Roxadustat protect mice from DSS-induced colitis in vivo by up-regulation of TLR4.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) is growing in the population. At present, the etiology of inflammatory bowel disease remains unclear, and there is no effective and low-toxic therapeutic drug. The role of the PHD-HIF pathway in relieving DSS-induced colitis is gradually being explored. METHODS: Wild-type C57BL/6 mice were used as a model of DSS-induced colitis to explore the important role of Roxadustat in alleviating DSS-induced colitis. High-throughput RNA-Seq and qRT-PCR methods were used to screen and verify the key differential genes in the colon of mice between normal saline (NS) and Roxadustat groups. RESULTS: Roxadustat could alleviate DSS-induced colitis. Compared with the mice in the NS group, TLR4 were significantly up-regulated in the Roxadustat group. TLR4 KO mice were used to verify the role of TLR4 in the alleviation of DSS-induced colitis by Roxadustat. CONCLUSION: Roxadustat has a repairing effect on DSS-induced colitis, and may alleviate DSS-induced colitis by targeting the TLR4 pathway and promote intestinal stem cell proliferation.

Cathepsin H Knockdown Reverses Radioresistance of Hepatocellular Carcinoma via Metabolic Switch Followed by Apoptosis.

Despite the wide application of radiotherapy in HCC, radiotherapy efficacy is sometimes limited due to radioresistance. Although radioresistance is reported with high glycolysis, the underlying mechanism between radioresistance and cancer metabolism, as well as the role of cathepsin H (CTSH) within it, remain unclear. In this study, tumor-bearing models and HCC cell lines were used to observe the effect of CTSH on radioresistance. Proteome mass spectrometry, followed by enrichment analysis, were used to investigate the cascades and targets regulated by CTSH. Technologies such as immunofluorescence co-localization flow cytometry and Western blot were used for further detection and verification. Through these methods, we originally found CTSH knockdown (KD) perturbed aerobic glycolysis and enhanced aerobic respiration, and thus promoted apoptosis through up-regulation and the release of proapoptotic factors such as AIFM1, HTRA2, and DIABLO, consequently reducing radioresistance. We also found that CTSH, together with its regulatory targets (such as PFKL, HK2, LDH, and AIFM1), was correlated with tumorigenesis and poor prognosis. In summary, our study found that the cancer metabolic switch and apoptosis were regulated by CTSH signaling, leading to the occurrence of radioresistance in HCC cells and suggesting the potential value of HCC diagnosis and therapy.

ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway.

Ferroptosis is the name given to the type of non-apoptotic cell death that is caused by iron accumulation and subsequent lipid peroxidation. However, how ionizing radiation (IR)-induced ferroptosis is regulated in estrogen receptor-positive (ER+) breast cancer cells remains unclear. To attempt to resolve this issue, bioinformatics analysis was performed to evaluate the prognostic value of estrogen receptor 1 (ESR1) in breast cancer tissues. A total of four breast cancer cell lines and an MCF10A non-malignant counterpart were used. Western blotting was used to analyze the levels of protein expression, whereas immunoprecipitation (IP) and ubiquitination experiments were used to test protein binding and ubiquitination levels, respectively. Flow cytometry was subsequently used to analyze cell death and lipid peroxidation levels. The results showed that a high expression level of ESR1 was significantly correlated with poor overall survival in breast cancer. ESR1 knockdown significantly enhanced IR-induced ferroptosis and increased the CD71 protein level. The IP results showed that ESR1 enhanced the binding of the E3 ubiquitin ligase NEDD4L to CD71, promoting the ubiquitination and degradation of CD71, suggesting that CD71 expression was regulated by both ESR1 and NEDD4L. Taken together, the findings in the present study have demonstrated a regulatory relationship between ESR1 and NEDD4L/CD71 in IR-induced ferroptosis. In addition, the ESR1/NEDD4L/CD71 axis may be a potential target for the radiotherapy of breast cancer.

Ce3+ and Fe2+ co-enhanced ratiometric fluorescence probe utilizing copper nanoclusters and coumarin for sensitive assay of hydrogen peroxide and glucose.

A novel ratiometric fluorescent probe was constructed for sensitive assay of hydrogen peroxide (H2O2) and glucose, which utilized the synergistically enhanced effects of Ce3+ and Fe2+ on copper nanoclusters (CuNCs) and coumarin. In the CuNCs-Ce3+/Fe2+-coumarin system, Ce3+ triggered the aggregation-induced emission phenomenon of CuNCs, and Fe2+ catalyzed the Fenton reaction to efficiently yield hydroxyl radical (•OH). In the presence of H2O2, the 625-nm red fluorescence of CuNCs was sharply quenched owing to the oxidation of CuNCs to Cu(II) by •OH, but the 460-nm blue fluorescence of 7-hydroxycoumarin from the oxidation of coumarin by •OH dramatically increased. Based on the reversible changes in two fluorescence signals, a satisfactorily ratiometric probe was constructed for H2O2 assay with a detection limit (LOD) of 0.6 µM accompanied by a visual color variation from red to blue. For glucose assay, this ratiometric probe gave a linear range of 3.2-160 µM and LOD of 0.96 µM owing to the oxidization of glucose to yield H2O2 in the presence of glucose oxidase and O2. Overall, the newly developed ratiometric probe shows a great prospect in real applications for visual assay of H2O2 and glucose by our naked eyes.

Cuproptosis-Related Biomarkers and Characterization of Immune Infiltration in Sepsis.

Introduction: Sepsis is a worldwide epidemic, with high morbidity and mortality. Cuproptosis is a form of cell death that is associated with a wide range of diseases. This study aimed to explore genes associated with cuproptosis in sepsis, construct predictive models and screen for potential targets. Methods: The LASSO algorithm and SVM-RFE model has been analysed the expression of cuproptosis-related genes in sepsis and immune infiltration characteristics and identified the marker genes under a diagnostic model. Gene-drug networks, mRNA-miRNA networks and PPI networks were constructed to screen for potential biological targets. The expression of marker genes was validated based on the GSE57065 dataset. Consensus clustering method was used to classify sepsis samples. Results: We found 381 genes associated with the development of sepsis and discovered significantly differentially expressed cuproptosis-related genes of 16 cell types in sepsis and immune infiltration with CD8/CD4 T cells being lower. NFE2L2, NLRP3, SLC31A1, DLD, DLAT, PDHB, MTF1, CDKN2A and DLST were identified as marker genes by the LASSO algorithm and the SVM-RFE model. AUC > 0.9 was constructed for PDHB and MTF1 alone respectively. The validation group data for PDHB (P=0.00099) and MTF1 (P=7.2e-14) were statistically significant. Consistent clustering analysis confirmed two subtypes. The C1 subtype may be more relevant to cellular metabolism and the C2 subtype has some relevance to immune molecules.The results of animal experiments showed that the gene expression was consistent with the bioinformatics analysis. Discussion: Our study systematically explored the relationship between sepsis and cuproptosis and constructed a diagnostic model. And, several cuproptosis-related genes may interfere with the progression of sepsis through immune cell infiltration.

Reparative effects after low-dose radiation exposure: Inhibition of atherosclerosis by reducing NETs release.

OBJECTIVE: The cardiovascular system effects of environmental low-dose radiation exposure on radiation practitioners remain uncertain and require further investigation. The aim of this study was to initially investigate and explore the mechanisms by which low-dose radiation may contribute to atherosclerosis through a multi-omics joint comprehensive basic experiment. METHODS: We used WGCNA and differential analyses to identify shared genes and potential pathways between radiation injury and atherosclerosis sequencing datasets, as well as tissue transcriptome immune infiltration level extrapolation and single-cell transcriptome data correction using the CIBERSORT deconvolution algorithm. Animal models were constructed by combining a high-fat diet with 5 Gy γ-ray whole-body low-dose ionizing radiation. The detection of NETs release was validated by enzyme-linked immunosorbent assay. RESULTS: Analysis reveals shared genes in both datasets of post-irradiation and atherosclerosis, suggesting that immune system neutrophils may be a key node connecting radiation to atherosclerosis. NETs released by neutrophil death can influence the development of atherosclerosis. Animal experiments showed that the number of neutrophils decreased (P < 0.05) and the concentration of NETs reduced after low-dose radiation compared with the control group, and the concentration of NETs significantly increased (P < 0.05) in the HF group. Endothelial plaques were significantly increased in the high-fat feed group and significantly decreased in the low-dose radiation group compared with the control group. CONCLUSIONS: Long-term low-dose ionizing radiation exposure stimulates neutrophils and inhibits their production of NETs, resulting in inhibition of atherosclerosis.

Development of an "on-off-on" fluoroprobe utilizing an anthrylimidazole-based fluorescent ionic liquid for sensitive Cr(VI) and ascorbic acid detection.

Developing a rapid detection method of Cr(VI) and ascorbic acid (AA) is vital in the food and environmental fields. Herein, an anthrylimidazole-based fluorescent ionic liquid (AI-FIL) with the advantageous fluorescent properties was successfully prepared and used to construct a promising "on-off-on" fluoroprobe for rapid/sensitive Cr(VI) and AA detection. Cr(VI) could effectively quench the fluorescence of AI-FIL owing to the inner-filter effect and photoinduced electron-transfer process. However, the decreased fluorescence could be rapidly recovered by AA owing to the redox reaction between AA and Cr(VI). For Cr(VI) detection, a satisfactorily linear response (0.03-300 µM) was achieved with the corresponding detection limit of 9 nM. For AA detection, a good linearity from 1 to 1000 µM was obtained with the resultant detection limit of 0.3 µM. Moreover, the AI-FIL based fluoroprobe was successfully utilized for Cr(VI) and AA detection in food and water samples with satisfactory accuracy and precision.

A novel ratiometric nanoprobe based on copper nanoclusters and graphitic carbon nitride nanosheets using Ce(III) as crosslinking agent and aggregation-induced effect initiator for sensitive detection of hydrogen peroxide and glucose.

Herein, glutathione-capped copper nanoclusters (CuNCs) and graphitic carbon nitride nanosheets (g-C3N4 NSs) were synthesized by a facile one-pot chemical reduction and directly thermal pyrolysis following ultrasonic exfoliation approaches, respectively. The introduction of Ce(III) (Ce3+) played dual functions in constructing a fluorescence-enhanced ratiometric nanoprobe (g-C3N4 NSs-Ce3+-CuNCs), i.e., triggering aggregation-induced emission of CuNCs and conjugating g-C3N4 NSs with CuNCs by virtue of electrostatic and coordination interactions. The as-fabricated nanohybrid displayed 460 and 625 nm dual-emitting peaks, attributing to the emission of g-C3N4 NSs and CuNCs, respectively. Upon addition of H2O2, the 625 nm emission was dramatically quenched, whereas the 460 nm emission remained nearly unchanged, thereby causing obvious color changes from purple to blue under a 365-nm UV lamp. A ratiometric fluorescent assay, based on g-C3N4 NSs-Ce3+-CuNCs, was devised for sensitive and visual detection of H2O2, which spanned the linear range of 2-100 µM with a detection limit of 0.6 µM. In the presence of glucose oxidase, the ratiometric nanoprobe could be simultaneously employed to detect glucose across the linear range of 1.6-320 µM with a detection limit of 0.48 µM. In milk and human serum samples, the fortified recoveries for H2O2 and glucose by the nanoprobe were in the range of 95.5-103.6% with RSDs <3.8%. The real detection levels for glucose are consistent with those by a standard glucometer. As such, the ratiometric nanoprobe offers a promising methodology for several practical applications, such as point-of-care diagnosis and workplace health evaluations.

Low-dose ionizing radiation increases the mortality risk of solid cancers in nuclear industry workers: A meta-analysis.

Low-dose ionizing radiation (LDIR) may increase the mortality of solid cancers in nuclear industry workers, but only few individual cohort studies exist, and the available reports have low statistical power. The aim of the present study was to focus on solid cancer mortality risk from LDIR in the nuclear industry using standard mortality ratios (SMRs) and 95% confidence intervals. A systematic literature search through the PubMed and Embase databases identified 27 studies relevant to this meta-analysis. There was statistical significance for total, solid and lung cancers, with meta-SMR values of 0.88, 0.80, and 0.89, respectively. There was evidence of stochastic effects by IR, but more definitive conclusions require additional analyses using standardized protocols to determine whether LDIR increases the risk of solid cancer-related mortality.

[Study on VNTR diversity of clinical Mycobacterium tuberculosis isolates from Qinghai].

OBJECTIVE: To investigate the variable number tandem repeats (VNTR) genetic polymorphisms, genotyping and distribution pattern of clinical Mycobacterium (M.) tuberculosis isolates from Qinghai province. METHODS: The clinical M. tuberculosis strains isolated from the patients with tuberculosis and related background data were collected from Qinghai Provincial Center for Disease Control and Prevention from 2009 to 2012. Genotyping was conducted by using multiple locus VNTR analysis (MLVA). Genomic DNA was extracted and 15 VNTR loci were amplified with PCR and the PCR products were detected with gel electrophoresis. The VNTR diversity and clusters of genotyping were analyzed with BioNumerics (Version 5.0). RESULTS: A total of 251 clinical M. tuberculosis isolates were analyzed with 15 VNTR loci showing that there were great genetic diversity in these isolates. Six of the 15 VNTR loci, showed that the Hunter-Gaston index (HGI) were higher than 0.6, in which the highest resolution was MIRU26. The clusters of genotyping showed that these isolates could be categorized into four gene clusters and 238 genotypes. The four gene clusters accounted for 4.9%, 91.9%, 1.6% and 1.6% of the clinical isolates, respectively. CONCLUSION: The results showed that there is great variety of VNTR genetic polymorphisms in clinical M. tuberculosis isolates in Qinghai province.