Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

Corrigendum: NUDT21 promotes tumor growth and metastasis through modulating SGPP2 in human gastric cancer.

[This corrects the article DOI: 10.3389/fonc.2021.670353.].

The signature of cuproptosis-related immune genes predicts the tumor microenvironment and prognosis of prostate adenocarcinoma.

Background: Cuproptosis plays a crucial role in cancer, and different subtypes of cuproptosis have different immune profiles in prostate adenocarcinoma (PRAD). This study aimed to investigate immune genes associated with cuproptosis and develop a risk model to predict prognostic characteristics and chemotherapy/immunotherapy responses of patients with PRAD. Methods: The CIBERSORT algorithm was used to evaluate the immune and stromal scores of patients with PRAD in The Cancer Genome Atlas (TCGA) cohort. Validation of differentially expressed genes DLAT and DLD in benign and malignant tissues by immunohistochemistry, and the immune-related genes of DLAT and DLD were further screened. Univariable Cox regression were performed to select key genes. Least absolute shrinkage and selection operator (LASSO)-Cox regression analyse was used to develop a risk model based on the selected genes. The model was validated in the TCGA, Memorial Sloan-Kettering Cancer Center (MSKCC) and Gene Expression Omnibus (GEO) datasets, as well as in this study unit cohort. The genes were examined via functional enrichment analysis, and the tumor immune features, tumor mutation features and copy number variations (CNVs) of patients with different risk scores were analysed. The response of patients to multiple chemotherapeutic/targeted drugs was assessed using the pRRophetic algorithm, and immunotherapy was inferred by the Tumor Immune Dysfunction and Exclusion (TIDE) and immunophenoscore (IPS). Results: Cuproptosis-related immune risk scores (CRIRSs) were developed based on PRLR, DES and LECT2. High CRIRSs indicated poor overall survival (OS), disease-free survival (DFS) in the TCGA-PRAD, MSKCC and GEO datasets and higher T stage and Gleason scores in TCGA-PRAD. Similarly, in the sample collected by the study unit, patients with high CRIRS had higher T-stage and Gleason scores. Additionally, higher CRIRSs were negatively correlated with the abundance of activated B cells, activated CD8+ T cells and other stromal or immune cells. The expression of some immune checkpoints was negatively correlated with CRIRSs. Tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH) and copy number variation (CNV) scores were all higher in the high-CRIRS group. Multiple chemotherapeutic/targeted drugs and immunotherapy had better responsiveness in the low-CRIRS group. Conclusion: Overall, lower CRIRS indicated better response to treatment strategies and better prognostic outcomes.

High-resolution mass spectrometry for glycoproteomics.

Tweetable abstract Bottom-up glycoproteomics combined with top-down strategy allows direct analysis of glycoform-mapped glycosylation and its glycans by high-resolution mass spectrometry.

Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES-2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES-2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS: To evaluate the role of mPGES-2 in NAFLD, whole-body or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet were used. Compared with control mice, mPGES-2-deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES-2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl-CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES-2 deficiency. Further, we confirmed the protective role of the mPGES-2 inhibitor SZ0232 in NAFLD therapy. CONCLUSION: Our study indicates the pathogenic role of mPGES-2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES-2 inhibition in liver steatosis and steatohepatitis.

Biosafe Bi2O2Se ultrathin nanosheet for water disinfection via solar-induced photothermal synergistic effect.

Solar-induced sterilization via photothermal synergy has attracted enormous attention due to its zero-energy consumption and the elimination of hazardous chemical disinfectant. Herein, we successfully synthesized a super biosafety Bi2O2Se with crossed nanosheet structure (Bi2O2Se-CN) for the sterilization of Escherichia coli (E. coli) via solar-induced photothermal synergistic effect. In comparison to bulk Bi2O2Se, the lower light reflection and more efficient photogenerated charge carrier separation under visible-infrared light irradiation resulted in the excellent sterilization effect of Bi2O2Se-CN, with a sterilization efficiency of 99.9% under the synergistic effect of light and heat. The crossed ultrathin nanosheet structure and suitable band gap width of Bi2O2Se-CN are fundamental reasons for its enhanced light absorption and charge carrier separation efficiency. Mechanistic studies showed that Bi2O2Se-CN can completely inactivate bacteria via generating a large amount of reactive oxygen species (•O2-, •OH, and 1O2) to attack the cell membrane, which further resulted in the reduced activity of intracellular enzymes and the leakage of intracellular contents. The biosafety property of Bi2O2Se-CN was confirmed by in vivo toxicological evaluation on the mice model. This work provided new ideas for the design of more efficient, energy-saving, biocompatible and environmental friendly solar water purification projects.

Thoracic Paravertebral Block Combined with General Anaesthesia or General Anaesthesia Alone for Thoracoscopic Lung Adenocarcinoma Surgery: A Retrospective Study.

Purpose: To investigate the effects of ultrasound-guided thoracic paravertebral block combined with general anaesthesia or general anaesthesia alone for thoracoscopic lung adenocarcinoma surgery, and to provide new thoughts for improving the clinical outcomes. Methods: This was a retrospective study. Data were retrieved for 195 patients with lung adenocarcinoma undergoing elective radical lobectomy via video-assisted thoracoscopy between January 2018 and August 2019 in The Second Hospital of Shandong University, including 86 patients who received thoracic paravertebral block (TPVB) combined with general anaesthesia (group TG), and 109 patients who received general anaesthesia alone (group GA). All patients were given self-controlled intravenous analgesia pump for 48 h after surgery. The primary outcome was the recurrence-free survival 2 years postoperatively (the time between surgery and the earliest date of recurrence, metastasis or lung cancer-cause death). The secondary outcomes included the average numeric rating scale (NRS) scores within 48 h postoperatively, the first time of postoperative ambulation, duration of chest tube drainage, length of postoperative hospitalization, perioperative opioid consumption and the postoperative side effects. Results: There were no statistical differences in the recurrence-free survival 2 years postoperatively between groups (Multivariate hazard ratio 0.706, 95% CI 0.126-3.941, P=0.691). The average NRS scores within 48 h postoperatively were significantly lower in group TG (P<0.05). The first time of postoperative ambulation, duration of chest tube drainage, and length of postoperative hospitalization in group TG were significantly reduced (P<0.05). Opioid consumption was significantly decreased in group TG (P<0.01). Finally, the incidence of postoperative nausea and vomiting (PONV) was significantly lower in group TG (P<0.05). Conclusion: TPVB for thoracoscopic lung adenocarcinoma surgery did not improve the recurrence-free survival 2 years postoperatively compared with general anaesthesia alone, but it significantly enhanced the postoperative analgesia effect, reduced opioid consumption as well as side effects, and accelerated postoperative early recovery. Clinical Trial Registration Number: The Chinese Clinical Trial Registry (ChiCTR-2100050454).

mPGES-2 blockade antagonizes ß-cell senescence to ameliorate diabetes by acting on NR4A1.

ß-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related ß-cell abnormalities that arise through unknown mechanisms. Here we show better ß-cell identity, less ß-cell senescence, enhanced glucose-stimulated insulin secretion and improved glucose homeostasis in global microsomal prostaglandin E synthase-2 (mPGES-2)-deficient mice challenged with a high-fat diet or bred with a genetic model of type 2 diabetes (db/db mice). Furthermore, the function of mPGES-2 in ß-cells is validated using mice with ß-cell-specific mPGES-2 deficiency or overexpression. Mechanistically, the protective role of mPGES-2 deletion is induced by antagonizing ß-cell senescence via interference of the PGE2-EP3-NR4A1 signalling axis. We also discover an inhibitor of mPGES-2, SZ0232, which protects against ß-cell dysfunction and diabetes, similar to mPGES-2 deletion. We conclude that mPGES-2 contributes to ageing-associated ß-cell senescence and dysfunction via the PGE2-EP3-NR4A1 signalling axis. Pharmacologic blockade of mPGES-2 might be effective for treating ageing-associated ß-cell dysfunction and diabetes.

Multiomics analysis of tumor mutational burden across cancer types.

Whether tumor mutational burden (TMB) is related to improved survival outcomes or the promotion of immunotherapy in various malignant tumors remains controversial, and we lack a comprehensive understanding of TMB across cancers. Based on the data obtained from The Cancer Genome Atlas (TCGA), we conducted a multiomics analysis of TMB across 21 cancer types to identify characteristics related to TMB and determine the mechanism as it relates to prognosis, gene expression, gene mutation and signaling pathways. In our study, TMB was found to have a significant relationship with prognosis for 21 tumors, and the relationship was different in different tumors. TMB may also be related to different outcomes for patients with different tumor subtypes. TMB was confirmed to be correlated with clinical information, such as age and sex. Mutations in GATA3 and MAP3K1 in beast invasive carcinoma (BRCA), TCF7L2 in colon adenocarcinoma (COAD), NFE2L2 in esophageal carcinoma (ESCA), CIC and IDH1 in brain lower grade glioma (LGG), CDH1 in stomach adenocarcinoma (STAD), and TP53 in uterine corpus endometrial carcinoma (UCEC) were demonstrated to be correlated with lower TMB. Moreover, we identified differentially expressed genes (DEGs) and differentially methylated regions (DMRs) according to different TMB levels in 21 cancers. We also investigated the correlation between enrichment of signaling pathways, immune cell infiltration and TMB. In conclusion, we identified multiomic characteristics related to the TMB in 21 tumors, providing support for a comprehensive understanding of the role of TMB in different tumors.

NUDT21 Promotes Tumor Growth and Metastasis Through Modulating SGPP2 in Human Gastric Cancer.

Gastric cancer is one of the major malignancies with poor survival outcome. In this study, we reported that NUDT21 promoted cell proliferation, colony formation, cell migration and invasion in gastric cancer cells. The expression levels of NUDT21 were found to be much higher in human gastric cancer tissues compared with normal gastric tissues. NUDT21 expression was positively correlated with tumor size, lymph node metastasis and clinical stage in gastric cancer patients. High level of NUDT21 was associated with poor overall survival (OS) rates in gastric cancer patients. The expression levels of NUDT21 were also much higher in gastric cancer tissues from patients with tumor metastasis compared with those of patients without tumor metastasis. Moreover, forced expression of NUDT21 in gastric cancer cells promoted tumor growth and cell proliferation in xenograft nude mice, and depletion of NUDT21 in gastric cancer cells restrained lung metastasis in vivo. Through high throughput RNA-sequencing, SGPP2 was identified to be positively regulated by NUDT21 and mediated the tumor promoting role of NUDT21 in gastric cancer cells. Therefore, NUDT21 played an oncogenic role in human gastric cancer cells. NUDT21 could be considered as a novel potential target for gastric cancer therapy.

Absolute quantification of 2-hydroxyglutarate on tissue by matrix-assisted laser desorption/ionization mass spectrometry imaging for rapid and precise identification of isocitrate dehydrogenase mutations in human glioma.

Isocitrate dehydrogenase (IDH) gene mutations are important predictive molecular markers to guide surgical strategy in brain cancer therapy. Herein, we presented a method using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) for absolute quantification of 2-hydroxyglutarate (2-HG) on tissues to identify IDH mutations and evaluate tumor residue. This analytical method was tested among 34 glioma patients and validated with gold standard clinical technologies. The cut-off value of 2-HG was set as 0.81 pmol/µg to identify IDH mutant (IDHmt) gliomas with 100% specificity and sensitivity. In addition, 2-HG levels and tumor cell density (TCD) showed positive correlation in IDHmt gliomas by this spatial method. This MALDI MSI-based absolute quantification method has great potentiality for incorporating into surgical workflow in the future.

A Novel Small Molecular Antibody, HER2-Nanobody, Inhibits Tumor Proliferation in HER2-Positive Breast Cancer Cells In Vitro and In Vivo.

Breast cancer is the most common malignant cancer in women worldwide, especially in developing countries. Herceptin is a monoclonal antibody with an antitumor effect in HER2-positive breast cancer. However, the large molecular weight of Herceptin limited its employment. In this study, we constructed and screened HER2-nanobody and verified its tumor-suppressive effect in HER2-positive breast cancer cells. HER2-nanobody was established, filtrated, purified, and was demonstrated to inhibit cell total number, viability, colony formation and mitosis, and promote cell apoptosis in HER2-positive breast cancer cells in vitro. Treated with HER2-nanobody, tumor growth was significantly inhibited by both intratumor injection and tail intravenous injection in vivo. The phosphorylation of ERK and AKT was restrained by HER2-nanobody in HER2-positive breast cancer cells. RAS-RAF-MAPK and PI3K-AKT-mTOR are two important pathways involved in HER2. It was credible for HER2-nanobody to play the tumor suppressive role by inhibiting the phosphorylation of ERK and AKT. Therefore, HER2-nanobody could be employed as a small molecular antibody to suppress HER2-positive breast cancer.

Copper and palladium co-catalyzed highly regio-selective 1,2-hydroarylation of terminal 1,3-dienes.

A practical copper and palladium co-catalyzed highly regio-selective hydroarylation of terminal 1,3-dienes has been developed. This chemistry afforded the terminal alkenyl group containing products, which are a kind of versatile precursor for organic synthesis, from 1,3-dienes by a practical one-step reaction. With good functional group tolerance, this protocol could be used to make a series of bio-active compounds using readily accessible starting materials. The mechanism of this reaction was explored by control experiments and kinetics studies.

Cu-Catalyzed highly regioselective 1,2-hydrocarboxylation of 1,3-dienes with CO2.

A practical copper-catalyzed highly regioselective 1,2-hydrocarboxylation of terminal 1,3-diene with carbon dioxide has been developed. Under mild reaction conditions, this chemistry afforded 2-benzyl-ß,γ-unsaturated acid derivatives as products, which are a kind of important unit for bio-active molecules and versatile precursors for organic synthesis, with good functional group tolerance. The key intermediate in this transformation is illustrated by control experiments.

Sterilization of Escherichia coli by Photothermal Synergy of WO3-x/C Nanosheet under Infrared Light Irradiation.

The application of photocatalytic sterilization technology for the sterilization of water has been broadly studied in recent years. However, developing photocatalysts with high disinfection efficiency remains an urgent challenge. Tungsten trioxide with coexisting oxygen vacancies and carbon coating (WO3-x/C) has been successfully synthesized toward the photothermal inactivation of Escherichia coli. Oxygen vacancies and carbon coating bring WO3-x/C strong absorption in the infrared region and enhance the carrier separation efficiency. As a result, a higher sterilization rate is obtained compared to WO3. WO3-x/C can completely inactivate E. coli under infrared light within 40 min through photothermal synergy process. During the process of inactivating bacteria over WO3-x/C, E. coli is killed by the destruction of their cell membrane to decrease the activity of enzymes and release the cell contents, which can be ascribed to the efficient generation of reactive oxygen species (O2•- and •OH) and thermal effect. This work demonstrates a novel approach for engineering efficient and energy-saving catalysts for water sterilization.

Effects of Photoperiod on Acetaminophen-Induced Hepatotoxicity in Mice.

PURPOSE: Acetaminophen (APAP) is a clinically popular analgesic and antipyretic drug, but excessive APAP can cause fatal hepatotoxicity. Many factors affect the degree of APAP-induced liver injury. This study aimed to investigate how circadian rhythm affects the development of APAP-induced hepatotoxicity and to clarify the roles of photoperiod and dietary rhythm on APAP-induced hepatotoxicity in mice. METHODS: APAP-induced hepatotoxicity models were established by intraperitoneal injection of APAP (400 mg/kg) to mice. The mice were then divided into three treatment groups: normal diet, reversed diet, and reversed photoperiod. RESULTS: More severe liver injury was observed at zeitgeber time 12 (ZT12) than at zeitgeber time 0 (ZT0) in all treatment groups, suggesting that photoperiod played a critical role in APAP-induced liver injury. We observed a change in the expression of the circadian gene Per2, which may be responsible for regulation of liver injury by photoperiod. Our results showed negligible change in Per2 expression with diet reversion, whereas Cry1, Cry2, and Dbp expressions were more highly affected by diet reversion than was Per2 expression. Downstream effects including liver enzyme expression, GSH level, and inflammation factors were also examined to identify the mechanism of liver injury. The results indicated that the circadian gene Per2 participated in APAP biometabolism by regulating the expression of Cyp2e1, which may explain the more severe hepatotoxicity at ZT12 than at ZT0. CONCLUSION: APAP-induced hepatotoxicity can be mediated by photoperiod through the circadian gene Per2, suggesting that medicines containing APAP should be administered not only with food but also according to the appropriate photoperiod.

Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury.

Acetaminophen (APAP)-induced liver injury is the main cause of acute liver failure. This study investigated the role of microsomal prostaglandin E synthase 2 (mPGES-2), discovered as one of the prostaglandin E2 (PGE2) synthases, in mediating APAP-induced liver injury. Using mPGES-2 wild-type (WT) and knockout (KO) mice, marked resistance to APAP-induced liver damage was found in mPGES-2 KO, as indicated by robust improvement of liver histology, changes in liver enzyme release, and marked decrease in APAP-cysteine adducts (APAP-CYS) and inflammatory markers. Moreover, the results confirmed that increase in liver PGE2 content in KO mice under basal conditions was not critical for the protection from APAP-induced liver injury. Importantly, mPGES-2 deletion inhibited the production of malondialdehyde (MDA), increasing glutathione (GSH) level. Enhanced GSH level may contribute to the inhibition of APAP toxicity in mPGES-2 KO mice. To further elucidate the role of mPGES-2 in the liver injury induced by APAP, adeno-associated viruses (AAV) were used to overexpress mPGES-2 in the liver. The results showed that mPGES-2 overexpression aggravates liver injury associated with an increase in inflammatory markers and chemokines after APAP treatment. Moreover, a lower level of GSH was detected in the mPGES-2 overexpression group compared to the control group. Collectively, our findings indicate that mPGES-2 plays a critical role in regulating APAP-induced liver injury, possibly by regulating GSH and APAP-CYS level, which may provide a potential therapeutic strategy for the prevention and treatment of APAP-induced liver injury.

Mangiferin ameliorates acetaminophen-induced hepatotoxicity through APAP-Cys and JNK modulation.

An overdose of the most popular analgesic, acetaminophen (APAP), is one of the leading causes of acute liver failure. It is well established that glutathione is exhausted by APAP-reactive intermediate N­acetyl­p­benzoquinone-imine (NAPQI). This leads to elevated phosphorylated-c-Jun N-terminal kinase (p-JNK), which further activates reactive oxygen species (ROS), initiates an inflammatory response, and finally leads to severe hepatic injury. The present study was conducted to investigate the protective role of mangiferin (MAN), a naturally occurring xanthone and anti-oxidant, on APAP-induced hepatotoxicity. C57BL/6 mice were pretreated with or without MAN at 1 h prior to APAP challenge. MAN was administered at a dose of 12.5-50 mg/kg along with APAP at a dose of 400 mg/kg. According to the ALT/AST ratio, 25 mg/kg MAN was the most potent dose for further experiments. Serum ALT and AST depletion were observed in APAP + MAN (25 mg/kg)-treated mice at 6, 12, and 24 h. Early (1 h after APAP treatment) GSH depletion by APAP overdose was restored by MAN treatment, which reduced APAP-Cys adduct formation and promoted protection. p-JNK downregulation and AMPK activation were observed in MAN-treated mice, which could mechanistically reduce oxidative stress and inflammation. MAN up-regulated liver GSH and SOD and reduced lipid peroxidation. HO-1 protein and p47 phox mRNA expression indicated that MAN regulated oxidative stress along with JNK deactivation. The expression of inflammatory response genes TNF-α, IL-6, MCP-1, CXCL-1, and CXCL-2 reached the basal levels after MAN treatment. mRNA, protein, and serum levels of IL-1ß were reduced, and NF-κB expression was similar to that of the MAN-treated APAP mice. MAN post-treatment (1 h after APAP treatment) also protected the mice from hepatotoxicity. In conclusion, MAN had a protective and therapeutic role in APAP-induced hepatotoxicity by improving the metabolism of acetaminophen and APAP-Cys adduct formation followed by JNK-mediated oxidative stress and inflammation.

Cp*CoIII-Catalyzed Synthesis of Pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-iums via Tandem C-H Activation and Subsequent Annulation from 1-(Pyridin-2-yl)-1H-indoles and Internal Alkynes.

A Cp*CoIII-catalyzed C2-selective C-H alkenylation/annulation cascade transformation of 1-(pyridin-2-yl)-1H-indoles with internal alkynes to afford pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-iums is presented. Moreover, 6,7-dihydro-4H-pyrido[2',1':2,3]pyrimido[1,6-a]indole, a new functionalized N-fused indole core heterocycle, could be constructed effectively via reduction of pyrido[2',1':2,3]pyrimido[1,6-a]indol-5-ium by NaBH4.