Anoikis-related signature identifies tumor microenvironment landscape and predicts prognosis and drug sensitivity in colorectal cancer.

Background: Anoikis, a mechanism of programmed apoptosis, plays an important role in growth and metastasis of tumors. However, there are still few available comprehensive reports on the impact of anoikis on colorectal cancer. Method: A clustering analysis was done on 133 anoikis-related genes in GSE39582, and we compared clinical features between clusters, the tumor microenvironment was analyzed with algorithms such as "Cibersort" and "ssGSEA". We investigated risk scores of clinical feature groups and anoikis-associated gene mutations after creating a predictive model. We incorporated clinical traits to build a nomogram. Additionally, the quantitative real-time PCR was employed to investigate the mRNA expression of selected anoikis-associated genes. Result: We identified two anoikis-related clusters with distinct prognoses, clinical characteristics, and biological functions. One of the clusters was associated with anoikis resistance, which activated multiple pathways encouraging tumor metastasis. In our prognostic model, oxaliplatin may be a sensitive drug for low-risk patients. The nomogram showed good ability to predict survival time. And SIRT3, PIK3CA, ITGA3, DAPK1, and CASP3 increased in CRC group through the PCR assay. Conclusion: Our study identified two distinct modes of anoikis in colorectal cancer, with active metastasis-promoting pathways inducing an anti-anoikis subtype, which has a stronger propensity for metastasis and a worse prognosis than an anoikis-activated subtype. Massive immune cell infiltration may be an indicator of anoikis resistance. Anoikis' role in the colorectal cancer remains to be investigated.

Rotenone nanoparticles based on mesoporous silica to improve the stability, translocation and insecticidal activity of rotenone.

Nanotechnology has been widely applied for pesticide carriers, which is an important way to improve the utilization, stability, and sustained release of pesticides. Mesoporous silica nanoparticles (MSNs) are a nanomaterial with adjustable particle and pore sizes, with a high specific surface area and good biocompatibility. Rotenone is a non-systemic botanical insecticide that is easily degraded in the environment. We used a modified soft-template method to prepare MSNs, in which rotenone was loaded using the solvent evaporation method. The prepared rotenone nanopesticide based on mesoporous silica showed considerable drug loading rates of 33.2%. Moreover, the prepared rotenone nanoparticles showed improved photostability and sustained release behavior, which improved the translocation of rotenone in tomato plants. Finally, the rotenone nanoparticles displayed superior insecticidal activity compared to traditional preparations. In summary, the rotenone nanopesticide improved the persistence and utilization rates of rotenone. These findings are of significance in reducing pesticide usage, mitigating environmental pollution, and ensuring food safety.

Limonin delays the progression of intervertebral disc degeneration in vivo and in vitro: the key role of the MAPK/NF-κB and necroptosis pathways.

OBJECTIVES: Limonin has received significant attention due to its multiple biological effects, intervertebral disc degeneration (IDD) is also of interest due to the high prevalence of this disease. In this study, we determined the effects of limonin on IDD and the underlying mechanism of action to find novel ways to treat IDD. METHODS: An IL-1ß-induced cell inflammation model and a lumbar instability model inducing IDD were established to assess the progression of IDD with or without limonin treatment. We further evaluated MAPK/NF-κB and necroptosis pathways and alterations in the extracellular matrix specific within the disc. KEY FINDINGS: Limonin suppresses inflammation in the nucleus pulposus in vitro by reducing the production of pro-inflammatory markers such as iNOS and COX-2. Limonin reduced the activation of the MAPK/NF-κB signalling pathway and the RIP1/RIP3/MLKL necroptosis pathway in the NP cells. Moreover, limonin delays the IDD progression in the lumbar instability model. CONCLUSIONS: Limonin could potentially delay IDD by inhibiting NP cell necroptosis and modulating peripheral matrix proteins within the intervertebral disc and is a potential pharmacological research direction for the therapy in patients with IDD.

The construction and analysis of a prognostic assessment model based on P53-related multi-genes in breast carcinoma.

BACKGROUND: Breast cancer ranks second in female tumor mortality, with an estimation of 2 million new cases diagnosed each year worldwide. METHODS: In our current study, we screened 13 genes highly distributed on the P53 phenotype which were significantly expressed and had a strong correlation with survival in the Cancer Genome Atlas breast cancer dataset. Least absolute shrinkage and selection operator Cox regression was conducted to construct the risk assessment model. Based on bioinformatics and statistical methods, we confirmed the credibility and validity of the model by training set and testing set. RESULTS: The result of comparing the other two previous hypoxia models was also satisfying. We also verified the model on one of the Gene Expression Omnibus datasets-GSE20685. Using clinical data from patients in the Cancer Genome Atlas, we acknowledged the risk score as an independent influence on breast cancer survival prognosis, and strong relevance was suggested between risk signature and age, lymphatic metastasis, tumor size and clinical stage by performing univariate and multivariate analysis. Immunology analysis demonstrated that the macrophages subset was positively associated with a risk score and other immune cell types had a negative effect with the risk score increases. The risk score was also emerging as a valuable prognostic factor for the prediction of chemotherapy drug curative effect because Gemcitabine, vinorelbine, paclitaxel and cisplatin known as a generic drug for breast cancer had more pleasing sensitivity in high-scored patients than low-scored patients. CONCLUSION: The P53-related risk assessment model is promising to be a potential predictor for the prognosis of patients with breast cancer and a powerful guide for the selection of therapeutic strategies.

NMR-based metabolomics approach to assess the ecotoxicity of prothioconazole on the earthworm (Eisenia fetida) in soil.

Prothioconazole (PTC) is a widely used agricultural fungicide. In recent years, studies have confirmed that it exerts adverse effects on various species, including aquatic organisms, mammals, and reptiles. However, the toxicological effects of PTC on soil organisms are poorly understood. Here, we investigated the toxic effects, via oxidative stress and metabolic responses, of PTC on earthworms (Eisenia fetida). PTC exposure can induce significant changes in oxidative stress indicators, including the activities of superoxide dismutase (SOD) and catalase (CAT) and the content of glutathione (GSH), which in turn affect the oxidative defense system of earthworms. In addition, metabolomics revealed that PTC exposure caused significant changes in the metabolic profiles of earthworms. The relative abundances of 16 and 21 metabolites involved in amino acids, intermediates of the tricarboxylic acid (TCA) cycle and energy metabolism were significantly altered after 7 and 14 days of PTC exposure, respectively. Particularly, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that multiple different metabolic pathways could be disturbed after 7 and 14 days of PTC exposure. Importantly, these alterations in oxidative stress and metabolic responses in earthworms reveal that the effects of PTC on earthworms were time dependent, and vary with exposure time. In conclusion, this study highlights that the effects of PTC on soil organisms are of serious concern.

Development of spirotetramat nanoparticles based on mesoporous silica: improving the uptake and translocation of spirotetramat in plants.

As an ideal nanocarrier, mesoporous silica nanoparticles (MSNs) have the characteristics of high specific surface area, adjustable pore size, and good biocompatibility, which are excellent carriers for improving the stability and sustained-release performance of pesticides and improving the utilization rate of pesticides In this study, three kinds of particle size MSNs (100 nm, 200 nm, and 400 nm) were prepared by hydrothermal synthesis method, and then, the spirotetramat (Stm) was loaded into MSNs with different particle sizes by solvent volatilization method to prepare Stm nanoparticles with different particle sizes (Stm@MSNs). The results of Stm@MSNs characterization showed that the three particle sizes of MSNs were 112.5, 200.1, and 439.4 nm, respectively. Besides, the pore sizes of the three MSNs were all in the range of 2~50 nm. And the FTIR spectra showed that the Stm was successfully loaded into the channel of MSNs. TGA analysis showed that Stm@MSNs-100, Stm@MSNs-200, and Stm@MSNs-400 had good thermal stability in the range of 200°C. The drug loads of Stm@MSNs-100, Stm@MSNs-200, and Stm@MSNs-400 to Stm were 38%, 21%, and 53%. The release test showed that all of them showed the characteristics of slow release. After 3 days of application on cucumber plants, Stm was detected in both upper and lower leaves of cucumber. Compared with MSNs-200 and MSNs-400, the nanocarrier MSNs-100 were more easily absorbed by cucumber plants and could carry more Stm into cucumber plants. This study provided a theoretical basis for the development and application of nanocarriers and the improvement of pesticide utilization rate by discussing the effects of different particle size MSNs on the slow release and systemicity of pesticides.

A key regulatory loop AK4P1/miR-375/SP1 in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the leading lethal human cancer types and is notorious for its poor prognosis. A series of bioinformatic analyses and experimental validations were employed to explore the role and mechanism of pseudogene-derived RNAs in pancreatic adenocarcinoma. Consequently, a total of 13 upregulated and 7 downregulated pseudogene-derived RNAs in pancreatic adenocarcinoma were identified. Survival analysis revealed a statistically predictive role of AK4P1 for unfavourable prognosis of patients with pancreatic adenocarcinoma. Subcellular location analysis indicated that AK4P1 was mainly located in cytoplasm, in which AK4P1 might competitively bind to tumour suppressive miR-375 in pancreatic adenocarcinoma. Further analysis showed that SP1 was a potential downstream target gene of miR-375 in pancreatic adenocarcinoma. Intriguingly, expression determination validated that SP1 could positively regulate AK4P1 levels in pancreatic adenocarcinoma. Finally, AK4P1 might also exert its effects by interacting with oncogenic parental gene AK4 in pancreatic adenocarcinoma. Conclusively, the present study elucidated a key regulatory loop AK4P1/miR-375/SP1 in pancreatic adenocarcinoma.

Bioaccumulation and toxicity effects of flubendiamide in zebrafish (Danio rerio).

Flubendiamide is a widely used diamide insecticide with many adverse effects on environmental organisms. This study assessed its bioaccumulation and toxicity effects in zebrafish (Danio rerio) using LC-MS/MS. The concentrations of flubendiamide in the whole zebrafish increased in the early stages and achieved steady levels at 14 days. The bioconcentration factors (BCFs) of flubendiamide was 1.125-2.011. Although flubendiamide did not significantly affect the growth phenotypes of zebrafish, it significantly changed the hepatic somatic index (HSI) of zebrafish. Histopathological analysis showed that flubendiamide could cause structural damage to the liver tissue of zebrafish. Further physiological and biochemical analysis showed that flubendiamide significantly changed the activity of catalase (CAT) and the contents of malondialdehyde (MDA) and glutathione (GSH) in liver of zebrafish. Moreover, flubendiamide significantly changed the mRNA expression levels of cell apoptosis-related genes, including p53, puma, caspase-3, caspase-9, apaf-1, and bax in liver of zebrafish. In summary, these results indicate that flubendiamide can cause liver damage by inducing oxidative stress and apoptosis in the liver of zebrafish. This study provides a background for further safety evaluation of flubendiamide to aquatic organisms.