ACADL-YAP axis activity in non-small cell lung cancer carcinogenicity.

BACKGROUND: The role of Acyl-CoA dehydrogenase long chain (ACADL) in different tumor types had different inhibiting or promoting effect. However, its role in non-small cell lung cancer (NSCLC) carcinogenicity is not clear. METHOD: In this study, we utilized The Cancer Genome Atlas (TCGA) database to analyze ACADL expression in NSCLC and its correlation with overall survival. Furthermore, we investigated the function of ACADL on cellular proliferation, invasion, colony, apoptosis, cell cycle in vitro with NSCLC cells. Mechanistically, we evaluated the regulatory effect of ACADL expression on its downstream factor yes-associated protein (YAP) by assessing YAP phosphorylation levels and its cellular localization. Finally, we verified the tumorigenic effect of ACADL on NSCLC cells through xenograft experiments in vivo. RESULTS: Compared to adjacent non-cancerous samples, ACADL significantly down-regulated in NSCLC. Overexpression of ACADL, effectively reduced the proliferative, colony, and invasive capabilities of NSCLC cells, while promoting apoptosis and inducing cell cycle arrest. Moreover, ACADL overexpression significantly enhanced YAP phosphorylation and hindered its nuclear translocation. However, the inhibitory effect of the overexpression of ACADL in NSCLC cells mentioned above can be partially counteracted by YAP activator XMU-MP-1 application both in vitro and in vivo. CONCLUSION: The findings suggest that ACADL overexpression could suppress NSCLC development by modulating YAP phosphorylation and limiting its nuclear shift. This role of ACADL-YAP axis provided novel insights into NSCLC carcinogenicity and potential therapeutic strategies.

Transcription factor ZEB1 regulates PLK1-mediated SKA3 phosphorylation to promote lung cancer cell proliferation, migration and cell cycle.

Lung cancer (LC) is one of the most common malignancies worldwide with low 5-year survival rate. The mechanism of spindle and kinetochore-associated complex subunit 3 (SKA3) in LC tumorgenesis remains largely unclear. The expression of SKA3 in LC cells was detected by quantitative PCR. Cell proliferation, migration and cell cycle were evaluated by functional assays including 5-ethynyl-2'-deoxyuridine, wound healing, transwell assays and flow cytometry analysis. Bioinformatics analysis, chromatin immunoprecipitation, luciferase reporter, co-immunoprecipitation and in vitro phosphorylation assays were applied to explore the interactions between zinc finger E-box binding homeobox 1 (ZEB1) and SKA3/polo-like kinase 1 (PLK1). SKA3 is highly expressed in LC cell lines and drives LC cell proliferation, migration and cell cycle. PLK1 also enhances the malignancy of LC cells. PLK1 can mediate SKA3 phosphorylation and enhance the stability of SKA3 protein, thus promoting LC progression. Besides, we found that transcription factor ZEB1 transcriptionally activates SKA3/PLK1 expression, contributing to LC cell malignancy. This study demonstrated that transcription factor ZEB1 modulates PLK1-mediated SKA3 phosphorylation to accelerate LC cell growth, migration and cycle, which might offer novel insight into LC treatment.

Construction of Core-Shell MOF CSMnP with Enzyme-Like Activity for Chemotherapy and Chemodynamic Therapy.

Materials with enzyme-like activity have received a lot of attention in the field of tumor catalytic therapy. Here, biocompatible core-shell MOF CSMnP with two valence states of Mn ion, which could process chemodynamic therapy (CDT), was designed and synthesized. Besides, it could also promote a series of catalytic processes in the tumor microenvironment (TME). CSMnP catalyzed endogenous hydrogen peroxide (H2O2) to oxygen (O2) via catalase-like activity and then combined with the outer layer Mn(II)-PBC to convert O2 into superoxide radicals (•O2-), exhibiting oxidase-like activity. Besides, intracellular glutathione (GSH) could be effectively consumed through the glutathione oxidase-like activity of Mn3+. The occurrence of the cascade reactions effectively amplified the enzymatic production to enhance CDT. Furthermore, the therapeutic effect of CSMnP was improved through the loading of cationic drug DOX. The loading capacity was 11.10 wt %, which was 2.2 times that of Mn(III)-PBC (4.95 wt %), and the release of DOX showed a characteristic response. Therefore, the core-shell MOF with enzyme-like activity had a potential application for tumor combination therapy.

Transcriptome reveals the toxicity and genetic response of zebrafish to naphthenic acids and benzo[a]pyrene at ambient concentrations.

Naphthenic acids (NAs) are typical contaminants in heavily crude oil. Benzo[a]pyrene (B[a]P) is also a component of crude oil, but their combined effects have not been systematically explored. In this study, zebrafish (Danio rerio) were used as the test organisms, and behavioral indicators and enzyme activities were used as toxicity indicators. Combined with the effects of environmental concentrations, the toxic effects of low concentrations of commercially available NAs (0.5 mg/LNA) and benzo[a]pyrene (0.8 µg/LBaP) at single and compound exposures (0.5 mg/LNA and 0.8 µg/LBaP) were assayed in zebrafish, and transcriptome sequencing technology was used to explore the molecular mechanism of the two compounds affecting zebrafish from the molecular biology level. Sensitive molecular markers that could indicate the presence of contaminants were screened. The results showed that (1) zebrafish in the NA and BaP exposure groups exhibited increased locomotor behavior, and the mixed exposure group exhibited inhibition of locomotor behavior. Oxidative stress biomarkers showed increased activity under single exposure and decreased activity under the mixed exposure. (2) NA stress led to changes in the activity of transporters and the intensity of energy metabolism; BaP directly stimulates the pathway of actin production. When the two compounds are combined, the excitability of neurons in the central nervous system is decreased, and the actin-related genes are down-regulated. (3) After BaP and Mix treatments, genes were enriched in the cytokine-receptor interaction and actin signal pathway, while NA increased the toxic effect on the mixed treatment group. In general, the interaction between NA and BaP has a synergistic effect on the transcription of zebrafish nerve and motor behavior-related genes, resulting in increased toxicity under combined exposure. The changes in expression of various zebrafish genes are manifested in the changes in the normal movement behavior of zebrafish and the intensification of oxidative stress in the apparent behavior and physiological indicators. CAPSULE ABSTRACT: We investigated the toxicity and genetic alterations caused by NA, B[a]P, and their mixtures in zebrafish in an aquatic environment using transcriptome sequencing technology and comprehensive behavioral analysis. These changes involved energy metabolism, the generation of muscle cells, and the nervous system.

Metal Hydrogen-Bonded Organic Framework as a pH Sensor for the Detection of Strong Acids.

pH detection is related to human beings' life closely. Herein, a porous metal hydrogen-bonded organic framework (MHOF) Co-CDI-CO32- was designed and synthesized, which could be utilized to detect the pH values of strong acids. The sensitivity of pH detection was in the range of pH 2.0-2.4 with an accuracy of 0.1, which mainly depended on the different degree of crystal surface damage. The MHOF Co-CDI-CO32- had potential applications with the advantages of low cost, easy storage, and great sensitivity for pH detection as a pH sensor.

Long Non-coding RNA LINC01426 Contributes to the Malignant Behaviors of NSCLC Via Acting As a Sponge for miR-143-3p.

Recently, long non-coding RNA (lncRNA) is proved to play critical roles in non-small cell lung cancer (NSCLC) progression. However, the detailed effects of LINC01426 in NSCLC and its functional mechanism remain unknown. The expression of LINC01426, microRNA-143-3p (miR-143-3p), and Ubiquitin-specific peptidase 28 (USP28) was assessed by quantitative real-time polymerase chain reaction (RT-qPCR). The colony-forming ability was determined by colony-forming assay. 5-ethynyl-2'-deoxyuridine (EdU) staining assay was performed to evaluate cell proliferation. The migrated and invaded abilities of cells were measured by transwell assays. Flow cytometry was used to examine cell apoptosis. The protein expression was analyzed by Western blot analysis. The glycolysis ability was analyzed by commercial kits. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA pull-down assay were used to confirm relationship among LINC01426, miR-143-3p, and USP28. A xenograft experiment was conducted to explore the effects of LINC01426 inhibition in vivo. Our results confirmed that LINC01426 and USP28 expression were increased, while miR-143-3p expression was decreased in NSCLC tissues and cells. Further functional experiments demonstrated that LINC01426 inhibition markedly impaired cell proliferation, migration, invasion, autophagy, and glycolysis while induced apoptosis in NSCLC cells, and LINC01426 derived malignant behaviors of NSCLC cells by sponging miR-143-3p. Additionally, LINC01426 regulated USP28 expression by sponging miR-143-3p. USP28 overexpression partly overturned the inhibitory effect of miR-143-3p on NSCLC progression. Consistently, silencing of LINC01426 significantly inhibited the growth of NSCLC tumor in vivo. LINC01426 accelerated the malignant progression of NSCLC. Mechanistically, LINC01426 acted as a competing endogenous RNA (ceRNA) for miR-143-3p to upregulate USP28 expression.

E3 ubiquitin ligase HECW1 promotes the metastasis of non-small cell lung cancer cells through mediating the ubiquitination of Smad4.

Lung cancer is the leading cause of cancer-related death globally. Ubiquitin modification plays a crucial role in the regulation of gene expression, and is closely associated with cancer pathogenesis. The aim of our study was to clarify the role and mechanisms of action for HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 (HECW1) in non-small cell lung cancer (NSCLC). Herein, we demonstrate that the expression of HECW1 was significantly increased in NSCLC cell lines and tissues. Upregulation of HECW1 markedly enhanced the proliferation of NSCLC cells, whereas downregulation of HECW1 significantly inhibited proliferation. Moreover, the expression levels of HECW1 positively correlated with the migration and invasiveness of NSCLC cells. Upregulation or downregulation of HECW1 only affected the protein expression levels of SMAD family member 4 (Smad4), but had no effect on the mRNA expression levels. Furthermore, after treatment with MG-132, the relative protein level of Smad4 significantly increased in NSCLC cells. HECW1 promoted the proliferation, migration, and invasiveness of NSCLC cells by inducing the ubiquitination and degradation of Smad4, thus our data provide a novel target for NSCLC treatment.

Camrelizumab in combination with neoadjuvant chemotherapy in resectable locally advanced esophageal squamous carcinoma cancer: Results from a retrospective study.

This study aimed to evaluate the safety and efficacy of camrelizumab combined with chemotherapy during preoperative neoadjuvant therapy in patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC) of clinical Stages II and III. The patients received camrelizumab plus chemotherapy regimen on Day 1 for up to three to four cycles (3 weeks per cycle). The probabilities of overall survival (OS) were 55.6% at 12 months and 35.6% at 18 months (45 patients). The disease-free survival (DFS) rates were 70.0% at 12 months and 63.3% at 18 months (30 patients). The median OS and DFS were not reached. The proportion of patients at postneoadjuvant pathological tumor stages ypT0, ypT2, and ypT3 were 10 (33.3%), 14 (46.7%), and 6 (20.0%), respectively, and those at stages ypN0 and ypN1 were 19 (63.3%) and 11 (36.7%), respectively. Additionally, the pathological complete response rate was 33.3% (95% confidence interval [CI]: 0.154-0.512), and the major pathologic response rate was 46.7% (95% CI: 0.277-0.656). Grade ≥3 adverse events (AEs) were reported in five patients (11.1%), with vomiting being the most common AE (three patients; 3.3%). Other common AEs of any grade included decreased lymphocyte count (48.9%), reactive capillary endothelial proliferation (46.7%), decreased white blood cell count (40.0%), anemia (31.1%), and vomiting (31.1%). The combination of camrelizumab and neoadjuvant chemotherapy in patients with locally advanced resectable ESCC demonstrated promising efficacy and acceptable safety.

Environmentally relevant concentrations of naphthenic acids initiate intestinal injury and gut microbiota dysbiosis in marine medaka (Oryzias melastigma).

Naphthenic acids (NAs) are important pollutants in marine crude oils and have obvious toxic effects on marine organisms. However, the effects of NAs on the intestine are largely unknown. Thus, we evaluated the effects of NAs exposure in the intestines of marine medaka. Fish were experimentally exposed to NAs (0.5 mg/L, 5 mg/L, and 10 mg/L) for 96 h and monitored for changes in intestinal histology, markers of oxidative stress, and intestinal microbiome responses. Significant mucosal damage, inflammation, and oxidative stress were observed in the intestines of marine medaka after exposure to NAs. In addition, significant changes in the gut microbiota were observed. Specifically, the relative abundance of Proteobacteria decreased, while that of Verrucomicrobiota increased in the high-concentration exposure group. In addition, nutrient synthesis and metabolism in the gut were affected. The results of this study contribute to a better understanding of the ecological risk of different concentrations of NAs to marine organisms. CAPSULE ABSTRACT: Changes in the gut microbial community of marine medaka (Oryzias melastigma) caused by naphthenic acids in the marine environment were investigated through the assessment of gut inflammatory factors and comprehensive analysis using 16S rDNA high-throughput sequencing. The results indicated the induction of intestinal inflammation and changes in the structural composition of the intestinal flora.

Differential fluorescent response to amino acids based on metal-organic framework Zn-PBC.

A novel metal-organic framework (MOF) Zn-PBC (H2PBC = pyridine-3,5-bis(phenyl-4-carboxylic acid)) was designed and synthesized via a solvothermal reaction with the H2PBC ligand, and produced a strong fluorescence. The material exhibited good stability and an ideal luminescent property in water. In addition, it was found that Zn-PBC displayed a different fluorescent response to different types of amino acids, and the mechanism was investigated. This research might give insight to the interaction between MOFs and amino acids, which would provide a strategy to fabricate MOF-based sensors for biomolecules in future.

Correction: Preparation of nanoscale cationic metal-organic framework Nano Mn(III)-TP for theranostics based on valence changes.

Correction for 'Preparation of nanoscale cationic metal-organic framework Nano Mn(III)-TP for theranostics based on valence changes' by Shijiang Yu et al., J. Mater. Chem. B, 2022, 10, 8988-8995, https://doi.org/10.1039/D2TB01619B.

Preparation of nanoscale cationic metal-organic framework Nano Mn(III)-TP for theranostics based on valence changes.

A single treatment strategy to produce a significant effect on cancer treatment is difficult due to the complex variability of the tumor environment. Herein, considering over-expressed glutathione (GSH) in the tumor environment can reduce Mn3+ to Mn2+, and Mn2+ exhibits an excellent T1-weighted magnetic resonance imaging performance and a good Fenton-like effect. A Mn-based nano-cation metal-organic framework (MOF) with a size of about 200 nm was synthesized and labeled as Nano Mn(III)-TP. It showed an outstanding T1-weighted MRI performance and Fenton-like effect due to valence changes of the Mn ions. Meanwhile, MTXNa@Nano Mn(III)-TP was obtained by loading with the anionic anticancer drug methotrexate disodium (MTXNa), and it could release MTXNa specifically in GSH solution with different pH values and temperatures, resulting in an improvement in the tumor suppressive effect of the Nano Mn(III)-TP. Based on the nanoplatform, the effective combination of magnetic resonance imaging (MRI), CDT and chemotherapy could be used as a potential therapeutic agent for multimodal therapy, which is also expected to be applied to clinical tumor treatment.

Major complications of minimally invasive Ivor Lewis oesophagectomy using the purse string-stapled anastomotic technique in 215 patients with oesophageal carcinoma.

OBJECTIVES: The purse string-stapled anastomotic technique is a method for minimally invasive oesophagectomy with intrathoracic anastomosis, in which a purse string is hand sewn without the necessity of specialized devices, such as OrVil and Endo-Stitch. Since this technique was first reported by our surgical team in 2012, several measures in the operation have been refined. Furthermore, there are very few literature reports on the major complications of minimally invasive oesophagectomy with this technique. This article studies the major complications of minimally invasive Ivor Lewis oesophagectomy with this technique and explores methods for prevention and treatment. METHODS: Clinical data of 215 patients with oesophageal cancer who underwent thoracoscopic laparoscopic oesophagectomy with intrathoracic anastomosis from October 2011 to December 2015 were analysed. No patients received preoperative radiotherapy and chemotherapy. During the operation, the purse string was simply hand sewn before it was tightened and tied, and anastomosis was performed using a circular stapler. RESULTS: Six (2.79%) patients developed anastomotic leakage, and all of them were treated conservatively. Three (1.40%) patients experienced postoperative haemorrhage; of them, 2 were cured with conservative treatment. The remaining patient was cured by endoscopic management using titanium clips. Thirty-nine (18.14%) patients experienced postoperative pulmonary complications. One (1.47%) patient died due to pulmonary infection with respiratory failure although he had received mechanical ventilator support after tracheotomy. Five (2.33%) patients developed chyle leakage and 5 (2.33%) patients developed recurrent laryngeal nerve injuries. CONCLUSIONS: The incidence of major complications is acceptable for thoracoscopic laparoscopic oesophagectomy with intrathoracic anastomosis using this purse string-stapled anastomotic technique, which is feasible and safe to perform. Some measures designed in the operation will be conducive to reduce the incidence of major complications.