suffered a high risk of LNM and recurrence, while those with low serum miR-21 + high serum miR-125b + high serum miR-370 had little risk for LNM and recurrence. CONCLUSIONS: Combining serum miR-21, miR-125b and miR-370 as a miRNA-based signature is promising for the detection and prognosis prediction of early-stage CC.

Monitoring of ultra-trace uranium and thorium in six-grade particles.

The natural radioactive elements uranium(U) and thorium(Th) in atmospheric environment should be given attention, and their particle size distribution and concentration are important for estimating their hazardous effects to the human body. The concentrations of U and Th in 360 aerosol samples collected using six-stage aerosol collector from June - December, 2016 in Beijing were determinated using ICP-MS after acid digestion. The mass concentration ranges of U in PM0.39-0.69, PM0.69-1.3, PM1.3-2.1, PM2.1-4.2, PM4.2-10.2, and PM10.2- reached 0.0030-0.079, 0.0020-0.069, 0.0015-0.095, 0.0053-0.054, 0.0039-0.098, and 0.0083-0.10 ng/m3, respectively. The mass concentration range of Th in PM0.39-0.69, PM0.69-1.3, PM1.3-2.1, PM2.1-4.2, PM4.2-10.2, and PM10.2- amounted to 0.011-0.11, 0.0065-0.11, 0.0026-0.18, 0.0078-0.14, 0.015-0.30, and 0.0021-0.19 ng/m3, respectively. The contents of U and Th in all PM increased from June to December, and the contents in PM2.1 increased more sharply compared with those in other PM. A positive correlation was observed between the concentrations of U and Th and air quality index and relative humidity, whereas a negative correlation was identified between temperature and PM2.1, PM10.2, and total suspended particulates (TSP) after the Spearman-rank correlation test. The formation of PM was affected by meteorological conditions, which concurrently influenced the contents of U and Th in PM. The atmospheric contents of U and Th at night were higher than those in daytime. Compared with Th, the dose contribution of U to the public can be negligible. The median effective dose in public owing to inhalation of natural radioactive U and Th in the atmosphere measures 1.206 µSv/a.